Clinical trial NCT02005471
Conditions: Chronic Lymphocytic Leukemia
Sponsor: Hoffmann-La Roche
Start date: 2014-03-17; Completion date: 2022-08-03
Enrollment: 389 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this open-label, multicenter, randomized, Phase III study is to evaluate the benefit of venetoclax in combination with rituximab compared with bendamustine in combination with rituximab in participants with relapsed or refractory CLL. Participants will be randomly assigned in 1:1 ratio to receive either venetoclax + rituximab (Arm A) or bendamustine + rituximab (Arm B).

Detailed description:

Arms: arm 1: Participants will receive bendamustine 70 milligrams per meter square (mg/m\^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 375 mg/m\^2 via IV infusion on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of Cycles 2-6. arm 2: Participants will be initially placed on a venetoclax 5 weeks ramp-up period, and will receive an initial dose of 20 milligrams (mg) via tablet orally once daily (QD). Then the dose will be incremented weekly up to a maximum dose of 400 mg. Participants will then continue receiving venetoclax 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards, as directed by the investigator, in combination with rituximab 375 mg/m\^2 via IV infusion on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of Cycles 2-6. arm 3: Participants entering the Crossover Substudy will have a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, Participants will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants will continue to take their daily dose of venetoclax during the rituximab cycles. Participants who have not progressed following the completion of the 6 cycles will continue to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Crossover Day 1 of the Substudy. arm 4: Participants entering the Re-Treatment Substudy will have a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, Participants will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants will continue to take their daily dose of venetoclax during the rituximab cycles. Participants who have not progressed following the completion of the 6 cycles will continue to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Re-Treatment Day 1 of the Substudy.
Interventions: intervention 1: Bendamustine intervention 2: Venetoclax intervention 3: Rituximab
Intervention descriptions: intervention 1: Bendamustine will be administered at a dose of 70 mg/m\^2 via IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles. intervention 2: Venetoclax will be administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during a 5-week ramp-up period. Venetoclax will be continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurs first.

R/C Substudy: venetoclax will be administered for 5-week dose ramp-up period to reach the target dose of 400 mg QD. Venetoclax will continue to be administered during the rituximab cycles until disease progression or for a maximum of 2 years from Cycle 1R/C Day 1 of the R/C Substudy. intervention 3: Rituximab will be administered at a dose of 375 mg/m\^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m\^2 on Day 1 of Cycles 2-6.

R/C Substudy: Following the venetoclax ramp-up period, rituximab will be administered for 6 cycles consisting of a single infusion on the first day of each 28-day cycle.

Protocol documents:
Prot_002.pdf: 
 
 
 
 
 
 
 
 
 
 Official Title:                A Multicenter, Phase III, Open-Label, Randomized Study in                 
                                        Relapsed/Refractory Patients With Chronic Lymphocytic  
                                        Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT- 
                                        199) Plus Rituximab Compared With Bendamustine Plus Rituximab 
 
 NCT Number:               NCT02005471 
 
 Document Date:          Protocol Version 9: 30 March 2018 


CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its 
control) and therefore is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional 
Review Board.  It is understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent from persons 
to whom the drug may be administered.
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
Protocol GO28667, Version 9
PROTOCOL
TITLE: 
A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED 
STUDY IN RELAPSED/REFRACTORY PATIENTS WITH 
CHRONIC LYMPHOCYTIC LEUKEMIA TO EVALUATE THE 
BENEFIT OF GDC-0199 (ABT-199) PLUS RITUXIMAB 
COMPARED WITH BENDAMUSTINE PLUS RITUXIMAB
PROTOCOL NUMBER:
GO28667
VERSION NUMBER:
9
EUDRACT NUMBER:
2013-002110-12
IND NUMBER:
110159
TEST PRODUCT:
Venetoclax (GDC-0199 [ABT-199]; (RO5537382)
MEDICAL MONITOR:
, Ph.D.
SPONSORS:
F. Hoffmann-La Roche Ltd and AbbVie Inc. will act as 
co-sponsors of this trial globally.*
DATE FINAL:
Version 1:  7 August 2013
DATES AMENDED:
Version 2:  26 November 2013
Version 3 (Korea):  28 February 2014
Version 4:  10 June 2014
Version 5:  16 October 2014
Version 6:  22 December 2015
Version 7:  21 November 2016
Version 8 (Korea): 3 June 2017
Version 9: See electronic date stamp below.
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant 
country are provided within the clinical trial agreement with the Investigator/Institution and the 
Clinical Trial Application with the Competent Authority.
PROTOCOL AMENDMENT APPROVAL
 
30-Mar-2018 04:28:50
(
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
2/Protocol GO28667, Version 9
PROTOCOL AMENDMENT, VERSION 9:
RATIONALE
Protocol GO28667, Version 9, merges the global and Version 8 (Korea) protocols.
Protocol GO28667, Version 9, encompasses the cumulative changes to the protocol that 
were made to Version 8 (Korea) along with changes specific to Version 9.
Changes specific to Version 9 include the extension of study duration and addition of the 
optional Re-Treatment/Crossover (R/C) Substudy.  These changes, along with a 
rationale for each change, are summarized below:

An exploratory objective has been added to evaluate best overall response rate 
(ORR) to next anti-chronic lymphocytic leukemia (CLL) treatment, as assessed by 
the investigator (Section 2.7).

An optional R/C Substudy has been added (Sections 2.8, 3.1, 3.1.3, 3.2, 3.3.7, 
4.3.2.4, 4.5.2.6, 4.6.1.1, 5.3.1, 6.12, 6.12.1, 6.12.2, and Appendix 14). At the 
interim analysis (now primary analysis), the study demonstrated that venetoclax and 
rituximab (venetoclaxR) is superior to bendamustine and rituximab (BR) in 
patients with relapsed/refractory CLL.  The primary endpoint of investigator 
assessed progression-free survival (PFS) showed significant improvement with 
venetoclaxR with a hazard ratio of 0.17 (95% CI: 0.11, 0.25; p0.0001). Key 
secondary endpoints, including overall survival (OS), ORR, and complete response 
rate, also showed consistent clinically meaningful improvements (Seymour et al. 
2018). Therefore, the Sponsor would now like to include an optional R/C Substudy 
to allow:
–
Eligible patients from Arm A (venetoclaxR) who have clinically progressed 
after finishing treatment, have not received new anti-CLL therapy, and are in 
need of treatment have the option to receive treatment with venetoclaxR 
again (re-treatment). This will allow the Sponsor to study the outcomes of 
patients who are re-treated with venetoclaxR following prior venetoclaxR 
treatment.
–
Eligible patients from Arm B (BR) who have clinically progressed after finishing 
treatment, have not received new anti-CLL therapy, and are in need of 
treatment have the option to cross over and receive venetoclaxR given the 
results of the primary analysis demonstrating superior outcome for
venetoclaxR treatment.

The study duration is extended for an additional 45 months to allow for the collection 
of long-term data including safety, PFS, and OS.  At the primary read out, PFS and 
OS outcomes for patients in the venetoclaxR arm exceed original protocol 
expectations, thus requiring longer follow-up to enable estimation of a robust 
efficacy and median PFS (Sections 3.1 and 4.5.2.4, and Appendix 1).

The reporting of secondary malignancies has been extended after the reporting 
period to capture all events regardless of causality in order to satisfy health authority 
requirements (Sections 3.1, 5.3.1, and 6.12.2).


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
3/Protocol GO28667, Version 9

The rationale for biomarker assessments has been updated to include 
next-generation sequencing analysis (Section 3.3.5). These analyses will provide a 
comprehensive characterization of genomics to enable the understanding of disease 
pathobiology.

Information regarding continued access to venetoclax has been updated to align 
with Roche Global Policy (Section 4.3.4).

Sample collection for peripheral blood minimal residual disease (MRD) samples has 
been extended until clinical progression because patients have demonstrated 
persistent MRD negativity and there is a need to better understand the MRD kinetics 
over longer period of time (Appendix 1).
Additional changes to the protocol include:

To further strengthen safety monitoring for special situations that may or may not 
result in an adverse event, instructions have been added to Sections 4.3.2.1, 4.3.2.2, 
4.3.2.3., 5.4, and 5.4.4 regarding the reporting of medication errors, accidental 
overdose, drug abuse, and drug misuse (Section 5.3.5.11 "Overdoses" has been 
deleted and subsequent sections re-numbered appropriately; new language has 
been added in Section 5.4; and Section 5.4.4 has been included).

The reporting of the term “sudden death” has been updated to also require the 
presumed cause of death (Section 5.3.5.8).

Event reporting for hospitalization has been clarified (Section 5.3.5.11).

Medical responsible has changed and contact information has been updated 
(Sections 5.4.1, 5.4.2, 5.4.3.1, and 5.6).

The process for reviewing and handling protocol deviations has been updated per 
internal standard operating procedures (Section 9.2).
Changes to Version 8 (Korea), along with a rationale for each change, are summarized 
below:

The description of the fixed sequence testing of the secondary efficacy endpoints in 
the statistical section of the protocol was streamlined and the details of the testing of 
secondary endpoints will be set out in the statistical analysis plan, in accordance 
with the international guideline on Statistical Principles for Clinical Trials (ICH E9).  
This amendment is implemented to allow for a change in the clinical prioritization of
the secondary efficacy endpoints to mirror the evolving relapsed/refractory CLL 
therapeutic and scientific landscape.

Minor changes have been made to improve clarity and consistency of the secondary 
efficacy endpoints. 

The sample list of prohibited and cautionary medications in Appendix 9 has been 
updated, incorporating the Food and Drug Administration’s updated guidelines.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This version of the protocol represents 
cumulative changes from all previous amendments to the protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 38
1.1
Background on Chronic Lymphocytic Leukemia.................... 38
1.2
Background on Venetoclax (GDC-0199) ............................... 38
1.2.1
Bcl-2 Protein Family .............................................................. 38
1.2.2
Venetoclax............................................................................. 39
1.2.2.1
Venetoclax Nonclinical Activity and 
Pharmacokinetic Profile......................................................... 39
1.2.2.2
Venetoclax Nonclinical Toxicology ........................................ 40
1.2.2.3
Venetoclax Clinical Experience ............................................. 42
1.2.2.4
Clinical Pharmacokinetics and 
Pharmacodynamics ............................................................... 50
1.3
Study Rationale and Benefit-Risk Assessment...................... 52
2.
OBJECTIVES.............................................................................................. 54
2.1
Efficacy Objectives ................................................................ 54
2.2
Safety Objective .................................................................... 55
2.3
Pharmacodynamic Objective................................................. 55
2.4
Pharmacokinetic Objective .................................................... 55
2.5
Patient-Reported Outcome Objectives .................................. 55
2.6
Health Economic Objective.................................................... 55
2.7
Exploratory Objectives........................................................... 55
2.8
Re-Treatment/Crossover Substudy Objectives...................... 56
3.
STUDY DESIGN......................................................................................... 56
3.1
Description of Study .............................................................. 56
3.1.1
Independent Review Committee............................................ 59
3.1.2
Independent Data Monitoring Committee .............................. 59
3.1.3
Re-Treatment/Crossover Substudy (Optional at 
Investigator's Discretion) ....................................................... 60
3.2
End of Study.......................................................................... 64
3.3
Rationale for Study Design.................................................... 64


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3.3.1
Rationale for Combination Therapy 
(Experimental Group) ............................................................ 64
3.3.1.1
Rationale for Venetoclax Dosage .......................................... 64
3.3.1.2
Rationale for Rituximab Dosage............................................ 65
3.3.1.3
Rationale for Duration of Therapy.......................................... 65
3.3.2
Rationale for Control Group................................................... 65
3.3.2.1
Rationale for BR Dosage....................................................... 66
3.3.3
Rationale for Patient Population ............................................ 66
3.3.4
Rationale for Including Patients with 17p Deletion................. 68
3.3.5
Rationale for Biomarker Assessments................................... 68
3.3.6
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 69
3.3.7
Rationale for Re-Treatment/Crossover Substudy.................. 70
3.4
Outcome Measures ............................................................... 70
3.4.1
Efficacy Outcome Measures.................................................. 70
3.4.1.1
Primary Efficacy Outcome Measure ...................................... 70
3.4.1.2
Secondary Efficacy Outcome Measures................................ 70
3.4.2
Safety Outcome Measures .................................................... 71
3.4.3
Pharmacodynamic Outcome Measure................................... 71
3.4.4
Pharmacokinetic Outcome Measures.................................... 71
3.4.5
Patient-Reported Outcome Measures ................................... 71
3.4.6
Health Economic Outcome Measure ..................................... 71
3.4.7
Exploratory Outcome Measures ............................................ 72
4.
MATERIALS AND METHODS .................................................................... 72
4.1
Patients.................................................................................. 72
4.1.1
Inclusion Criteria.................................................................... 72
4.1.2
Exclusion Criteria................................................................... 74
4.2
Method of Treatment Assignment and Blinding..................... 76
4.3
Study Treatment.................................................................... 76
4.3.1
Formulation, Packaging, and Handling.................................. 76
4.3.1.1
Venetoclax............................................................................. 76
4.3.1.2
Rituximab............................................................................... 77
4.3.1.3
Bendamustine........................................................................ 77


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4.3.2
Dosage, Administration, and Compliance.............................. 78
4.3.2.1
Venetoclax............................................................................. 78
4.3.2.2
Rituximab............................................................................... 80
4.3.2.3
Bendamustine........................................................................ 81
4.3.2.4
Re-Treatment/Crossover Substudy (Optional at 
the Investigator’s Discretion) ................................................. 82
4.3.3
Investigational Medicinal Product Accountability ................... 82
4.3.4
Continued Access to Venetoclax........................................... 83
4.4
Concomitant Therapy and Food ............................................ 84
4.4.1
Permitted Therapy................................................................. 84
4.4.1.1
Premedication before Rituximab............................................ 84
4.4.1.2
Prophylaxis and Management of Tumor Lysis 
Syndrome .............................................................................. 85
4.4.1.3
Prophylaxis for Infections....................................................... 96
4.4.1.4
Prophylaxis of Hepatitis B Reactivation ................................. 96
4.4.2
Prohibited and Cautionary Therapy....................................... 96
4.4.3
Prohibited Food ..................................................................... 97
4.5
Study Assessments ............................................................... 98
4.5.1
Description of Study Assessments ........................................ 98
4.5.1.1
Medical History and Demographic Data ................................ 98
4.5.1.2
Physical Examinations........................................................... 98
4.5.1.3
Vital Signs and ECOG Performance Status........................... 98
4.5.1.4
Electrocardiogram ................................................................. 99
4.5.1.5
Assessment of Left Ventricular Ejection Fraction .................. 99
4.5.1.6
Tumor and Response Evaluations......................................... 99
4.5.1.7
Laboratory Assessments ..................................................... 101
4.5.1.8
Patient-Reported Outcomes ................................................ 102
4.5.1.9
Samples for Roche Clinical Repository................................ 104
4.5.2
Timing of Study Assessments ............................................. 106
4.5.2.1
Screening and Pretreatment Assessments.......................... 106
4.5.2.2
Assessments during Treatment........................................... 107
4.5.2.3
Assessments at Early Treatment Termination 
Visit...................................................................................... 107
4.5.2.4
Follow-Up Assessments ...................................................... 107


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4.5.2.5
Assessments at Unplanned Visits ....................................... 108
4.5.2.6
Re-Treatment/Crossover Substudy Assessments............... 108
4.6
Patient, Study, and Site Discontinuation.............................. 109
4.6.1
Patient Discontinuation........................................................ 109
4.6.1.1
Discontinuation from Study Drug/Treatment........................ 109
4.6.1.2
Withdrawal from Study......................................................... 110
4.6.2
Study and Site Discontinuation............................................ 110
5.
ASSESSMENT OF SAFETY..................................................................... 111
5.1
Safety Plan .......................................................................... 111
5.1.1
Risks Associated with Venetoclax ....................................... 111
5.1.1.1
Tumor Lysis Syndrome........................................................ 111
5.1.1.2
Cytopenia ............................................................................ 111
5.1.1.3
Infectious Complications...................................................... 112
5.1.1.4
Effects on Cardiac Function................................................. 112
5.1.1.5
Effects on Fertility ................................................................ 112
5.1.1.6
Drug Interactions ................................................................. 112
5.1.2
Risks Associated with Rituximab Therapy........................... 112
5.1.2.1
Infusion-Related Reactions.................................................. 112
5.1.2.2
Tumor Lysis Syndrome........................................................ 113
5.1.2.3
Hepatitis B Reactivation....................................................... 113
5.1.2.4
Progressive Multifocal Leukoencephalopathy...................... 114
5.1.2.5
Cardiac Toxicity ................................................................... 114
5.1.2.6
Infection............................................................................... 114
5.1.2.7
Severe Mucocutaneous Reactions...................................... 115
5.1.2.8
Bowel Obstruction and Perforation...................................... 115
5.1.3
Risks Associated with Bendamustine .................................. 115
5.1.3.1
Myelosuppression................................................................ 115
5.1.3.2
Infection............................................................................... 115
5.1.3.3
Infusion Reactions............................................................... 115
5.1.3.4
Tumor Lysis Syndrome........................................................ 115
5.1.3.5
Cutaneous Reactions .......................................................... 116
5.1.3.6
Long-Term Stem-Cell Toxicity ............................................. 116
5.1.3.7
Extravasation of Bendamustine........................................... 116


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5.1.3.8
Transfusion-Associated Graft versus Host 
Disease................................................................................ 116
5.1.3.9
Drug Interactions ................................................................. 116
5.1.4
Risks Associated with Venetoclax and Rituximab 
Combination Therapy .......................................................... 116
5.1.5
Management of Specific Adverse Events ............................ 117
5.2
Safety Parameters and Definitions ...................................... 123
5.2.1
Adverse Events ................................................................... 124
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 124
5.2.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ............................ 125
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 125
5.3.1
Adverse Event Reporting Period ......................................... 125
5.3.2
Eliciting Adverse Event Information..................................... 126
5.3.3
Assessment of Severity of Adverse Events ......................... 126
5.3.4
Assessment of Causality of Adverse Events ....................... 127
5.3.5
Procedures for Recording Adverse Events.......................... 128
5.3.5.1
Diagnosis versus Signs and Symptoms............................... 128
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 128
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 129
5.3.5.4
Abnormal Laboratory Values ............................................... 129
5.3.5.5
Abnormal Vital Sign Values ................................................. 130
5.3.5.6
Abnormal Liver Function Tests............................................ 130
5.3.5.7
Deaths ................................................................................. 131
5.3.5.8
Preexisting Medical Conditions............................................ 131
5.3.5.9
Lack of Efficacy or Worsening of CLL.................................. 132
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 132
5.3.5.11
Patient-Reported Outcome Data ......................................... 132
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 133
5.4.1
Emergency Medical Contacts.............................................. 133


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5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest.................................................................... 134
5.4.3
Reporting Requirements for Pregnancies............................ 134
5.4.3.1
Pregnancies in Female Patients.......................................... 134
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 135
5.4.3.3
Abortions ............................................................................. 135
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 135
5.4.4
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ................... 136
5.5
Follow-Up of Patients after Adverse Events ........................ 138
5.5.1
Investigator Follow-Up......................................................... 138
5.5.2
Sponsor Follow-Up .............................................................. 138
5.6
Post-Study Adverse Events................................................. 138
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 139
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 139
6.1
Determination of Sample Size ............................................. 140
6.2
Summaries of Conduct of Study.......................................... 140
6.3
Summaries of Treatment Group Comparability ................... 140
6.4
Efficacy Analyses ................................................................ 140
6.4.1
Primary Efficacy Endpoint.................................................... 141
6.4.2
Secondary Efficacy Endpoints............................................. 142
6.5
Safety Analyses................................................................... 143
6.6
Pharmacodynamic Analyses ............................................... 144
6.7
Pharmacokinetic Analyses................................................... 144
6.8
Patient-Reported Outcome Analyses .................................. 144
6.9
Health Economic Analysis ................................................... 145
6.10
Exploratory Analyses........................................................... 145
6.11
Interim Analyses .................................................................. 145
6.12
Re-Treatment/Crossover Substudy Analysis....................... 146
6.12.1
Efficacy Analyses for Re-Treatment/Crossover 
Substudy.............................................................................. 146


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6.12.2
Safety Analyses for Re-Treatment/Crossover 
Substudy.............................................................................. 147
7.
DATA COLLECTION AND MANAGEMENT ............................................. 147
7.1
Data Quality Assurance....................................................... 147
7.2
Electronic Case Report Forms............................................. 148
7.3
Electronic Patient-Reported Outcome Data......................... 148
7.4
Source Data Documentation................................................ 148
7.5
Use of Computerized Systems ............................................ 149
7.6
Retention of Records........................................................... 149
8.
ETHICAL CONSIDERATIONS.................................................................. 149
8.1
Compliance with Laws and Regulations .............................. 149
8.2
Informed Consent................................................................ 150
8.3
Institutional Review Board or Ethics Committee.................. 151
8.4
Confidentiality...................................................................... 151
8.5
Financial Disclosure ............................................................ 152
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 152
9.1
Study Documentation .......................................................... 152
9.2
Protocol Deviations.............................................................. 152
9.3
Site Inspections ................................................................... 152
9.4
Administrative Structure....................................................... 153
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 153
9.6
Protocol Amendments ......................................................... 154
10. REFERENCES ......................................................................................... 155
LIST OF TABLES
Table 1
Administration of First and Subsequent Infusions of 
Rituximab.................................................................................... 81
Table 2
Summary of TLS Prophylaxis and Monitoring Measures ............ 93
Table 3
Dose Modifications for Hematologic Toxicity during the 
Combination Therapy Period (Venetoclax Rituximab) 
and/or Venetoclax Monotherapy ............................................... 118


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Table 4
Dose Modifications for Non-Hematologic Toxicity during the 
Combination Therapy Period (Venetoclax Rituximab) 
and/or Venetoclax Monotherapy ............................................... 120
Table 5
Venetoclax Dose Reduction...................................................... 121
Table 6
Bendamustine Dose Reduction................................................. 122
Table 7
Dose Modification Guidelines for Bendamustine....................... 123
Table 8
Adverse Event Severity Grading Scale ..................................... 127
LIST OF FIGURES
Figure 1
Study M12-175: Preliminary Mean (SD) Venetoclax 
Plasma ConcentrationTime Profiles Following Oral 
Administration of Venetoclax (GDC-0199 [ABT-199]) in 
Patients with CLL/SLL (Log-Linear Scale) .................................. 51
Figure 2
Study Schema............................................................................. 57
Figure 3
Re-Treatment/Crossover Substudy Schema............................... 63
Figure 4
Venetoclax Dosing Scheme during the Ramp-Up Period ........... 79
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 161
Appendix 2
Schedule of Pharmacokinetic Assessments ............................. 177
Appendix 3
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-
C30).......................................................................................... 178
Appendix 4
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire (EORTC QLQ-CLL16) .... 181
Appendix 5
M.D. Anderson Symptom Inventory (MDASI) Questionnaire .... 182
Appendix 6
EQ-5D (U.S. Version) ............................................................... 184
Appendix 7
ECOG Performance Status Scale............................................. 186
Appendix 8
Treatment Options for CLL (Adapted from NCCN Version 
4.2014 and 2011 ESMO Clinical Practice Guidelines).............. 187
Appendix 9
Sample List of Prohibited and Cautionary Medications............. 190
Appendix 10
Definitions of Response and Progression for Patients with 
Chronic Lymphocytic Leukemia ................................................ 193
Appendix 11
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome............. 201
Appendix 12
National Cancer InstituteSponsored Working Group 
Hematologic Adverse Event Grading Scale for Chronic 
Lymphocytic Leukemia for Patients with Baseline Abnormal 
Hematologic Laboratories ......................................................... 205
Appendix 13
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL ...................................... 206


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Appendix 14
Re-Treatment/Crossover Substudy Schedule of 
Assessments............................................................................. 208


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
13/Protocol GO28667, Version 9
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A MULTICENTER, PHASE III, OPEN-LABEL, 
RANDOMIZED STUDY IN 
RELAPSED/REFRACTORY PATIENTS WITH 
CHRONIC LYMPHOCYTIC LEUKEMIA TO 
EVALUATE THE BENEFIT OF GDC-0199 (ABT-199) 
PLUS RITUXIMAB COMPARED WITH 
BENDAMUSTINE PLUS RITUXIMAB
PROTOCOL NUMBER:
GO28667
VERSION NUMBER:
9
EUDRACT NUMBER:
2013-002110-12
IND NUMBER:
110159
TEST PRODUCT:
Venetoclax (GDC-0199 [ABT-199]; RO5537382)
MEDICAL MONITOR:
, Ph.D.
SPONSORS:
F. Hoffmann-La Roche Ltd and AbbVie Inc. will act as 
co-sponsors of this trial globally.*
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant 
country are provided within the clinical trial agreement with the Investigator/Institution and the 
Clinical Trial Application with the Competent Authority.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please return the signed original of this form to your local study monitor.  Please retain a 
copy for your study files.


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
14/Protocol GO28667, Version 9
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED 
STUDY IN RELAPSED/REFRACTORY PATIENTS WITH CHRONIC 
LYMPHOCYTIC LEUKEMIA TO EVALUATE THE BENEFIT OF 
GDC-0199 (ABT-199) PLUS RITUXIMAB COMPARED WITH 
BENDAMUSTINE PLUS RITUXIMAB
PROTOCOL NUMBER:
GO28667
VERSION NUMBER:
9
EUDRACT NUMBER:
2013-002110-12
IND NUMBER:
110159
TEST PRODUCT:
Venetoclax (GDC-0199 [ABT-199]; RO5537382)
PHASE:
III
INDICATION:
Chronic Lymphocytic Leukemia
SPONSORS:
F. Hoffmann-La Roche Ltd and AbbVie Inc. will act as co-sponsors of 
this trial globally.*
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant 
country are provided within the clinical trial agreement with the Investigator/Institution and the 
Clinical Trial Application with the Competent Authority.
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of venetoclax and rituximab (venetoclax R) compared with 
bendamustine and rituximab (BR) in patients with relapsed or refractory chronic lymphocytic 
leukemia (CLL) as measured by investigator-assessed progression-free survival (PFS)
The secondary efficacy objectives for this study are as follows:

To analyze Independent Review Committee (IRC)-assessed PFS in the subset of CLL 
patients with 17p deletion identified by fluorescence in situ hybridization (FISH) testing 
performed at a central laboratory

To evaluate PFS as assessed by an IRC

To analyze investigator-assessed PFS in the subset of CLL patients with 17p deletion 
identified by FISH testing performed at a central laboratory

To evaluate rate of best overall response (OR; defined as complete response [CR], 
complete response with incomplete marrow  recovery [CRi], nodular partial response [nPR], 
and partial response [PR]), as assessed by the investigator

To evaluate rates of OR rate, CR, CRi, nPR, and PR at end of combination treatment 
response visit, as assessed by the investigator

To evaluate OR, CR, CRi, nPR, and PR rates at end of combination treatment response 
visit, as assessed by the IRC 


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
To evaluate overall survival (OS)

To evaluate event-free survival (EFS)

To evaluate duration of response (DOR) for patients with a best overall response of CR, 
CRi, nPR, or PR

To evaluate time to next anti-CLL treatment (TTNT)

To evaluate the proportion of patients with minimal residual disease (MRD) negativity at the 
disease response assessment timepoints
Safety Objective
The safety objective for this study is as follows:

To evaluate the safety of venetoclax and rituximab compared with BR in patients with 
relapsed or refractory CLL, focusing on serious adverse events, National Cancer Institute 
Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0) 
Grade ≥3 adverse events, and Grade ≥3 laboratory toxicities
Pharmacodynamic Objective
The pharmacodynamic objective for this study is as follows:

To assess changes in lymphocyte subset counts during the study (e.g., T and B cells)
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the pharmacokinetics of venetoclax in patients with relapsed or 
refractory CLL
Patient-Reported Outcome Objectives
The patient-reported outcome (PRO) objectives for this study are as follows:

To compare treatment-related symptoms following treatment with venetoclax and rituximab 
compared with BR in patients with relapsed or refractory CLL, as measured by 
M. D. Anderson Symptom Inventory (MDASI) and European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and 
associated CLL module (QLQ-CLL16)

To evaluate changes from baseline CLL symptoms scores using MDASI and EORTC 
QLQ-C30 and QLQ-CLL16 questionnaires

To evaluate time to disease-related symptom progression using EORTC QLQ-CLL16 
health-related quality of life (HRQoL) using global health status/quality of life (QOL) and 
other functional subscales of QLQ-C30

To assess interference of treatment and disease-related symptoms on QOL using the 
MDASI questionnaire
Health Economic Objective
The health economic objective for this study is as follows:

To compare the health economic effects of venetoclax in combination with rituximab versus 
BR in patients with relapsed or refractory CLL.  The EuroQol 5 Dimension (EQ-5D) 
questionnaire will be used to support health economic/pharmacoeconomic analyses and will 
be analyzed post hoc.
Exploratory Objectives
The exploratory objectives for this study are as follows:

To evaluate the relationship between efficacy outcome and potential biomarkers, including 
Bcl-2 expression, for patients treated with venetoclax and rituximab compared with BR

To evaluate potential biomarkers that are prognostic and/or predictive of response and 
resistance to treatment with venetoclax and rituximab or with BR


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
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
To evaluate rate of best OR (defined as CR, CRi, nPR, and PR) of next anti-CLL 
treatment, as assessed by the investigator
Patients receiving venetoclax R as the next anti-CLL treatment in the 
Re-Treatment/Crossover (R/C) Substudy will be analyzed separately.
Re-Treatment/Crossover Substudy Objectives
The efficacy objectives for the R/C Substudy are as follows:

OR, CR, CRi, nPR, and PR rates at the End of Combination Treatment Response in the 
Re-Treatment/Crossover Study (EOCTR-R/C) Visit as assessed by the investigator

OS, defined as the time from first treatment exposure in the R/C Substudy to death from 
any cause

MRD response rate as measured at a central laboratory on peripheral blood samples and 
bone marrow aspirate samples at each sampling timepoint as well as Best MRD negativity 
in the R/C Substudy
Study Design
Description of Study
This is an open-label, international, multicenter, randomized, phase III study to investigate the 
efficacy and safety of venetoclax in combination with rituximab (venetoclaxR) compared with 
bendamustine in combination with rituximab (BR) in patients with relapsed or refractory CLL.
Approximately 370 patients will be recruited from approximately 150 centers in up to 
29 countries and randomly assigned in 1:1 ratio to receive either venetoclaxR (Arm A) or BR 
(Arm B).  Randomization will be stratified according to the following factors:

17p deletion:  yes or no

Risk status:  high risk or low risk
High risk:  defined as harboring 17p deletion or no response to front-line 
chemotherapy-containing regimen or relapsed within 12 months after chemotherapy or 
within 24 months after chemoimmunotherapy
Low risk:  defined as relapse more than 12 months after chemotherapy or 24 months 
after chemotherapy or chemoimmunotherapy

Geographic region:  United States/Canada, Australia/New Zealand, Western Europe, 
Central and Eastern Europe, Asia, or Latin America
Patients randomized to Arm A (venetoclax R) will have a 5-week venetoclax dose ramp-up 
period to reach the target dose of 400 mg daily.  Following the venetoclax ramp-up period, 
patients will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 
28-day cycle.  Patients will continue to take their daily dose of venetoclax during the rituximab 
cycles.  Patients who have not progressed following the completion of the 6 cycles will continue 
to receive venetoclax until disease progression or for a maximum of 2 years from Cycle 1 
Day 1.
Patients randomized to Arm B (BR) will receive 6 cycles of BR consisting of a single infusion of 
rituximab on Day 1 and bendamustine infusions on Days 1 and 2 of each 28-day cycle.
All patients will have baseline tumor assessment and will be assessed for response to treatment 
by the investigator using standard clinical and laboratory examinations and computed 
tomography (CT) scans according to international workshop on Chronic Lymphocytic Leukemia 
(iwCLL) guidelines at screening and at the following timepoints (selected to mirror those used in 
current phase III CLL protocols [CLL10, CLL11]):

Clinical response assessment only on Day 1 of every cycle of combination therapy

Full response assessment, including CT scans, at interim response assessment (within 
14 days of Cycle 4 Day 1)


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
Clinical response assessment only at completion of combination therapy (4 weeks 7 days 
after Day 1 of the last cycle of rituximab venetoclax [Arm A] or BR [Arm B] or Day 1 of the 
last treatment cycle in case of early termination)

Full response assessments, including CT scans, at 812 weeks after combination therapy 
(defined as 812 weeks after Day 1 of Cycle 6 or 812 weeks after Day 1 of the last cycle 
for early termination).
Following 6 cycles of combination therapy, patients in both arms will be followed clinically every 
3 months through Year 3 from initiation of combination therapy (Cycle 1 Day 1).  Patients will 
then be followed every 6 months until PD, study withdrawal, or end of study, whichever 
occurs first.  At each follow-up visit, patients will be assessed for response/progression by 
clinical assessment only.  After PD, patients will enter survival follow-up and be followed for 
OS.  Information on new anti-CLL therapy will also be collected at survival follow-up.  This 
survival follow-up may be conducted by telephone.  If eligible, patients randomized to either 
Arm A or Arm B who have PD, are in need of therapy (per iwCLL), and have not received 
new anti-CLL therapy have the option to enter the R/C Substudy with venetoclax R.
At any time during the study when clinical or laboratory findings suggest that the response may 
have improved from stable disease (SD) to PR, or from PR to CR, imaging should be performed 
to confirm the response.  Imaging is not routinely required to determine progressive disease 
(PD), as objective evidence of PD is most often documented by measurement of elevated 
peripheral CLL cells.  However, when PD cannot be documented by increasing peripheral blood 
counts, imaging is required to document PD detected by physical examination or suspected 
based on symptoms.  A bone marrow biopsy may also be conducted at any time during the 
study to confirm a CR.
A bone marrow aspirate should be obtained for MRD assessment in all responders (CR PR) at 
the End of Combination Treatment Response Visit.  In addition, MRD samples in the peripheral 
blood are collected at baseline, within 14 days of C4D1 (interim assessment), completion of 
combination therapy/early treatment termination visit (if applicable), End of Combination 
Treatment Response Visit, and at the timepoints specified in Appendix 1 during the follow-up or 
at any visit during the follow-up where a patient has a response (PR or CR status).  Samples 
will be measured at a central laboratory.
After disease progression during the follow-up period, patients will be followed for OS and new 
anti-CLL therapy every 24 weeks until the end of study.  This follow-up may be conducted by 
telephone.
Patients who receive a new anti-CLL therapy any time during follow-up in the absence of PD will 
be followed on the same schedule of assessment (see protocol) for PD and then for OS.
Patients who discontinue all components of study therapy either prior to completion of planned 
therapy or prior to disease progression (e.g., for toxicity) will continue to be followed for MRD 
levels, PD, and OS (regardless of whether they subsequently receive new anti-CLL therapy).
An independent review of the responses of all patients will also be conducted to confirm the 
primary PFS endpoint, including blinded review of clinical and laboratory findings as well as 
blinded radiology review of imaging assessments.
Re-Treatment /Crossover Substudy (Optional at Investigator’s Discretion)
If eligible, patients in either Arm A or Arm B who have progressed clinically, are in need of 
therapy (per iwCLL) and have not received new anti-CLL therapy have the option to enter the 
R/C Substudy:

Patients randomized to Arm A (venetoclax R) may receive re-treatment with 
venetoclax R.

Patients randomized to Arm B (BR) may cross over from the BR arm to receive 
venetoclax R treatment.
Patients entering the R/C Substudy will have a 5-week venetoclax dose ramp-up period to 
reach the target dose of 400 mg QD.  Following the venetoclax ramp-up period, patients will 
receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day 
cycle.  Patients will continue to take their daily dose of venetoclax during the rituximab 


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cycles.  Patients who have not progressed following the completion of the 6 cycles will 
continue to receive venetoclax monotherapy until disease progression or for a maximum of 
2 years from Cycle 1R/C Day 1 of the R/C Substudy.
An EOCTR-R/C Visit will be scheduled 12 weeks after Cycle 6R/C Day 1 or at disease 
progression, whichever occurs first.  After the EOCTR-R/C Visit, patients who have not 
progressed will be followed clinically every 24 weeks (Follow-Up R/C Visits).  Follow-Up R/C 
Visits will continue until completion of venetoclax treatment at 2 years from Cycle 1R/C 
Day1 (Completion of Venetoclax Treatment Response in the Re-treatment/Crossover 
Substudy[COVTR-R/C] Visit) or PD, whichever occurs first.  If patients discontinue early 
due to toxicity or at disease progression, EOCTR-R/C Visit will be scheduled immediately.  
After the COVTR-R/C Visit or disease progression, patients should be followed for OS, PD (if 
not progressed already), and new anti-CLL therapy.  These Survival Follow Up Visits will be 
captured every 24 weeks until the end of study and may be conducted by telephone.
A full tumor assessment is required at Screening-R/C and EOCTR-R/C Visits by the 
investigator using standard clinical and laboratory examinations, bone marrow evaluation 
and CT scans according to iwCLL guidelines.  The EOCTR-R/C Visit is to be scheduled 
12 weeks (7 days) after Cycle 6R/C Day 1. Following the EOCTR-R/C Visit, patients will 
be followed clinically every 24 weeks in Follow-Up R/C Visits until the COVTR-R/C Visit.  
Patients will also have a clinical response assessment at the COVTR-R/C Visit to be 
scheduled at the completion of venetoclax monotherapy (i.e., 2 years from Cycle 1R/C Day 1).  
If patients discontinue prior to completion of venetoclax treatment, COVTR-R/C Visit will be 
scheduled immediately.  Additional response assessments may be performed according to 
institutional guidelines and recorded in eCRFs.  Additional CT scan evaluations should be 
performed during Follow-Up R/C or COVTR-R/C Visits to confirm a suspected change in 
response status, that is, SD to PR or PR to CR/CRi.  If a patient’s response improves to a CR 
or CRi during Follow-Up R/C or COVTR-R/C Visits, a bone morrow biopsy must be 
performed to confirm the CR.
A bone marrow aspirate should be obtained for MRD assessment in the bone marrow in all 
patients at Screening-R/C and in all responders (CR or PR) at the EOCTR-R/C Visit.  In 
addition, MRD samples in peripheral blood will be collected for all patients at Screening-R/C, 
EOCTR-R/C, Follow-Up R/C, and COVTR-R/C Visits.  Samples will be analyzed at a central 
laboratory.
Investigators should report deaths, serious adverse events, adverse events Grade 3, adverse 
events of special interest throughout the treatment duration and 28 days after the last dose of 
venetoclax and 90 days after the last dose of rituximab, second primary malignancies, and 
adverse events leading to treatment discontinuation on the Adverse Event eCRF.  Adverse 
events will be graded using NCI CTCAE, v4.0.
Number of Patients
Approximately 370 patients will be recruited from approximately 150 centers in up to 
29 countries and randomly assigned in 1:1 ratio to receive either venetoclaxR (Arm A) or BR 
(Arm B).
Target Population
The target population for this study is adult patients with relapsed or refractory CLL requiring 
treatment.
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed informed consent

Age 18 years


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
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
Diagnosis of CLL that meets published diagnostic criteria.  Patients must have peripheral 
blood B-lymphocyte counts which clonally express CD5, CD19/20, and CD23 and are either 
kappa or lambda light-chain-restricted.  Pro-lymphocytes may comprise no more than 55% 
of total circulating lymphocytes.  At initial diagnosis of CLL (i.e., prior to front-line treatment), 
the peripheral lymphocyte count must have been 5000/mm3.  Patients must meet the 
following criteria for relapsed or refractory CLL (per the iwCLL guidelines:
Relapsed disease:  a patient who previously achieved a CR or PR, but after a period 
of 6 months or more demonstrates evidence of progression
Refractory disease:  treatment failure or disease progression within 6 months of the 
last anti-leukemia therapy

Previously treated with at least one but not more than three lines of therapy (a line of 
therapy is defined as completing at least two cycles of treatment for a given line of therapy), 
including at least one prior standard chemotherapy-containing regimen according to current 
guidelines

For patients with 17p deletion, previously treated with at least one but not more than three 
lines of therapy, including at least one prior standard chemotherapy-containing regimen 
according to current guidelines OR at least one prior alemtuzumab-containing therapy

Patients previously treated with bendamustine only if their DOR was 24 months

Patient requires treatment in the opinion of the investigator

Eastern Cooperative Oncology Group (ECOG) performance score of 1

Adequate bone marrow function independent of growth factor or transfusion support within 
2 weeks of screening, at screening as follows unless cytopenia is clearly due to marrow 
involvement of CLL:
Platelet count 75,000/mm3; in cases of thrombocytopenia clearly due to marrow 
involvement of CLL (per the discretion of the investigator), platelet count should be 
30,000/mm3
Absolute neutrophil count (ANC) 1000/mm3 unless neutropenia is clearly due to 
marrow involvement of CLL (per the discretion of the investigator)
Total hemoglobin 9 g/dL unless anemia is due to marrow involvement of CLL (per 
the discretion of the investigator)

Adequate renal and hepatic function, per laboratory reference range at screening as follows:
Calculated creatinine clearance 50 mL/min using 24-hour creatinine clearance or 
modified CockcroftGault equation (using ideal body mass [IBM] instead of mass):
eCCr
(140Age) IBM (kg) [0.85 if female]
72 serum creatinine (mg/dL)
Or, if serum creatinine is in mol/L:
eCCr
(140Age) IBM (kg) [1.23 if male, 1.04 if female]
serum creatinine (mol/L)
(IBM) should be used:
IBM (kg) [(height in cm154) 0.9] (50 if male, 45.5 if female)
AST and ALT 3.0 the upper limit of normal (ULN) of the institution's normal range
Bilirubin 1.5 ULN.  Patients with Gilbert's syndrome may have a bilirubin level 
1.5 ULN, per discussion between the investigator and the Medical Monitor
Prothrombin time (or international normalized ratio) and partial thromboplastin time 
not to exceed 1.2 the institution’s normal range (patients with an elevated 
prothrombin time and known lupus anticoagulant may be eligible for participation after 
consulting the Medical Monitor)


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
Female patients must be surgically sterile, postmenopausal (for at least 1 year), or have 
negative results for a pregnancy test performed as follows:
At screening, on a serum sample obtained within 14 days prior to initiation of study 
treatment, and
Prior to dosing, on a urine sample obtained on the first day of study treatment if it has 
been 7 days since obtaining the serum pregnancy test result

Female patients who are not surgically sterile or postmenopausal (for at least 1 year) must 
practice at least one of the following methods of birth control throughout the duration of 
study participation and for at least 30 days after study treatment or 12 months after 
completing therapy with rituximab, whichever is later:
Total abstinence from sexual intercourse
A vasectomized partner
Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that started at 
least 3 months prior to study drug administration
Double-barrier method (condom diaphragm or cervical cup with spermicidal 
contraceptive sponge, jellies, or cream)

Non-vasectomized male patients must practice at least one of the following methods of birth 
control throughout the duration of study participation and for at least 3 months after study 
treatment or 12 months after completing therapy with rituximab, whichever is later:
A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is 
taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at 
least 3 months prior to study drug administration
Total abstinence from sexual intercourse
Double-barrier method (condom diaphragm or cervical cup with spermicidal, 
contraceptive sponge, jellies, or cream)
Inclusion Criteria: R/C Substudy

Signed R/C Substudy Informed Consent Form

Patients randomized to Arm A or Arm B with a confirmed disease progression of CLL per 
iwCLL criteria

Patients who have not received new anti-CLL therapy following disease progression in 
Arm A or Arm B

Adequate renal and hepatic function per laboratory reference range
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Transformation of CLL to aggressive non-Hodgkin’s lymphoma (NHL) (e.g., Richter’s 
transformation, prolymphocytic leukemia, or diffuse large B-cell lymphoma [DLBCL] or CNS 
involvement by CLL

Undergone an allogeneic stem cell transplant

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

History of intolerance to prior bendamustine treatment (defined as toxicity requiring 
permanent discontinuation of bendamustine) or other contraindication to bendamustine 
treatment

History of severe (i.e., requiring permanent discontinuation of prior rituximab therapy) prior 
allergic or anaphylactic reactions to rituximab

Known HIV positivity

Positive test results for chronic hepatitis B infection (defined as positive HBsAg serology) 
Patients with occult or prior hepatitis B infection (defined as positive total HBcAb and 
negative HBsAg) may be included if HBV DNA is undetectable.  These patients must 
be willing to undergo monthly polymerase chain reaction (PCR) HBV DNA testing. 


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
Positive test results for hepatitis C (HCV antibody serology testing)
Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.

Requires the use of warfarin (due to potential drug drug interactions that may potentially 
increase the exposure of warfarin).  Patients may be eligible if able to be taken off warfarin 
and started on an alternative anticoagulant.

Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study 
treatment

Received any of the following agents within 28 days prior to the first dose of study treatment:
Any anti-cancer therapy including chemotherapy or radiotherapy and steroid therapy 
for anti-neoplastic intent, investigational therapy, including targeted small-molecule 
agents

Has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of 
any previous therapy

Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and clarithromycin) 
within 7 days prior to the first dose of study treatment

Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, St. John’s 
wort) within 7 days prior to the first dose of study treatment

History of prior venetoclax treatment

Consumed grapefruit or grapefruit products, Seville oranges (including marmalade 
containing Seville oranges), or star fruit within 3 days prior to the first dose of study drug

A cardiovascular disability status of New York Heart Association Class 3.  Class 3 is 
defined as cardiac disease in which patients are comfortable at rest but marked limitation of 
physical activity due to fatigue, palpitations, dyspnea, or anginal pain.

A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, 
cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely 
affect the patient’s participation in this study or interpretation of study outcomes.

Major surgery within 30 days prior to the first dose of study treatment

A patient who is pregnant or breast-feeding

History of prior other malignancy that could affect compliance with the protocol or 
interpretation of results with the exception of the following:
Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix at any time prior to study
Other cancers not specified above which have been curatively treated by surgery 
and/or radiation therapy from which patient is disease-free for 5 years without further 
treatment

Malabsorption syndrome or other condition that precludes enteral route of administration

Known allergy to both xanthine oxidase inhibitors and rasburicase

Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, 
uncontrolled systemic infection (viral, bacterial, or fungal)

Vaccination with a live vaccine within 28 days prior to randomization
Exclusion Criteria R/C Substudy

Transformation of CLL to aggressive NHL (e.g., Richter’s transformation, prolymphocytic 
leukemia, or DLBCL) or CNS involvement by CLL

Evidence of other clinically significant uncontrolled condition(s) including, but not 
limited to, uncontrolled systemic infection (viral, bacterial, or fungal)

Development of other malignancy since enrollment into the study, with the exception of 
curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia


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
History of severe (i.e., requiring permanent discontinuation of prior rituximab therapy) 
prior allergic or anaphylactic reactions to rituximab

Known HIV positivity

Positive test results for chronic hepatitis B infection (defined as positive hepatitis B 
surface antigen [HbsAg] serology)
Patients with occult or prior hepatitis B infection (defined as positive total hepatitis 
B core antibody [HBcAb] and negative HBsAg) may be included if hepatitis B virus 
[HBV] DNA is undetectable.  These patients must be willing to undergo monthly 
polymerase chain reaction (PCR) HBV DNA testing.

Positive test results for hepatitis C virus (HCV; HCV antibody serology testing)
Patients positive for HCV antibody are eligible only if PCR is negative for HCV 
RNA.

Requires the use of warfarin (due to potential drugdrug interactions that may 
potentially increase the exposure of warfarin)
Patients may be eligible if able to be taken off warfarin and started on an alternative 
anticoagulant.

Has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) 
of any previous therapy

Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and 
clarithromycin) within 7 days prior to the first dose of study treatment

Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, 
St. John’s wort) within 7 days prior to the first dose of study treatment

Consumed grapefruit or grapefruit products, Seville oranges (including marmalade 
containing Seville oranges), or star fruit within 3 days prior to the first dose of study 
treatment

A cardiovascular disability status of New York Heart Association Class 3
Class 3 is defined as cardiac disease in which patients are comfortable at rest but 
have marked limitation of physical activity due to fatigue, palpitations, dyspnea, or 
anginal pain.

A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, 
cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely 
affect the patient’s participation in this study or interpretation of study outcomes

Major surgery within 30 days prior to the first dose of study treatment

A patient who is pregnant or breastfeeding

Malabsorption syndrome or other condition that precludes enteral route of administration

Known allergy to both xanthine oxidase inhibitors and rasburicase

Vaccination with a live vaccine within 28 days prior to randomization
Length of Study
The approximate length of the study will be 101 months, based on an enrollment period of 
20 months and the end of study as defined below.
End of Study
The end of the study will be approximately 81 months after the last patient is enrolled in the 
main study, allowing for the collection of long-term safety, PFS, and OS data.  This will also 
allow for completion of the maximum duration of planned therapy in the R/C Substudy (in the 
absence of disease progression) as well as at least 1 month of follow-up for all patients in the 
R/C Substudy.


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Efficacy Outcome Measures
Primary Efficacy Outcome Measures
The primary efficacy outcome measure for this study is investigator-assessed PFS, defined as 
the time from randomization to the first occurrence of progression or relapse, determined using 
standard iwCLL guidelines, or death from any cause, whichever comes first.
While the primary efficacy endpoint is investigator-assessed PFS, PFS based on IRC
assessments will also be analyzed to support the primary analysis.  In the United States, 
IRC-assessed PFS will be the basis for regulatory decisions.
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are as follows:

IRC-assessed PFS in the subset of CLL patients with 17p deletion identified by FISH testing 
at a central laboratory

Investigator-assessed PFS in the subset of CLL patients with 17p deletion identified by 
FISH testing at a central laboratory

Best OR (defined as CR, CRi, nPR, and PR)rate as assessed by the investigator

OR CR, CRi, nPR, and PR rates at end of combination treatment response visit, as 
assessed by the investigator.  Disease response will be assessed according to the iwCLL 
guidelines

OR, CR, CRi, nPR, and PR rates at end of combination treatment response visit, as 
assessed by the IRC

OS, defined as the time from randomization to death from any cause

EFS, defined as the time between randomization and the date of disease 
progression/relapse, death from any cause, or start of a new anti-therapy

DOR, defined for patients with a best OR of CR, CRi, nPR, or PR as the time from first 
occurrence of a CR, CRi, nPR, or PR to disease progression/relapse, as assessed by the 
investigator, or death from any cause

TTNT, defined as the time from randomization to start of new non-protocol anti-CLL therapy 
or death from any cause

MRD response rate (determined as the proportion of patients with MRD negativity) at End 
of Combination Treatment Response Visit as measured at a central laboratory on peripheral 
blood and/or bone marrow samples
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of adverse events and serious adverse events 

Changes in clinical laboratory results (including hematology and chemistry) during and 
following administration of study treatment

Incidence of adverse events of special interest:
Grade 3 TLS and infusion-related reactions (IRRs)
Measures of immune function, including serial immunoglobulin levels (IgG, IgM, IgA) 
following treatment with venetoclaxR or BR
Pharmacodynamic Outcome Measure
The pharmacodynamic outcome measure for this study is as follows:

Serial assessment of B- and T-cell lymphocyte subsets by flow cytometry
Pharmacokinetic Outcome Measures
The PK outcome measures for this study include:

Plasma venetoclax concentrations at the specified timepoints


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
Apparent clearance, apparent volume of distribution, and other appropriate PK parameters 
of venetoclax characterized using population PK techniques, as data allow
Patient-Reported Outcome Measures
The PRO outcome measures for this study are as follows:

MDASI

EORTC QLQ-C30 and QLQ-CLL16
Health Economic Outcome Measure
The health economic outcome measure for this study is as follows:

The EQ-5D questionnaire
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Evaluation of the relationship between response and PFS and various potential biomarkers, 
including Bcl-2 expression, for patients treated with venetoclaxR or BR

Assessment of potential biomarkers that are prognostic and/or predictive of response and 
resistance to treatment with venetoclaxR or BR

MRD response rate as measured at a central laboratory on peripheral blood samples and/or 
bone marrow aspirate samples at the disease response assessment timepoints
Investigational Medicinal Products
Test Product
Arm A: Venetoclax and Rituximab (venetoclaxR)
Venetoclax tablets will be administered daily orally, starting with a daily dose of 20 mg on Day 1 
of the venetoclax dose ramp-up period, followed by 50 mg daily from Day 8, followed by 100 mg 
daily from Day 15, followed by 200 mg daily from Day 22, followed by 400 mg daily from Day 29.  
Venetoclax will then be self-administered at 400 mg per day for a maximum of 2 years from 
Cycle 1, Day 1 or until disease progression (whichever is earlier).  Combination therapy 
consisting of 6 cycles of rituximab and daily venetoclax dosing will start after completion of the 
venetoclax ramp-up period.
Rituximab will be administered intravenously at a dose of 375 mg/m2 on Day 1 of Cycle 1 
followed by 500 mg/m2 IV on Day 1 of Cycles 2 through 6.
Comparator
Arm B: Bendamustine and Rituximab (BR)
Bendamustine will be administered at 70 mg/m2 IV on Days 1 and 2 of Cycles 1 through 6.
Rituximab will be administered at 375 mg/m2 IV on Day 1 of Cycle 1 and 500 mg/m2 IV on Day 1 
of Cycles 2 through 6.
R/C Substudy
Patients entering the R/C Substudy will follow an initial venetoclax ramp-up period, 
including TLS prophylaxis treatments, and then will take venetoclax 400 mg QD PO in 
combination with rituximab administered intravenously.  After completion of combination 
therapy, patients will continue to take venetoclax 400 mg QD PO as monotherapy until 
disease progression or for a maximum of 2 years from Cycle 1R/C Day 1 of re-treatment or 
crossover.
Non-Investigational Medicinal Products
Permitted Concomitant Therapy and Clinical Practice
Patients who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use for the duration of the study or at least 30 days after the last 
dose of study drug or one year after the last dose of rituximab, whichever is longer.


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Necessary supportive measures for optimal medical care will be given throughout the study 
according to institutional standards, including the use of growth factors (e.g., erythropoietin) if 
clinically indicated.  Granulocyte colony-stimulating factor (G-CSF) may be administered as 
primary prophylaxis in each cycle of therapy, as per the American Society of Clinical Oncology 
(ASCO) guidelines or each site’s institutional standards.
Anti-emetic therapy may be instituted for any patient if clinically indicated.  Bendamustine has a 
moderate risk of emesis.  It is recommended that bendamustine infusions be administered 
following premedication with a serotonin (5-HT3) antagonist (i.e., dolasetron, ondansetron, etc.) 
or as per institutional practice.
Systemic steroid therapy will not be allowed either during or within 7 days prior to the first dose 
of study treatment with the exception of inhaled corticosteroids for the treatment of asthma or 
chronic obstructive pulmonary disease (COPD), single infusions of hydrocortisone prior to 
rituximab infusions, topical steroids, or replacement corticosteroid therapy for an inherited or 
acquired deficiency.
Premedication before rituximab infusion:

Oral acetaminophen/paracetamol (6501000 mg) at least 30 minutes prior to the start of 
infusion (mandatory for all infusions)

Antihistamine such as diphenhydramine (2550 mg) approximately 30 minutes prior to the 
start of the first infusion for all subsequent infusions unless previous antibody infusions did 
not result in an IRR NCI CTCAE Grade 1 and there was no interruption to the infusion.

A single dose of hydrocortisone (up to 100 mg or an equivalent dose of methylprednisolone) 
may also be administered with rituximab if this is the usual practice at the site.
Prophylaxis and Management of Tumor Lysis Syndrome (TLS)
Clinical data from CLL patients treated to date with venetoclax suggest that patients with 
baseline lymph nodes 5 cm diameter are at a greater risk for TLS than those with baseline 
lymph nodes less than 5 cm.  In addition, the data showed that creatinine clearance of 
80 mL/min at screening was a secondary risk factor for TLS.  On the basis of the data review 
performed by the Sponsors, the following are three TLS risk categories identified:
1.
TLS low-risk category: the presence of all measurable lymph nodes with the largest 
diameter 5 cm by radiographic assessment AND absolute lymphocyte counts 25 109/L
2.
TLS medium-risk category: the presence of all measurable lymph nodes with the largest 
diameter 5 cm and 10 cm by radiologic assessment OR absolute lymphocyte 
count 25 109/L
3.
TLS high-risk category: the presence of any lymph node with the largest diameter 10 cm 
by radiologic assessment OR the presence of BOTH an absolute lymphocyte 
count 25 109/L AND a measurable lymph node with the largest diameter 5 cm by 
radiologic assessment
All patients enrolling in the study will be assessed at screening and categorized in a TLS risk 
category as described above.
Initial Doses:  20 and 50 mg
All patients, irrespective of their TLS risk category, must receive the following TLS prophylaxis 
measures prior to the initiation of the first doses of venetoclax:

Administration of an oral uric acid reducer (such as allopurinol 300 mg/day) beginning at 
least 72 hours prior to dose and continued until the first week of combination therapy with 
venetoclax and rituximab is completed

Oral hydration consisting of fluid intake of approximately 1.52 L/day starting at least 
48 hours prior to the start of treatment and continued for at least 24 hours after the first 
dose


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
Serum chemistry and hematology laboratory samples must be drawn anytime within 
72 hours prior to first dose and electrolyte values should be reviewed and not demonstrate 
any clinically significant abnormalities prior to the first dose of venetoclax.  If clinically 
significant laboratory abnormalities are observed in this baseline laboratory assessment, 
first dose of venetoclax must be delayed until resolution and management per the protocol, 
Recommendations for Initial Management of Electrolyte Imbalances and Prevention of 
Tumor Lysis Syndrome, must be initiated.  If active correction of electrolytes was performed, 
the first dose of venetoclax can only be given when electrolytes have been stable without 
any more treatment for at least 24 hours.  If needed, patient should receive additional 
prophylactic treatment prior to the initiation of dosing.
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS risk 
category as follows.
TLS Low Risk
Low-risk patients will receive their initial doses of 20 and 50 mg as outpatients.
For patients unable to maintain oral hydration at 1.52 L/day starting at least 48 hours prior to 
the start of treatment, IV hydration in the outpatient setting on the day of dosing during the clinic 
stay is recommended in order to assure that this full amount of hydration is achieved.  For 
patients for whom volume overload is considered a significant risk, hospitalization should be 
considered. 
Serum chemistry, hematology, and vital signs will be performed before dosing (defined as up to 
4 hours before venetoclax dose), 8 and 24 hours after dosing timepoints.  Laboratory samples 
should be sent and analyzed immediately.  
For patients in whom the laboratory values required to be done within 72 hours prior to the first 
dose were in fact obtained within 24 hours before dosing and were within normal limits, results 
from “before dosing” laboratory values are not required to be available prior to initiating 
venetoclax treatment, but rather will serve only as a baseline for post-dosing laboratory results 
comparisons. 
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient clinic 
that day. 
Furthermore, the investigator or subinvestigator must review the 24-hour laboratory results prior 
to dosing on the next day.  
Additional laboratory assessments may be performed per investigator discretion.
TLS Medium Risk
Medium-risk patients who have creatinine clearance 80 mL/min will receive their initial doses 
of 20 and 50 mg as outpatients.  Patients with creatinine clearance 80 mL/min and/or who 
have higher tumor burden (defined per the discretion of the investigator) may be handled as 
High-Risk patients (see the High Risk section for details of hydration, laboratory, etc.).
In addition to oral hydration stated above, IV hydration (1.52 L) will be given in the outpatient 
setting during the clinic stay.  For patients for whom volume overload is considered a significant 
risk, hospitalization should be considered.
Serum chemistry, hematology, and vital signs will be performed before dosing (defined as up to 
4 hours before venetoclax dose), 8 and 24 hours after dosing timepoints.  Laboratory samples 
should be sent and analyzed immediately.
For patients in whom the laboratory values required to be done within 72 hours prior to the first 
dose were in fact obtained within 24 hours before dosing and were within normal limits, results 
from “before dosing” laboratory values are not required to be available prior to initiating 
venetoclax treatment, but rather will serve only as a baseline for post-dosing laboratory results 
comparisons. 
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient clinic 
that day. 
Furthermore, the investigator or subinvestigator must review the 24-hour laboratory results prior 
to dosing on the next day.  
Additional laboratory assessments may be performed per investigator discretion


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TLS High Risk
High-risk patients will be hospitalized to receive their initial doses of 20 and 50 mg.  
Hospitalization will begin the evening prior to each initial dose of venetoclax and continue for 
24 hours after.
Upon admission, serum chemistry and hematology laboratory samples should be drawn and IV 
hydration should be started with a target of approximately 23 L per day or as clinically 
appropriate.
Rasburicase must be administered per regional standards/institutional guidelines as prophylaxis 
prior to the first dose of venetoclax for high-risk patients with high uric acid levels at pre-dose 
(above the local laboratory ULN or Cairo-Bishop threshold of 476 µmol/L).  For patients with a 
contraindication to rasburicase (i.e., glucose-6-phosphate dehydrogenase deficiency), the TLS 
risk-mitigation plan must be reviewed with the Medical Monitor.  Uric acid levels following 
treatment with rasburicase must be analyzed using specific guidelines.
Nephrology (or acute dialysis service) consultation should be considered on admission (per 
institutional standards or based on investigator discretion) for hospitalized patients to ensure 
emergency dialysis is available and the appropriate staff is aware and prepared to handle any 
necessary intervention for TLS.  Telemetry should also be considered.
Serum chemistry, hematology, and vital signs will be performed before dosing and at 4 (serum 
chemistry only), 8, 12 (serum chemistry only), and 24 hours after dosing.  These samples are to 
be sent immediately to the laboratory, and the results must be reviewed promptly by the 
investigator or subinvestigator.  The 24-hour post-dose laboratory results must be reviewed by 
the investigator or subinvestigator before the patient leaves the hospital or receives any 
additional study drug.  Additional laboratory assessments may be performed per investigator 
discretion.
Subsequent Dose Increases during the Venetoclax Ramp-Up Period:  100, 200, and 
400 mg
All patients, irrespective of their risk category, must receive the following TLS prophylaxis 
measures prior to subsequent dose increases of venetoclax:

Continued administration of an oral uric acid reducer as indicated above.

Oral hydration consisting of fluid intake of approximately 1.52 L/day starting at least 
48 hours prior to dosing.  IV hydration is encouraged at subsequent dose increases for 
patients unable to maintain such oral hydration.  IV hydration in the outpatient setting on the 
day of dosing during the clinic stay is recommended in order to assure this full amount of 
hydration is achieved.  For patients for whom volume overload is considered a significant 
risk, hospitalization should be considered.

Serum chemistry and hematology laboratory samples must be drawn within 72 hours prior 
to dose and electrolyte values should be reviewed and not demonstrate any clinically 
significant abnormalities prior to each dose increase of venetoclax, or the patient should 
receive additional prophylactic treatment prior to dosing.  If clinically significant laboratory
abnormalities are observed in this laboratory assessment, dose of venetoclax must be 
delayed until resolution, and management per the protocol, Recommendations for Initial 
Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome, must be 
initiated.  If needed, patient should receive additional prophylactic treatment prior to the 
initiation of dosing.  If active correction of electrolytes was performed, the first or 
subsequent dose of venetoclax can only be given when electrolytes have been stable 
without any more treatment for at least 24 hours.
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS risk 
category as follows.
TLS Low Risk
Low-risk patients will receive the subsequent dose increases (100, 200, and 400 mg) as 
outpatients.
Serum chemistry, hematology, and vital signs will be performed before dosing (defined as up to 
4 hours before venetoclax dose) and at 8 and 24 hours after dosing timepoints.  Laboratory 
samples should be sent and analyzed immediately.


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For patients in whom the laboratory values required to be done within 72 hours prior to the first 
dose were in fact obtained within 24 hours before dosing and were within normal limits, results 
from “before dosing” laboratory values are not required to be available prior to initiating 
venetoclax treatment, but rather will serve only as a baseline for post-dosing laboratory results 
comparisons.
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient clinic 
that day.
Furthermore, the investigator or subinvestigator must review the 24-hour laboratory results prior 
to dosing on the next day.
Additional laboratory assessments may be performed per investigator discretion.
TLS Medium Risk
Medium-risk patients who have creatinine clearance ≥ 80 mL/min will receive their subsequent 
dose increases as outpatient.  Patients with creatinine clearance < 80 mL/min and/or who have 
high tumor burden (defined per the discretion of the investigator) may be hospitalized.
For patients who receive this subsequent dose increases as outpatient, serum chemistry, 
hematology, and vital signs will be performed before dosing (defined as up to 4 hours before 
venetoclax dose) and 8 and 24 hours after dosing timepoints.  Laboratory samples should be
sent and analyzed immediately.
For patients in whom the laboratory values required to be done within 72 hours prior to the first 
dose were in fact obtained within 24 hours before dosing and were within normal limits, results 
from “before dosing” laboratory values are not required to be available prior to initiating 
venetoclax treatment, but rather will serve only as a baseline for post-dosing laboratory results 
comparisons.
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient clinic 
that day.
Furthermore, the investigator or subinvestigator must review the 24-hour laboratory results prior 
to dosing on the next day.
Additional laboratory assessments may be performed per investigator discretion.
For patients hospitalized during subsequent dose increases, serum chemistry, hematology, and 
vital signs will be performed before dosing (defined as up to 4 hours before venetoclax dose) 
and 4, 8, 12, and 24 hours after dosing.  These samples are to be sent immediately to the 
laboratory, and the results must be reviewed promptly by the investigator or subinvestigator.  
The 24-hour after dosing laboratory results must be reviewed by the investigator or 
subinvestigator before the patient leaves the hospital or receives any additional study drug.
IV hydration should be started with a target of approximately 23 L per day or as clinically 
appropriate for patients who are hospitalized.
TLS High Risk
High-risk patients with creatinine clearance of ≥ 80 mL/min will receive the subsequent dose 
increases as outpatients.  Patients with creatinine clearance < 80 mL/min and/or high tumor 
burden (defined per the discretion of the investigator) may be hospitalized.  Hospitalization will 
begin the evening prior to the dose of venetoclax and continuing for 24 hours after.
IV hydration (1.52 L) will be given in the outpatient setting during the clinic stay.  For patients 
who are hospitalized, IV hydration should be started with a target of approximately 23 L per 
day or as clinically appropriate.
For patients not hospitalized, serum chemistry, hematology, and vital signs will be performed 
before dosing (defined as up to 4 hours before venetoclax dose) and 8 and 24 hours after 
dosing timepoints.  Laboratory samples should be sent and analyzed immediately.
For patients in whom the laboratory values required to be done within 72 hours prior to the first 
dose were in fact obtained within 24 hours before dosing and were within normal limits, results 
from “before dosing” laboratory values are not required to be available prior to initiating 
venetoclax treatment, but rather will serve only as a baseline for post-dosing laboratory results 
comparisons.
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient clinic 
that day.


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Furthermore, the investigator or subinvestigator must review the 24-hour laboratory results prior 
to dosing on the next day.  
For patients hospitalized during subsequent dose increases, serum chemistry, hematology, and 
vital signs will be performed before dosing and 4, 8, 12, and 24 hours after dosing.  These 
samples are to be sent immediately to the laboratory, and the results must be reviewed 
promptly by the investigator or subinvestigator.  The 24-hour after dosing laboratory results 
must be reviewed by the investigator or subinvestigator before the patient leaves the hospital or 
receives any additional study drug.
Additional laboratory assessments may be performed per investigator discretion.
Any patient who, at any dose, develops clinically significant electrolyte abnormalities must have 
his or her subsequent venetoclax dose held until the electrolyte abnormalities resolve.  Patients 
who develop electrolyte abnormalities should undergo aggressive management and further 
monitoring per Recommendations for Initial Management of Electrolyte Imbalances and 
Prevention of Tumor Lysis Syndrome.  If active correction of electrolytes was performed, the 
first dose of venetoclax can only be given when electrolytes have been stable without any more 
treatment for at least 24 hours.  If venetoclax was held for 7 days or less, the patient may 
resume venetoclax at the same dose level or at one lower dose level as determined by the 
investigator based on a risk assessment (including tumor burden status).  Dose must be 
resumed at one lower dose level if interruption lasted more than 7 days.  All patients must 
receive the intended dose for at least 7 days before increasing to the next ramp-up dose.
First Rituximab Dose
All patients will have the following procedures regardless of TLS risk category:
The first dose of rituximab will be given in an outpatient setting.  Patients may be hospitalized 
for the first dose of rituximab at the investigator’s discretion following discussion with the 
Medical Monitor. 
Oral hydration consisting of fluid intake of approximately 1.52 L/day starting at least 48 hours 
prior to dosing.  IV hydration is encouraged for patients unable to maintain such oral hydration.  
IV hydration in the outpatient setting on the day of dosing during the clinic stay is recommended 
in order to assure this full amount of hydration is achieved.  For patients for whom volume 
overload is considered a significant risk, hospitalization should be considered.
IV hydration (1.52 L) will be given in the outpatient setting during the clinic stay.  For patients 
who are hospitalized, IV hydration should be started with a target of approximately 23 L per 
day or as clinically appropriate.
Venetoclax will be taken at least 30 minutes prior to starting the rituximab infusion.
Serum chemistry, hematology, and vital signs will be performed before dosing (defined as up to 
4 hours before venetoclax dose) and 8 and 24 hours after dosing of venetoclax.  Laboratory 
samples should be sent and analyzed immediately.  Results from predose laboratory values are 
not required to be available prior to initiating venetoclax treatment provided laboratory values 
obtained within 24 hours before dosing were within normal limits.  The 8-hour laboratory results 
must be reviewed prior to the patient leaving the clinic.
The 24-hour chemistry values must be reviewed before the patient receives the next day dose 
of venetoclax.  If there is no evidence of TLS 24 hours after rituximab and venetoclax dose, 
patients can continue on venetoclax daily dosing.
Patients who develop any electrolyte changes suggestive of TLS should have his or her 
subsequent venetoclax dose held until the electrolyte abnormalities resolve, undergo 
aggressive management and further monitoring per Recommendations for Initial Management 
of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome.  If active correction of 
electrolytes was performed, the first dose of venetoclax can only be given when electrolytes 
have been stable without any more treatment for at least 24 hours.


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Downgrading TLS Risk Category
Patients classified as TLS high-risk at screening due to an absolute lymphocyte count 
25 109/L AND a measurable lymph node with the largest diameter 5 cm but less than 
10 cm by radiologic assessment may have a re- evaluation of their TLS risk category based on 
their most recent ALC for dose increases above 50 mg.  Based on those results, one of the 
following two options may be implemented:
If the patient’s ALC decreases to 25 × 109/L, the patient may be categorized as TLS 
medium-risk and follow the management guidelines for the TLS medium-risk category for 
subsequent dose increases (to 100, 200, 400 mg) of venetoclax during the Ramp-Up Period.
If the patient’s ALC remains 25 109/L, the patient will remain in the TLS high-risk category 
and continues to follow management guidelines for TLS high-risk patients for subsequent dose 
increases of venetoclax during the Ramp-Up Period.  Re-assessment of the patient’s TLS risk 
category can occur prior to each subsequent dose increase.
Statistical Methods
Primary Analysis
Efficacy
The primary efficacy endpoint is investigator-assessed PFS, defined as the time from 
randomization to the first occurrence of progression or relapse (determined using standard 
iwCLL guidelines), or death from any cause, whichever comes first.  For patients who have not 
progressed, relapsed, or died at the time of analysis, PFS will be censored on the date of the 
last disease assessment.  If no disease assessments were performed after the baseline visit, 
PFS will be censored at the time of randomization 1 day. Although the primary efficacy 
endpoint is investigator-assessed PFS, PFS based on IRC assessments will also be analyzed 
to support the primary analysis.  In the United States, IRC-assessed PFS will be the basis of 
regulatory decisions.
Treatment comparison will be made using a two-sided stratified log-rank test (0.05 significance 
level, appropriately adjusted for an interim analysis) stratified by 17p deletion status (yes or no), 
risk status (high or low risk),and geographic region (United States/Canada, Australia/New 
Zealand, Western Europe, Central and Eastern Europe, Asia, or Latin America).  If the null 
hypothesis is rejected and the observed hazard ratio is favorable for the venetoclaxR 
combination, then it is shown that venetoclaxR has significantly longer PFS than BR.
If the study meets its primary endpoint of prolonging PFS assessed by the investigator in all 
randomized patients, then formal statistical tests of specific key secondary efficacy endpoints will be 
performed. To adjust for multiple testing of the primary and key secondary efficacy endpoints, 
thereby controlling the overall type I error rate at a 2-sided significance level of 0.05, a fixed 
sequence testing procedure will be used.  Additional secondary endpoints will not be tested formally. 
Further details of the fixed sequence testing will be described in the Statistical Analysis Plan.
Secondary efficacy outcome measures include:

Investigator-assessed PFS in patients with 17p deletion per central laboratory FISH test

IRC-assessed PFS in patients with 17p deletion per central laboratory FISH test

Investigator-assessed best OR rate, CR, CRi, nPR, and PR rates

IRC-assessed best OR rate, CR, CRi, nPR, and PR rates 

OR, CR, CRi, nPR, and PR rates at end of combination treatment response visit as
assessed by the investigator

OR, CR, CRi, nPR, and PR rates at end of combination treatment response visit, as 
determined by the IRC

OS, defined as the time from the date of randomization to the date of death from any cause.  
Patients who were not reported as having died at the time of analysis will be censored at 
the date when they were last known to be alive as documented by the investigator.


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
EFS, defined as the time between date of randomization and the date of disease 
progression/relapse, death, or start of a new anti-CLL treatment. If the specified event (disease 
progression/relapse, death, start of a new anti-CLL treatment) does not occur, patients will be 
censored at the date of last tumor assessment.  For patients without an event who have not had post-
baseline tumor assessments, EFS will be censored at the time of randomization.

DOR, defined for patients with a best OR of CR, CRi, nPR, or PR as the time from first 
occurrence of a documented CR or PR to disease progression/relapse as assessed by the 
investigator or death from any cause. For patients achieving a response who have not progressed, 
relapsed, or died at the time of analysis, DOR will be censored on the date of last response assessment.  
Patients who have never had responded will not be included in this analysis.

TTNT, defined as the time from randomization to start of new non-protocol anti-CLL therapy
or death from any cause. For patients who have not received the next anti-CLL treatment or died 
at the time of analysis, TTNT will be censored at the date when the patient was last known to be alive 
without having received additional anti-lymphoma treatment.

MRD response rate (determined as the proportion of patients with MRD negativity) at End 
of Combination Treatment Response Visit as measured at a central laboratory on peripheral 
blood and/or bone marrow samples 
Time-to-event endpoints such as OS, EFS, and TTNT will be analyzed using the same 
statistical methods described for the primary analysis of PFS.
Time-to-event analysis of DOR will incorporate data only from the subset of patients in both 
treatment arms that achieved a CR, CRi, nPR, or PR status.  As this a nonrandomized 
comparison, a formal statistical test will not be conducted, and the results will only be 
summarized by the treatment arm estimates and confidence intervals.
Response rates in the treatment groups will be compared using stratified 
CochranMantelHaenszel (CMH) tests.  Stratification factors are identical to those used for the 
primary endpoint.  Rates and 95% confidence intervals will be reported for each treatment 
group.
Safety
The safety analyses will include all randomized patients who received at least one dose of study 
treatment (venetoclax, rituximab, or bendamustine), with patients grouped according to the 
treatment actually received.
Treatment exposure will be summarized, including the number of cycles received by each 
patient, and the cumulative dose will be summarized by treatment arm.
Verbatim descriptions of adverse events will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms.  All adverse events occurring during or after the first
treatment will be summarized by treatment arm and NCI CTCAE grade.  In addition, all serious 
adverse events will be summarized.
Deaths reported during the study treatment period and those reported after treatment 
completion/discontinuation will be summarized by treatment arm.
Adverse events leading to early treatment discontinuation and early study withdrawal will be 
summarized by arm and reason.
Laboratory data with values outside of the normal ranges will be identified.  Additionally, select 
laboratory data will be summarized by treatment arm and grade using the NCI CTCAE.  Of note, 
abnormal laboratory data that are clinically significant will be reported as adverse events and 
summarized in the adverse event tables.
Vital signs and other physical findings will be summarized by treatment arm.
Pharmacodynamics
The exploratory pharmacodynamic biomarker analyses will include patients with at least one 
predose and/or one post-dose biomarker assessment, with patients grouped according to the 
treatment actually received.
Blood samples for biomarker assessments will be assayed using analytically qualified methods 
(e.g., immunohistochemistry, ELISA, quantitative real-time polymerase chain reaction, and 
fluorescence-activated cell sorting).


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Pharmacokinetics
Individual plasma concentrations of venetoclax will be tabulated after appropriate grouping, 
summarized (e.g., mean, standard deviation, coefficient of variation, median, minimum, and 
maximum), and plotted. 
Population PK methods will be used to characterize the pharmacokinetics of venetoclax in this 
study in conjunction with appropriate historical data.  Apparent clearance, apparent volume of 
distribution, and other appropriate PK parameters of venetoclax may be calculated and 
summarized as data allow.
Potential correlations of exposure with dose, demographics, pharmacodynamic variables, safety, 
and efficacy outcomes may be explored as warranted by the data.  The results from the 
population PK analysis may be reported separately from the Clinical Study Report.
At the discretion of the Sponsor, all analyses may be extended to include relevant 
biotransformation products of venetoclax.
Patient-Reported Outcomes
Scoring for the MDASI, EORTC QLQ-C30, and EORTC QLQ-CLL16 questionnaires will be 
based on their corresponding user manuals.  For the MDASI, EORTC QLQ-C30, and EORTC 
QLQ-CLL16 scales with more than 50% of the constituent items completed, a pro-rated score 
will be computed consistent with the scoring manuals and validation papers.  For subscales with 
less than 50% of the items completed, the subscale will be considered as missing.
Summary statistics of the MDASI, EORTC QLQ-C30, and EORTC QLQ-CLL16 scales and their 
changes from baseline will be calculated at each assessment timepoint for both study arms.  
Disease-related symptom progression will be measured by EORTC QLQ-C30 and EORTC 
QLQ-CLL questionnaires.  Time-to-event Kaplan-Meier analysis on CLL symptoms will be used 
to demonstrate the time from first treatment to worsening in disease-related symptoms.  An 
event is a change in symptom score by 10 points or more as defined as being clinically 
important.
Health Economics
Health economic data, as assessed by the EQ-5D, will be evaluated for patients with a baseline 
assessment and at least one post-baseline EQ-5D assessment that generate a score.  Scores 
at baseline and change from baseline scores for each timepoint will be quantified using 
descriptive statistics.
Determination of Sample Size
The primary endpoint of PFS was used to determine the sample size for the study.  Estimates of 
the number of events required to demonstrate efficacy with regard to PFS are based on the 
following assumptions:

Two-sided log-rank test at the 0.05 level of significance

80% power to detect a hazard ratio (HR) for venetoclax R versus BR of 0.66, 
corresponding to an approximate median improvement of 15.2 months to 23 months 
(34% reduction in risk of a PFS event)

Exponential distribution of PFS

An annual dropout rate of 5%

One interim analysis for efficacy
With these assumptions, 186 PFS events are required to achieve 80% power for the primary 
analysis of PFS in all patients for detecting a trend in favor of venetoclax R arm over BR arm 
(HR 0.66).  In total, it is planned to enroll approximately 370 patients across 2 arms, 
randomized with 1:1 ratio.  It is expected that, after a 9-month enrollment ramp-up, 24 patients 
per month will be recruited, and the total enrollment is expected to take approximately 
20 months.
Interim Analyses
An interim analysis is planned when approximately 140 investigator-assessed PFS events or 
deaths have occurred in both treatment arms combined (75% of the 186 events required for the 
final primary efficacy analysis).


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Re-Treatment/Crossover Substudy Analysis
Exploratory analyses will be performed to determine the efficacy of venetoclax R for patients 
who have clinically progressed on prior venetoclax R or BR regimens when all patients who 
entered the R/C Substudy complete the EOCTR-R/C Visit and at the end of the study.
Efficacy Analyses for R/C Substudy
The efficacy population will be defined as all patients who entered the R/C Substudy and 
received at least one dose of study treatment (venetoclax or rituximab), with patients grouped 
according to the prior venetoclax R (re-treatment) or BR (crossover) regimens.  Disease 
response will be assessed according to the iwCLL guidelines.  Newer iwCLL guidelines may be 
utilized in addition if published prior to start of enrollment in the R/C Substudy.
Efficacy endpoints for the R/C Substudy include:

OR, CR, CRi, nPR, and PR rates at EOCTR-R/C Visit as assessed by the investigator

OS, defined as the time from first treatment exposure in the R/C Substudy to death from 
any cause

MRD response rate as measured at a central laboratory on peripheral blood samples and 
bone marrow aspirate samples at each sampling timepoint as well as Best MRD negativity 
in the R/C Substudy
Safety Analyses for R/C Substudy
The safety analyses will include all patients who entered the R/C Substudy and received at 
least one dose of study treatment (venetoclax or rituximab), with patients grouped according 
to the prior venetoclax R or BR regimens.  Safety endpoints include deaths, serious adverse 
events, adverse events Grade 3, select adverse events (TLS, Grade 3 neutropenia, Grade 3 
infections), second primary malignancies, Richter’s transformation, and adverse events 
leading to treatment discontinuation.  Treatment exposure will be summarized, including the 
number of cycles received by each patient, dose modification, treatment discontinuation and 
the cumulative dose by the prior venetoclax R or BR regimens.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADCC
antibody-dependent cellular cytotoxicity
AE
adverse event
ALC
absolute lymphocyte count
ALL
acute lymphoblastic leukemia
AML
acute myeloid leukemia
ANC
absolute neutrophil count
anti-HBc
hepatitis B core antibody
ASCO
American Society of Clinical Oncology
ASCT
allogeneic stem cell transplantation
ASO-PCR
allele-specific oligonucleotide polymerase chain 
reaction
AST
aspartate aminotransferase
AUC
area under the concentrationtime curve
AUC0-24
area under the concentrationtime curve from time 0 
to 24 hours post-dose
BCRP
breast cancer resistance protein
BR
bendamustine and rituximab
BSA
body surface area
CDC
complement-dependent cytotoxicity
CHOP
cyclophosphamide, doxorubicin, vincristine, prednisone
CLL
chronic lymphocytic leukemia
CR
complete response
CRi
complete response with incomplete bone marrow 
recovery
CRO
contract research organization
CT
computed tomography
CTLS
clinical tumor lysis syndrome
COVTR-R/C
Completion of Venetoclax Treatment Response in the 
Re-treatment/Crossover Substudy
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
event-free survival


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Abbreviation
Definition
EOCTR-R/C
End of Combination Treatment Response in the 
Re-Treatment/Crossover Substudy
EORTC
European Organisation for Research and Treatment of 
Cancer
ePRO
electronic patient-reported outcome
EQ-5D
EuroQol 5 Dimension
ESMO
European Society for Medical Oncology
FC
fludarabine and cyclophosphamide
FCR
fludarabine, cyclophosphamide, rituximab
FDA
U.S. Food and Drug Administration
FISH
fluorescence in situ hybridization
FL
follicular lymphoma
FR
fludarabine, rituximab
G-CSF
granulocyte colony-stimulating factor
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVcAB
hepatitis C virus core antibody
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
HR
hazard ratio
HRQoL
health-related quality of life
IBM
ideal body mass
ICH
International Council for Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IRC
Independent Review Committee
IRR
infusion-related reaction
IV
intravenous
IVRx
interactive voice response solution
iwCLL
international workshop on Chronic Lymphocytic 
Leukemia
IxRS
interactive voice/Web-based system


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Abbreviation
Definition
LTLS
laboratory tumor lysis syndrome
LVEF
left ventricular ejection fraction
MDASI
M. D. Anderson Symptom Inventory
MDS
myelodysplastic syndrome
miRNA
microRNA
MRD
minimal residual disease
MRI
magnetic resonance imaging
MUGA
multi-gated acquisition
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NCI-WG
National Cancer Institute Working Group
NGS
next-generation sequencing
NHL
non-Hodgkin’s lymphoma
nPR
nodular partial response
OATP1B1 
organic anion transporter protein 1B1
OATP1B3 
organic anion transporter protein 1B3
OCT1
organic cation transporter 1
OR
overall response
OS
overall survival
P-gp
P-glycoprotein 1
PCR
polymerase chain reaction
PD
progressive disease
PE
polyethylene
PFS
progression-free survival
PK
pharmacokinetic
PML
progressive multifocal leukoencephalopathy
PR
partial response
PRO
patient-reported outcome
PT
prothrombin time
PTT
partial thromboplastin time
PUR
polyurethane
PVC
polyvinyl chloride
QD
once daily
QLQ-C30
Quality of Life Questionnaire Core 30
QLQ-CLL16
Quality of Life Questionnaire CLL module
QOL
quality of life


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Abbreviation
Definition
R/C
Re-Treatment/Crossover
RCR
Roche Clinical Repository
RNA
ribonucleic acid
RNA-seq
RNA sequencing
ROW
rest of world
SAE
serious adverse event
Screening-R/C
Re-Treatment/Crossover Substudy Screening
SD
stable disease
SLL
small lymphocytic lymphoma
SmPC
Summary of Product Characteristics
STD
severely toxic dose
TEN
toxic epidermal necrolysis
TLS
tumor lysis syndrome
TTNT
time to next anti-CLL treatment
ULN
upper limit of normal
USPI
United States Product Insert
WES
whole exome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON CHRONIC LYMPHOCYTIC LEUKEMIA
Chronic lymphocytic leukemia (CLL) is the most common of the chronic leukemias, 
comprising 30% of all adult leukemias, with a median age at diagnosis of 72 years.  CLL 
is a clonal disease of unknown etiology, characterized by the accumulation of mature 
B cells in blood, lymph nodes, spleen, liver, and bone marrow.
Morphologically, CLL cells are relatively mature appearing but immunologically 
incompetent.  About 95% of CLL is of B-cell origin (B-CLL) with a characteristic 
phenotype (CD5, CD23; weak surface expression of CD19, CD20, and CD79b; and 
IgM- or IgD-restricted).  Chromosomal abnormalities of the leukemia cells are found in 
80% of cases, with the most common being deletion 13q14 (incidence 55%), 
deletion 11q- (18%), trisomy 12 (16%), and deletion 17p (7%) (Döhner et al. 2000).
More than 50% of CLL patients are asymptomatic at diagnosis and require no treatment.  
Symptoms appear as the disease progresses.  Treatment is initiated when a patient’s 
disease becomes symptomatic or progressive as defined by the international workshop 
on Chronic Lymphocytic Leukemia (iwCLL)’s updated guidelines for diagnosis and 
treatment of CLL (Hallek et al. 2008).
Response rates to initial treatment are high, but relapsed or refractory disease is often 
characterized by resistance to chemotherapy (i.e., fludarabine or alkylating agents).  
Relapsed disease is associated with a median survival between 15 and 44 months 
and is dependent of CLL risk status, time to relapse, and choice of regimen 
(Lamanna et al. 2006; Wierda et al. 2010; Badoux et al. 2011; Fischer et al. 2011).  
Rituximab is approved for the treatment of both previously treated and previously 
untreated CLL in combination with chemotherapy in Europe and with fludarabine and 
cyclophosphamide (FC) in the United States.  Besides the regimen of FC and rituximab 
(FCR), the combination regimen approved in the United States, one of the more 
commonly used and active regimens in relapsed CLL is the combination of 
bendamustine and rituximab (BR).  The BR regimen was demonstrated to have 
meaningful clinical activity in relapsed/refractory CLL patients with an observed overall
response (OR) rate of 59% and a median progression-free survival (PFS) of 
15.2 months (Fischer et al. 2011).
Despite recent progress, CLL remains incurable; therefore, there is a need for the 
development of new treatments that could improve both response rate and the survival 
of these patients.
1.2
BACKGROUND ON VENETOCLAX (GDC-0199)
1.2.1
Bcl-2 Protein Family
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) 


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chromosomal translocation results in significant overexpression of Bcl-2 protein in 
B cells.  The Bcl-2 family of genes encodes a group of closely related proteins that 
exhibit pro- or anti-apoptotic activity and share up to four Bcl-2 homology domains 
(Korsmeyer 1999; Cory and Adams 2002; Borner 2003; Cory et al. 2003).  Bcl-2 
overexpression is a major contributor to the pathogenesis of several lymphoid 
malignancies and is overexpressed in acute and chronic leukemias.
In CLL cells, the microRNAs (miRNAs) miR15a and miR16-1 that negatively regulate the 
transcription of Bcl-2 are deleted or down-regulated, resulting in uncontrolled expression 
of Bcl-2 (Calin et al. 2008).  Although Bcl-2 expression levels are variable across 
patients, high expression of Bcl-2 (compared with normal white blood cells) is observed 
in CLL cells in 95% of CLL patients (unpublished data from Phase II study of 
ABT4710n [navitoclax]).
Bcl-2 overexpression represents one common mechanism for evading apoptosis.  
However, CLL cells may concurrently express high levels of Bcl-2 prebound to pro-death 
proteins such as Bim, thus priming these cells for death such that treatment with a BH3 
mimetic like venetoclax will rapidly drive them into apoptosis 
(Del Gaizo Moore et al. 2007; Del Gaizo Moore and Letai 2008).  Nonclinical data in 
non-Hodgkin’s lymphoma (NHL) cell lines support a model analogous to CLL, where 
higher levels of Bcl-2 expression correlate strongly with greater sensitivity to venetoclax
(unpublished data, Abbott Inc.).  CLL and many NHL cells are therefore dependent on 
high levels of Bcl-2 for survival, making them potentially attractive targets for venetoclax.  
Furthermore, this sensitivity to Bcl-2 inhibition may provide the possibility for a 
chemotherapy-sparing option for CLL patients.
1.2.2
Venetoclax
1.2.2.1
Venetoclax Nonclinical Activity and Pharmacokinetic Profile
Venetoclax (synonymous with GDC-0199 and ABT-199 and referred to as venetoclax
throughout the protocol) is a highly selective, orally available small-molecule Bcl-2 family 
protein inhibitor that binds with high affinity (dissociation constant [Ki] 0.10 nM) to Bcl-2 
and with lower affinity to other Bcl-2 family proteins Bcl-XL and Bcl-w (480-fold and 
2000-fold lower affinity than to Bcl-2, respectively).  Overexpression of anti-apoptotic 
Bcl-2 family proteins is associated with resistance to chemotherapy, and antagonism of 
the action of these proteins might overcome resistance and enhance response to 
therapy.  Anti-apoptotic Bcl-2 family members are associated with tumor initiation, 
disease progression, and drug resistance, making them compelling targets for antitumor 
therapy.
In vitro, venetoclax demonstrated broad cell-killing activity against a panel of lymphoma 
and leukemia cells including B-cell FLs, mantle cell lymphomas, diffuse large B-cell 
lymphomas (DLBCLs), and acute myeloid leukemias (AMLs).  Venetoclax was especially 
potent against cell lines expressing high levels of Bcl-2.  Leukemia and lymphoma cell 


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lines bearing the t(14;18) translocation were significantly more sensitive to venetoclax
than were wild-type cell lines.
Venetoclax inhibited subcutaneous murine xenograft growth of human tumor cell lines 
derived from acute lymphoblastic leukemia (ALL) and NHL.
The pharmacokinetic (PK) profile of venetoclax was evaluated in multiple animal species.  
In mice, rats, monkeys, and dogs, low plasma clearance and low volumes of distribution 
characterized the venetoclax PK profile.  Half-lives ranged from 2.2 hours in monkeys to 
12 hours in dogs.  Food had a marked effect on the oral bioavailability in dogs.
Venetoclax demonstrated high protein binding to human, rat, dog, and monkey plasma 
proteins (99.9%).  In rats, venetoclax was widely distributed into liver, kidneys, spleen, 
heart, lungs, small intestine, and white fat, but was poorly distributed in testes, brain, 
muscle, and bone.  Liver metabolism was the major route of elimination with biliary 
excretion of the parent drug playing the secondary role in rats.  Venetoclax showed 
moderate metabolic stability in in vitro hepatic systems across species tested, except for 
low to moderate stability in dog hepatocytes.
In vitro, venetoclax is metabolized by CYP3A4. Thus, co-administration of venetoclax 
with drugs that inhibit CYP3A4 is predicted to cause a significant increase in the 
exposure of venetoclax.  At clinically relevant concentrations for the 400 mg once daily 
(QD) dose regimen, venetoclax and M27 are not predicted to inhibit or induce CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.  Venetoclax is a 
substrate for P-glycoprotein 1 (P-gp) and breast cancer resistance protein (BCRP).  
Active uptake of venetoclax or it’s major human metabolite(M27) was not observed in 
cells overexpressing organic anion transporter protein 1B1 (OATP1B1), organic anion 
transporter protein 1B3 (OATP1B3), or organic cation transporter 1 (OCT1), indicating 
that venetoclax is not a substrate for those transporters in vitro.  Venetoclax is a P-gp, 
BCRP and OATP1B1 inhibitor in vitro.  
M27 are not predicted to inhibit or induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6 or CYP3A4.
See the Venetoclax Investigator’s Brochure for a detailed discussion of the nonclinical 
activity of venetoclax.
1.2.2.2
Venetoclax Nonclinical Toxicology
Venetoclax has been assessed in repeated-dose general toxicology studies and in 
genetic, developmental/reproductive, and safety pharmacology studies.
Repeated-dose oral toxicity studies with venetoclax were conducted in mice and dogs.  
GLP-compliant definitive toxicity studies consisted of IND-enabling studies in mice and 
dogs with 4 weeks of dosing followed by a 4-week (dose-free) recovery period; a 2-week 


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toxicity study in dogs that focused on lymphocyte recovery over an extended (18 weeks) 
recovery period; and chronic toxicity studies in mice (6 months) and dogs (9 months).  
No recovery periods were included in the chronic toxicity studies.  The maximum 
venetoclax plasma exposures (mean AUC0-24 h) achieved in the 4-week studies were 
92 µghr/mL (at 600 mg/kg/day) in mice and 572 µghr/mL (at 150 mg/kg/day) in dogs.  
In the chronic toxicity studies, AUCs reached 34.1 µhh/mL (at 300 mg/kg/day) in mice 
and 85.6 µhh/mL (at 20 mg/kg/day) in dogs.  In addition, repeat-dose toxicity studies 
(with no recovery periods) were conducted in wild-type variants of the Tg.rasH2 mouse 
strain and in Sprague-Dawley rats to select dosages for possible carcinogenicity 
assessments.
The primary toxicities associated with venetoclax administration included effects on the 
hematologic system (decreased lymphocytes and erythrocytes) in mice, rats, and dogs; 
the male dog reproductive system (testicular germ cell depletion); and embryofetal 
toxicity in mice.
Venetoclax produced robust, generally dose-related decreases in lymphocytes in the 
peripheral blood (up to 75% in mice, 64% in rats, and 81% in dogs) and in 
lymphoid tissues.  In dogs, the recovery of lymphocyte counts (total lymphocytes, 
CD4and CD8T cells and mature B cells) was prolonged, requiring up to 18 weeks 
after completion of 2 weeks of dosing.  B cells were the most sensitive lymphocyte 
subtype based on the magnitude of decrease and/or the length of time required for 
recovery (i.e., 25%111% of individual baseline; mean reversal to 54% of baseline 
average).  Tcell subsets reversed more readily and showed more dose-dependence in 
recovery time and extent.  Decreases of lymphocytes in lymphoid tissues were 
reversible in mice and reversible to partially reversible in dogs.  Venetoclax-related
decreases in lymphocytes in blood and lymphoid tissues are considered 
pharmacologically-mediated and non-adverse.
In the 4-week mouse and dog studies, dose-related reversible decreases in RBC mass 
were observed.  Effects on RBC mass were typified by hemoglobin decreases.  At the 
highest dosages administered, decreases in hemoglobin reached 21% in mice at 
600 mg/kg/day and 23% in dogs at 150 mg/kg/day and were considered to be adverse 
based on a criterion of -20% decrease.  In rats, decreases in hemoglobin were more 
severe than in mice and dogs at comparable exposures and reached 30% to 49% at 
150 mg/kg/day.  Hematologic parameters (lymphocyte counts and RBC mass) are 
readily monitored in clinical study subjects.
No effects of venetoclax have been identified in female reproductive tissues in mice or 
dogs in general toxicology studies.  However, in dogs, venetoclax produced adverse, 
non-reversible, non-dose-related microscopic findings of testicular germ cell depletion at 
all dosages tested; there were no testicular effects in mice or rats.  The translatability of 
the testicular findings in dogs to humans is unknown, but this change may be related to 


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venetoclax pharmacology, as one or more members of the Bcl-2 family of proteins play a 
role in spermatogenesis (Olderied et al. 2001; Sugiyama et al. 2001; Yan et al. 2003).
Venetoclax resulted in increased postimplantation loss and decreased fetal body weights 
in the mouse embryofetal development study at the highest dosage administered 
(150 mg/kg/day); the no-observed-adverse-effect level (NOAEL) was defined at the 
mid-dose of 50 mg/kg/day.  Venetoclax was not teratogenic, and there were no other 
effects on development or fertility.
Venetoclax produced loss of hair pigmentation in dogs (reversibility has not been 
assessed).  Evidence from Bcl-2 knockout mouse (Bcl-2 -/-) studies indicates that hair 
hypopigmentation is consistent with the pharmacological effect of Bcl-2 functional loss, 
and occurs due to loss of hair follicle melanocytes dependent on Bcl-2 for survival.  A 
dedicated physical examination of the skin and extensive ophthalmic examinations 
determined that pigmentation of the skin and in the eye (particularly, the iris and fundus) 
of the dog appears unaffected and was confirmed by histopathology.
Other effects of venetoclax included single cell necrosis in various epithelial tissues in 
dogs (i.e., gallbladder, stomach, exocrine pancreas, and epididymides).  These changes 
were minimal except for nondose-dependent, minimal to mild, single-cell necrosis in the 
pylorus of the stomach at 2 mg/kg/day in the 9-month study.  After 4 weeks of dosing 
and a 4-week recovery period, reversibility was observed in the gallbladder and exocrine 
pancreas, but minimal, single-cell necrosis was still present in the epididymides and 
prostate (potentially related to the testicular effects) and in the stomach.  Single-cell 
necrosis was considered not to be adverse due to its minimal-to-mild magnitude and 
because no loss of mucosal integrity was observed microscopically.  
There was no evidence of in vitro or in vivo genetic toxicity of venetoclax.
Venetoclax was tested in a battery of safety pharmacology assays and produced no 
effects in CNS/neurobehavioral or respiratory studies in mice at oral doses up to 
600 mg/kg.  In dogs, mild reductions in cardiac contractility and cardiac output were 
observed at plasma concentrations of 16 µg/mL; these concentrations exceeded the 
concentration of venetoclax in humans (3.39 µg/mL at the 900-mg dose).  No effects on 
blood pressure, heart rate, or ECG parameters were observed in dogs at a maximum 
drug concentration of 46 µg/mL.
See the Venetoclax Investigator’s Brochure for details on the nonclinical studies.
1.2.2.3
Venetoclax Clinical Experience
As of 3 February 2014, 267 patients have received venetoclax either as monotherapy or 
in combination with other agents across different trials for multiple oncology indications.  
Five ongoing studies have enrolled 160 patients with relapsed/refractory CLL/small 
lymphocytic lymphoma (SLL) (95 patients in M12-175, 38 patients in M13-365, 17 


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patients in M13-982, 8 patients in GP28331, and 2 patients in GO28440).  The 
firstin-human venetoclax monotherapy dose-escalation study (Study M12-175) is 
ongoing in patients with relapsed or refractory CLL/SLL and NHL.  Study M13-365 
(venetoclax in combination with rituximab in relapsed/refractory CLL), Study M13-982 
(venetoclax monotherapy in relapsed/refractory CLL harboring 17p deletion), 
Study GP28331 (venetoclax in combination with obinutuzumab), and Study GO28440 
(venetoclax in combination with bendamustine plus rituximab) are also ongoing.  
Preliminary safety, PK, and efficacy data are summarized below on the basis of data 
cutoff dates of 3 February 2014 for safety listings (see the Venetoclax Investigator's 
Brochure for details on clinical studies).  Dose-limiting toxicity (DLT) assessments are 
available for patients enrolled in Study M12-175 (through Cohort 8 with a target 
venetoclax dose of 1200 mg) and in Study M13-365 (through Cohort 5 with a target 
venetoclax dose of 600 mg).
Study M12-175 includes relapsed/refractory CLL/SLL and NHL patients with measurable 
disease, Eastern Cooperative Oncology Group (ECOG) Performance Status 1, and 
adequate marrow function who are enrolled in Arm A (CLL/SLL) or Arm B (NHL).  
Patients receive a single dose of venetoclax on Day 7 followed by continuous QD 
dosing from Day 1 until progressive disease (PD) or unacceptable toxicity.
Study M13-365 includes relapsed/refractory CLL patients with measurable disease, 
ECOG Performance Status 1, and adequate bone marrow function.  Patients received 
venetoclax starting at 50 mg/day and were dose-escalated to the target cohort dose of 
venetoclax over 3 weeks followed by continuous daily dosing of venetoclax at the target 
cohort dose until disease progression.  Rituximab was administered starting on Week 4 
Day 1 at 375 mg/m2 (the dose could be split over Cycle 1 Days 1 and 2 at the discretion 
of the investigator) followed by subsequent administrations of rituximab at 500 mg/m2 on 
Day 1 of Weeks 5, 6, 10, 14, 18, 22, and 26. 
Study M13-982 includes relapsed or refractory CLL patients harboring the 17p deletion.  
The primary objective of this study is to evaluate the efficacy of venetoclax monotherapy 
in patients with relapsed or refractory CLL harboring the 17p13 (TP53 locus) deletion 
(17p deletion).  Efficacy will be measured by OR rate.  The secondary objectives are to 
evaluate the CR, partial response PR, duration of response (DOR), PFS, time to 
progression, overall survival (OS) and percent of patients who move on to stem cell 
transplant.  Patients will receive venetoclax orally QD continuously.  To mitigate the risk 
for TLS, a lead-in period (up to 5 weeks) is employed to evaluate a step-wise dose 
escalation.  Patients start with 20 mg of venetoclax on Week 1 Day 1 and, if no 
significant findings occur, receive 50 mg venetoclax QD for the remainder of Week 1.  
After 1 week at 50 mg, the dose is increased weekly first to 100 mg, then 200 mg, then 
400 mg (or additional lead-in steps to designated 400-mg dose), as tolerated.  A lower 
starting dose and/or modification to the lead-in regimen may be implemented for 
individuals at particularly high risk for TLS.


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Study GP28331 is an open-label, dose-finding and safety study of venetoclax in 
combination with obinutuzumab in relapsed/refractory and previously untreated CLL 
patients.  Venetoclax is administered in escalating doses over 2 to 5 weeks with target 
doses of venetoclax ranging from 100 mg/day to 600 mg/day.  Patients receive 6 cycles 
of obinutuzumab (28-day cycles).  Obinutuzumab infusions occur on Days 1, 2, 8 and 15 
of Cycle 1 and on Day 1 of Cycles 2 to 6.  Following completion of 6 cycles of 
combination therapy, patients will continue on venetoclax as a single agent at the target 
venetoclax dose to which they were assigned until disease progression or end of study 
(whichever occurs first).  Following completion of the dose-finding stage in each patient 
population (relapsed/refractory and previously untreated CLL), a dose and schedule will 
be selected for use in the expansion stage of the study.  The expansion stage for each 
patient population will have at least 14 patients.
Study GO28440 is an open-label, dose-finding and safety study of venetoclax in 
combination with BR in relapsed/refractory and previously untreated patients with CLL.  
Venetoclax is administered in escalating doses over 2 to 5 weeks with target doses of 
venetoclax ranging from 100 mg/day to 600 mg/day.  Rituximab is administered IV once 
every 28-day cycle for up to 6 cycles.  The initial dose is 375 mg/m2 in Cycle 1, followed 
by 500 mg/m2 in Cycles 2 to 6.  Bendamustine is administered IV at 70 mg/m2 for 2 
consecutive days of each 28-day cycle for 6 cycles in patients with relapsed/refractory 
CLL, and at 90 mg/m2 in previously untreated patients with CLL.  Following completion of 
6 cycles of combination therapy, patients will continue on venetoclax as a single agent at 
the target venetoclax dose to which they were assigned until disease progression or end 
of study (whichever occurs first). Following completion of the dose-finding stage in each 
patient population (relapsed/refractory and previously untreated CLL), a dose and 
schedule will be selected for use in the expansion stage of the study.  The expansion 
stage for each patient population will have at least 14 patients.
See the Venetoclax Investigator’s Brochure for more details on these and additional 
studies.
1.2.2.3.1
Preliminary Safety Data Summary
This section summarizes safety events observed in patients with relapsed/refractory 
CLL/SLL enrolled in Studies M12-175, M13-365, M13-982, GP28331, and GO28440.  
See the Venetoclax Investigator’s Brochure for details.  A detailed description of 
laboratory and clinical tumor lysis syndrome (TLS) events is presented in 
Section 1.2.2.3.2.
Data on venetoclax and human pregnancy or venetoclax and drug abuse/drug 
dependency are not available.


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Study M12-175
Preliminary safety data as of 3 February 2014 for 95 patients with CLL/SLL enrolled in 
Study M12-175 study are summarized below.  The data include patients treated at 
dose-escalation cohorts with target doses from 50 to 1200 mg of venetoclax.
The most common adverse events, occurring in 10% of patients, were diarrhea 
(38.9%), neutropenia (37.9%), nausea (34.7%), upper respiratory tract infection (30.5%), 
fatigue (27.4%), and cough (20%).  The most common Grade 3 and above adverse 
events were neutropenia (34.7%) and anemia (10.5%).  The most frequently reported 
(10%) adverse events considered possibly or probably related to venetoclax include
neutropenia (34.7%), nausea (22.1%), diarrhea (24.2%), and fatigue (15.8%). 
Serious adverse events were reported in 36 patients (37.9%).  Those reported in more 
than 2 patients were febrile neutropenia (5.3%), autoimmune thrombocytopenia (3.2%), 
and TLS (3.2%).  One serious adverse event resulted in death:  a patient with an 
ongoing event of TLS experienced sudden death (see Section 1.2.2.3.2 for details).
A total of 6 patients (6.3%) experienced adverse events that led to death:  malignant 
neoplasm progression (2), multi-organ failure (1), sudden death (1), small intestinal 
obstruction (1), and mental status changes (1).
A total of 11 patients (11.6%) experienced adverse events that led to study 
discontinuation.  These adverse events included:  thrombocytopenia, general physical 
health deterioration, sudden death, multi-organ failure, mental status change, 
esophageal adenocarcinoma, and diarrhea/vomiting.
In addition, Richter’s transformation had been noted at the time of disease progression 
for 14 (14.7%) patients with CLL.  
See the Venetoclax Investigator’s Brochure for more details on these patients. 
Study M13-982
In study M13-982, 15 out of the 17 patients enrolled (88.2%) reported 
treatment-emergent adverse events.  The most common adverse events were nausea 
(35.3%) and neutropenia and fatigue (23.5% each).  Seven (41.2%) patients 
experienced adverse events Grade 3 or above.  The most common adverse events 
Grade 3 and above were anemia and neutropenia (17.6% each) and thrombocytopenia 
and lymphocyte count decreased (11.8% each).  Seven patients (41.2%) experienced 
serious adverse events.  Serious adverse events of anemia, febrile neutropenia, and 
abdominal pain upper were considered to have a reasonable possibility of being related 
to venetoclax.  No patients experienced adverse events that resulted in venetoclax
discontinuation or death.


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Study M13-365
As of 3 February 2014, preliminary safety results are available for 38 patients enrolled in 
Study M13-365.  Six patients were enrolled in Cohort 1 (designated venetoclax cohort 
dose of 200 mg), 10 patients were enrolled in Cohort 2 (designated venetoclax cohort 
dose of 300 mg), 7 patients were enrolled in each of Cohorts 3, 4, and 5 (designated 
venetoclax cohort doses of 400, 500, and 600 mg, respectively).  Most patients (94.7%) 
reported at least one treatment-emergent adverse event.  The most common adverse 
events were neutropenia (50%), nausea (42.1%), diarrhea and headache (28.9% each), 
cough (26.3%), and thrombocytopenia, fatigue, pyrexia, and upper respiratory tract 
infection (23.7% each).  
Twenty-seven patients (71.1%) were reported to have Grade 3 adverse events.  The 
most commonly reported Grade 3 adverse events occurring in more than 2 patients 
were neutropenia (50%), thrombocytopenia (18.4%), and anemia (10.5%).  Serious 
adverse events were reported in 14 patients (36.8%).  TLS was reported in 2 patients 
(5.3%), and each of the following events was reported in 1 patient (2.6%) each:  febrile 
neutropenia, histiocytosis hematophagic, lower gastrointestinal hemorrhage, non-cardiac 
chest pain, pyrexia, bronchitis bacterial, influenza, lung infection, pneumonia hemophilus, 
rotavirus infection, infusion-related reaction (IRR), hyperkalemia, lymphoma 
transformation, Richter's syndrome, and pulmonary mass.  Both events of TLS and 
individual events of bronchitis bacterial, pneumonia hemophilus, rotavirus infection, and 
hyperkalemia were considered to have a reasonable possibility of being related to 
venetoclax.
As described above, 1 patient experienced a serious adverse event of hyperkalemia in a 
setting of TLS that resulted in study discontinuation and death (see Section 1.2.2.3.2).  
Two additional patients experienced adverse events that resulted in discontinuation of 
venetoclax (lymphoma transformation and Richter’s syndrome).  
See the Venetoclax Investigator’s Brochure for more details on these patients.
Study GP28331
In Study GP28331, 5 of the 8 patients who received venetoclax reported 
treatment-emergent adverse events.  In this study, the most commonly reported adverse 
events related to venetoclax were diarrhea and IRR (in 3 patients each; 37.5%) and 
hyperphosphatemia, anemia, flatulence, pollakiuria, and fatigue (in 2 patients each; 
25.0%).  Hyperphosphatemia was reported as a serious event in the setting of laboratory 
TLS that occurred after the third dose of venetoclax in a patient who had not received 
obinutuzumab.  The event resolved with IV hydration and discontinuation of study 
therapy.


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Study GO28440 
Two patients have been enrolled in the study and had data available.  Study enrollment 
is continuing.  No treatment-emergent adverse events have been reported in the 
2 enrolled patients.
See the Venetoclax Investigator’s Brochure for more details on these studies.
1.2.2.3.2
Summary of TLS Events in CLL Patients with Venetoclax
In Study M12-175, substantial antitumor activity was observed in the first 3 patients with 
CLL following a single dose of venetoclax of 100200 mg.  Within 24 hours, dramatic 
reductions in lymphocyte count (95%) were observed in the 2 patients with 
pretreatment lymphocytosis, and laboratory TLS developed in all 3 patients (per 
Cairo-Bishop Criteria [see Cairo and Bishop 2004]; see the Venetoclax Investigator’s 
Brochure for details regarding these patients).  The TLS resolved without clinical 
complications in all 3 patients, and the patients were able to commence daily dosing of 
venetoclax at reduced doses (50100 mg) within 7 days and later escalated to the target 
cohort dose of 200 mg.
Subsequently, changes to the venetoclax dose and schedule were implemented to 
obtain a more gradual tumor response and reduce the risk of TLS.  The initial venetoclax
dose was reduced to 50 mg (with the option of administering doses less than 50 mg in 
patients with bulky disease and lymphocytosis), and 23 weekly escalation steps were 
introduced to reach the final cohort dose.  Intensified monitoring and standard TLS 
prophylaxis measures including hydration and treatment to prevent hyperuricemia have 
been mandated in all patients.  In the subsequent seven cohorts, 53 patients with 
CLL/SLL were enrolled.  In Cohort 2, 1 of 6 patients showed only laboratory (chemical) 
changes in potassium and phosphate.  The electrolyte changes were not considered 
clinically significant, and the patient received venetoclax without delay or dose reduction 
and without clinical sequelae.  In Cohort 4, a serious adverse event of clinical TLS 
(considered related to venetoclax) was reported after the initial dose of 50 mg 
venetoclax.  The patient, a 
-year-old female with bulky abdominal lymphadenopathy, 
had marked laboratory changes consistent with laboratory TLS after the first dose of 
50 mg venetoclax.  She did not receive protocol-mandated TLS prophylaxis.  The patient 
underwent cardiac catheterization for suspected cardiac ischemia as a result of ECG 
changes induced by hyperkalemia.  Subsequently, she developed acute renal failure 
requiring dialysis, in which the contrast dye likely contributed to the acute renal failure.
In 
, two fatal adverse events in the setting of TLS were reported.  The 
first death occurred in Study M13-365 within 24 hours after the patient received a first 
dose of 50 mg venetoclax.  This patient had not yet received a dose of rituximab.  The 
second death occurred in a patient in Study M12-175 after escalation to the 1200 mg 
venetoclax dose.  The patient received 50 mg venetoclax for 7 days and 150 mg for the 
next 7 days, and then the dose was escalated to 1200 mg.  After the first dose of 
1200 mg, elevated laboratory values consistent with laboratory TLS as well as an 


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increase in creatinine were observed.  The patient received a second dose of 1200 mg 
venetoclax the following day, and subsequently that night the patient was found dead at 
home.  No autopsy was performed and the cause of death cannot be confirmed.
Following the two fatal events in 
, the dose of venetoclax was reduced in 
all active patients to 600 mg or less.  Overall, six DLTs of TLS and two DLTs of fatalities 
in the setting of TLS were reported in the venetoclax clinical program (Arm A of 
Study M12-175 and Study M13-365).  Details of these events are provided in the 
Venetoclax Investigator’s Brochure.  Based on data of 77 CLL/SLL patients treated in 
the program up to that point, protocol amendments were then implemented in patients 
with CLL/SLL to include:

Modified venetoclax dosing regimens (i.e., a reduction in the starting dose to 20 mg, 
implementation of a more gradual 5-step dose ramp-up of 20, 50, 100, and 200 mg 
up to the final dose) and with a maximum dose of 600 mg allowed. 

Guidance regarding identification of TLS risk categories:
TLS low-risk:  All measurable lymph nodes with the largest diameter 5 cm 
AND 25 109/L absolute lymphocyte count (ALC) 
TLS medium-risk:  Any measurable lymph node with the largest diameter 
5 cm and 10 cm OR 25109/L ALC
TLS high-risk:  Any measurable lymph node with the largest diameter 10 cm 
OR 25109/L ALC AND any measurable lymph node with the largest diameter 
≥5 cm but 10 cm

Enhanced TLS prophylaxis and monitoring measures 
Clinical hold was released in May 2013 and all studies globally were able to fully resume 
as of that time with new TLS measures in place.
The safety profile of venetoclax with regard to TLS has now been further characterized 
in 58 patients with relapsed/refractory CLL/SLL treated with venetoclax and who 
completed the monotherapy ramp-up period with the above TLS measures in place (data 
cutoff date 17 January 2014).  
There was a marked reduction in severity and frequency of TLS per Cairo-Bishop 
(Cairo and Bishop 2004) and Howard definitions (Howard et al. 2011) in the analysis for 
these 58 patients with CLL/SLL who received venetoclax using the mentioned TLS 
prophylaxis and monitoring measures as compared with the findings in the 77 patients 
with CLL/SLL in the previous analysis.
None of the 58 patients experienced any serious (including fatal) or nonserious event of 
clinical TLS (CTLS) or laboratory TLS (LTLS) or had study treatment discontinued 
because of TLS.  Eight patients (13.8%) were determined to have LTLS (per 
Cairo-Bishop definition) after medical adjudication:  none in 13 low-risk patients, 5 in 


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19 medium-risk patients (26.3%), and 3 in 26 high-risk patients (11.5%).  Three of the 
8 patients had a nonserious Grade 1 adverse event related to an electrolyte change; no 
adverse event was reported in the other 5 patients.  One additional high-risk patient had 
a serious adverse Grade 2 event of cytokine release syndrome considered to be in the 
TLS setting with no electrolyte changes.  These findings differ from those in the previous 
analysis (N 77) where 3 high-risk patients (3.9%) experienced CTLS and 16 patients 
(20.8%) experienced LTLS (6 in 27 medium-risk patients [22.2%] and 10 in 25 high-risk 
patients [40.0%]).  When using the Howard definition for TLS (Howard et al. 2011), 
which requires both electrolyte changes to be outside the Cairo-Bishop thresholds, none 
of the 58 patients experienced CTLS or LTLS, whereas 3 (3.9%) and 7 (9.1%) patients 
experienced CTLS and LTLS, respectively, among the 77 patients with CLL/SLL in the 
previous analysis. 
Moreover, consistent with the previous analysis, the risk of TLS with venetoclax in 
patients with CLL/SLL is characterized as highest when initiating venetoclax dosing and 
with a higher initial dose of venetoclax as well as higher in patients with a large tumor 
burden.
In addition, there were no adverse events of TLS identified in the period after completion 
of the ramp-up when patients received venetoclax monotherapy at the target dose or 
were dosed with combination agents in all ongoing clinical studies evaluating venetoclax
in patients with CLL/SLL.
On the basis of the recent analysis, further modifications to the TLS prophylaxis 
measures for patients with CLL are done in this protocol amendment (see 
Section 4.4.1.2).
More details of TLS events associated with venetoclax are provided in the Venetoclax
Investigator’s Brochure.
1.2.2.3.3
Preliminary Activity in CLL/SLL Patients
Study M12-175
Preliminary efficacy data for the patients in the CLL/SLL arm of Study M12-175 are 
available as of 17 January 2014.  A total of 93 patients were enrolled, with a median time 
on study of 6.1 months (range:  027 months).  Twenty-three patients (24%) had CLL 
with 17p13 (TP53 locus) deletion (17p deletion), 55 subjects (59%) had 
fludarabine-refractory CLL, and 32 of the 42 patients with available status had 
unmutated IGHV.  The median number of prior therapies was 4 (range:  111).
Seventy patients were evaluable for overall response based on the 2008 updated 
International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.  The OR rate
(complete response [CR]/CR with incomplete bone marrow recovery [CRi] PR) was 
76% (53 of 70 evaluable patients), with CR/CRi in 14 patients (20%) and PR in 
39 patients (56%).  This included 17 of 23 patients with unmutated IGHV (74% OR rate, 


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with 4 CR/CRi), 15 of 21 patients with 17p deletion (71% OR rate, with 3 CR/CRi), and 
29 of 39 patients with fludarabine-refractory CLL (74% OR rate, 6 CR/CRi).
The median DOR was 20.5 months [95% CI; 13.8, -] for the 53 responding patients.  At 
12 months, 91% of patients with CR and 67% of patients with PR remained progression-
free.  Of the 14 subjects with CR/CRi, 9 were evaluated in local laboratories by flow 
cytometry for minimal residual disease (MRD); 5 were MRD negative and of these, 
2 were IGHV unmutated, 4 were fludarabine-refractory, and 1 had 17p deletion.
Study M13-365
Preliminary efficacy data for Study M13-365 are available as of 17 January 2014.  A total 
of 37 patients were enrolled, with a median time on study of 4.8 months (range:  0 to 
15.2 months).  Nine patients (24%) had 17p deletion, 9 patients (24%) had fludarabine-
refractory CLL, and 9 (24%) had rituximab-refractory CLL.  The median number of prior 
therapies was 2 (range:  1 to 5).  A total of 18 patients who completed combination 
therapy or discontinued prior to completion were evaluable for OR rate.  The OR rate 
(CR/CRiPR) was 78% (14 of 18 patients), with 7 (39%) patients achieving CR/CRi and 
7 (39%) achieving PR.  MRD was evaluated by local laboratory in 6 of 7 subjects with 
CR; 4 patients were MRD negative in the bone marrow.  Of the 19 patients yet to 
complete combination therapy, 4 had confirmed PR, 9 have unconfirmed PR, and 6 were 
not yet evaluable for response.
1.2.2.4
Clinical Pharmacokinetics and Pharmacodynamics
Preliminary PK results are available from 53 patients with relapsed/refractory CLL/SLL 
from Study M12-175.  The plasma concentrationtime profiles of venetoclax in CLL/SLL 
patients are presented in Figure 1 following multiple doses of venetoclax at Day 7 
(single dose) and Week 6 Day 1.




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CLL cells collected 68 hours after initial dosing of venetoclax show increased 
Annexin-BB staining and caspase-3 activation (Roberts et al. 2012), consistent with a 
mechanism of action based on Bcl-2 inhibition.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Despite the progress made in the treatment of patients with CLL, a significant number of 
patients experience relapsed disease that is associated with progressively shorter 
durations of response to therapy.  Patients with disease that is refractory to upfront 
treatment are at a similar disadvantage.  The only potentially curative strategy for CLL is 
an allogeneic hematopoietic stem cell transplantation for which the majority of patients 
with CLL are not eligible secondary to age or comorbid conditions.  Improved treatment 
options are therefore critically important for this population.
Rituximab has been shown to be an effective treatment for low-grade, CD20-positive 
B-cell malignancies and is commonly used both as a single agent and in combination 
with cytotoxic chemotherapy.  Rituximab is a chimeric murine/human monoclonal 
antibody that binds to CD20, a hydrophobic, transmembrane protein that is present on 
the cell surface of preB lymphocytes and mature B lymphocytes but not on 
hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissue.  In 
particular, CD20 is present on malignant B lymphocytes in the majority of patients with 
mature B-cell lymphomas and leukemias.  The binding of rituximab to CD20 on 
B lymphocytes eliminates these cells via a number of different possible mechanisms, 
including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent 
cytotoxicity (CDC), and induction of apoptosis (Maloney et al. 2002).
Single-agent activity of rituximab with the use of a standard NHL dose has been 
marginal in CLL patients (Nguyen et al. 1999).  However, in the past decade, more 
intensive doses and schedules of rituximab have been explored and demonstrated a 
good safety profile and significant activity in CLL (Byrd 2003; Hainsworth et al. 2003; 
Ferrajoli et al. 2011).
Studies in Bcell CLL patients treated with rituximab have shown a correlation with 
caspase activation and the depletion of Blymphocytes, linking efficacy of this agent to 
activation of the intrinsic apoptotic pathway (Byrd et al. 2002).  In vitro, 
rituximab-resistant lymphoma clones have recently been shown to up-regulate 
pro-survival Bcl-2 family members relative to wild-type cells and to exhibit a higher 
degree of resistance to numerous chemotherapeutic agents.  Cutaneous Bcell 
lymphoma samples obtained after clinical relapse from rituximab treatment also 
exhibited a strong up-regulation of Bcl-2 compared with those before therapy, potentially 
linking anti-apoptotic Bcl-2 proteins to therapy resistance (Wobser et al. 2007).  These 
data suggest that by lowering the apoptotic threshold, a Bcl-2 antagonist may act 
synergistically with rituximab in a variety of settings.


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Venetoclax inhibits subcutaneous xenograft growth of human tumor cell lines derived 
from ALL and NHL and is highly efficacious with use of various doses and regimens.  
Venetoclax enhanced the activity of a broad variety of chemotherapeutic agents 
(e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]; BR; and 
bortezomib) in other human hematological models (see the Venetoclax Investigator’s 
Brochure).
In a xenograft model of NHL (DoHH-2), venetoclax dosed as monotherapy caused 
significant tumor growth delay compared with the vehicle.  Combining rituximab with 
venetoclax resulted in significantly (p0.001) improved tumor inhibition compared with 
venetoclax dosed as monotherapy (Genentech Report No. 10/974).
The unique mechanism of action of venetoclax suggests that it may represent a novel 
approach to targeting CLL.  To date, the efficacy data from the single-agent Phase I 
dose-escalation Study M12-175 suggest that the majority of patients respond to 
treatment with venetoclax.  Furthermore, combining venetoclax with rituximab in a 
chemotherapy-free regimen may be a more tolerable therapy for this generally older 
population.
Because TLS is a special concern in patients treated with venetoclax, intense monitoring 
requirements (including hospitalizations and frequent laboratory assessments) have 
been incorporated into this protocol; see Section 4.4.1.2 (which includes a description of 
patients at low, medium, and high risk for developing TLS following treatment with 
venetoclax), as well as Appendix 1 and Appendix 11 for monitoring guidelines.
Details regarding the safety monitoring plan for other potential risks associated with 
venetoclax are described in Section 5.  Although the clinical experience with venetoclax
in humans is limited, the safety data available to date suggest that toxicity with repeated 
dosing is acceptable.
Bendamustine and rituximab were selected as the comparator arm for this study 
because they are considered an efficacious regimen for relapsed CLL, as described in a 
Phase II trial of relapsed/refractory patients; specifically, patients were treated with 
therapies as disparate as single-agent chemotherapy and multi-agent 
chemoimmunotherapy (Fischer et al. 2011).  There is no uniform opinion on treatment of 
relapsed/refractory CLL; however, BR is considered a reasonable option per the 
National Comprehensive Cancer Network (NCCN) guidelines, the European Society for 
Medical Oncology (ESMO) guidelines (Appendix 8), and a recent international 
consensus statement (Cheson et al. 2010).  The limitations of BR include the toxicities of 
myelosuppression and infections (Fischer et al. 2011).
Since relapsed/refractory CLL represents an incurable disease for the majority of 
patients, there exists a need to introduce new agents that may improve clinical outcomes.  
The mechanism of action of venetoclax along with the available nonclinical and Phase I 


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data suggest that venetoclax may represent a more effective treatment option than 
current standard regimens.  A treatment regimen that is demonstrated in a Phase III 
setting to provide a clinically meaningful increase in PFS with similar or reduced toxicity 
compared with BR would be considered by investigators to provide a clinically beneficial 
option for patients.  The precautionary safety measures including the enhanced TLS risk 
mitigation processes in place and regular monitoring of safety in the study by an 
independent Data Monitoring Committee (iDMC) and by the Sponsors enables early 
identification of safety signals and minimizes the risk to patients enrolled.  In conclusion, 
it is considered that the potential for benefit-risk ratio for this study is favorable.
2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of venetoclax and rituximab (venetoclaxR) compared with 
BR in patients with relapsed or refractory CLL as measured by 
investigator-assessed PFS
The secondary efficacy objectives for this study are as follows:

To analyze Independent Review Committee (IRC)assessed PFS in the subset of 
patients with CLL with 17p deletion identified by fluorescence in situ hybridization 
(FISH) testing performed at a central laboratory

To evaluate PFS as assessed by an IRC

To analyze investigator-assessed PFS in the subset of CLL patients with 
17p deletion identified by FISH testing performed at a central laboratory

To evaluate rate of best OR (defined as CR, CRi, nodular partial response [nPR], 
and PR), as assessed by the investigator

To evaluate OR rate, CR, CRi, nPR, and PR) at end of combination treatment 
response visit, as assessed by the investigator

To evaluate OR, CR, CRi, nPR, and PR rates at end of combination treatment 
response visit, as assessed by the IRC

To evaluate OS

To evaluate event-free survival (EFS)

To evaluate DOR for patients with a best OR of CR, CRi, nPR, or PR

To evaluate time to next anti-CLL treatment (TTNT)

To evaluate the proportion of patients with MRD negativity at the disease response 
assessment timepoints


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2.2
SAFETY OBJECTIVE
The safety objective for this study is as follows:

To evaluate the safety of venetoclax and rituximab compared with BR in patients 
with relapsed or refractory CLL, focusing on serious adverse events, National 
Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 
(NCI CTCAE, v4.0) Grade 3 adverse events, and Grade 3 laboratory toxicities
2.3
PHARMACODYNAMIC OBJECTIVE
The pharmacodynamic objective for this study is to assess changes in lymphocyte 
subset counts during the study (e.g., T and B cells).
2.4
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the pharmacokinetics of venetoclax in
patients with relapsed or refractory CLL.
2.5
PATIENT-REPORTED OUTCOME OBJECTIVES
The patient-reported outcome (PRO) objectives for this study are as follows:

To compare treatment-related symptoms following treatment with venetoclax and
rituximab compared with BR in patients with relapsed or refractory CLL, as 
measured by M. D. Anderson Symptom Inventory (MDASI) and European 
Organisation for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire Core 30 (QLQ-C30) and associated CLL module (QLQ-CLL16)

To evaluate changes from baseline CLL symptoms scores with use of MDASI and 
EORTC QLQ-C30 and QLQ-CLL16 questionnaires

To evaluate time to disease-related symptom progression with use of EORTC 
QLQ-CLL16 health-related quality of life (HRQoL) with use of global health 
status/quality of life (QOL) and other functional subscales of QLQ-C30

To assess interference of treatment and disease-related symptoms on QOL with 
use of the MDASI questionnaire
2.6
HEALTH ECONOMIC OBJECTIVE
The health economic objective for the study is to compare the health economic effects of 
venetoclax in combination with rituximab versus BR in patients with relapsed or 
refractory CLL.  The EuroQol 5 Dimension (EQ-5D) questionnaire 
(Rabin and deCharro 2001) will be used to support health economic/pharmacoeconomic 
analyses and will be analyzed post hoc.
2.7
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To evaluate the relationship between efficacy outcome and potential biomarkers, 
including Bcl-2 expression, for patients treated with venetoclax and rituximab 
compared with BR


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
To evaluate potential biomarkers that are prognostic and/or predictive of response 
and resistance to treatment with venetoclax and rituximab or with BR

To evaluate rate of best OR (defined as CR, CRi, nPR, and PR) of next anti-CLL 
treatment, as assessed by the investigator
Patients receiving venetoclax R as the next anti-CLL treatment in the 
Re-Treatment/Crossover (R/C) Substudy will be analyzed separately.
2.8
RE-TREATMENT/CROSSOVER SUBSTUDY OBJECTIVES
The efficacy objectives for the R/C Substudy are as follows:

OR, CR, CRi, nPR, and PR rates at the End of Combination Treatment Response 
in the Re-Treatment/Crossover Study (EOCTR-R/C) Visit as assessed by the 
investigator

OS, defined as the time from first treatment exposure in the R/C Substudy to death 
from any cause

MRD response rate as measured at a central laboratory on peripheral blood samples 
and bone marrow aspirate samples at each sampling timepoint as well as Best MRD 
negativity in the R/C Substudy
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is an open-label, international, multicenter, randomized, Phase III study to 
investigate the efficacy and safety of venetoclax in combination with rituximab 
(venetoclaxR) compared with bendamustine in combination with rituximab (BR) in 
patients with relapsed or refractory CLL.
Approximately 370 patients will be recruited from approximately 150 centers in up to 
29 countries and randomly assigned in 1:1 ratio to receive either venetoclaxR (Arm A) 
or BR (Arm B).  Randomization will be stratified according to the following factors:

17p deletion:  yes or no

Risk status:  high risk or low risk
High risk:  defined as harboring 17p deletion or no response to front-line 
chemotherapy-containing regimen or relapsed within 12 months after 
chemotherapy or within 24 months after chemoimmunotherapy
Low risk:  defined as relapse more than 12 months after chemotherapy or 
24 months after chemotherapy or chemoimmunotherapy

Geographic region:  United States/Canada, Australia/New Zealand, Western Europe, 
Central and Eastern Europe, Asia, or Latin America
Patients randomized to Arm A (venetoclaxR) (see Figure 2) will have a 5-week 
venetoclax dose ramp-up period to reach the target dose of 400 mg daily.  Following the 
venetoclax ramp-up period, patients will receive 6 cycles of rituximab consisting of a 


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single infusion on the first day of each 28-day cycle.  Patients will continue to take their 
daily dose of venetoclax during the rituximab cycles.  Patients who have not progressed 
following the completion of the 6 cycles will continue to receive venetoclax until disease 
progression or for a maximum of 2 years from Cycle 1 Day 1.
Patients randomized to Arm B (BR) (see Figure 2) will receive 6 cycles of BR consisting 
of a single infusion of rituximab on Day 1 and bendamustine infusions on Days 1 and 2 
of each 28-day cycle.
Figure 2
Study Schema
randomized 1:1
Observation to PD or end 
of study
Venetoclax 400 mg PO QD 
to PD or 2 years from start 
of combination therapy 
(Cycle 1, Day 1); 
then observation to PD
Arm A: Venetoclax + R (N=185)
Venetoclax: 400 mg PO (QD Cycles 1-6) 
(5 week dose ramp-up period prior to Cycle 1)*
Rituximab: 375 mg/m2 (Day 1, Cycle 1) 
500 mg/m2 (Day 1, Cycles 2-6)
370 patients 
with relapsed/
refractory CLL
Arm B: BR (N=185)
Bendamustine: 70 mg/m2 (Day 1 and 2, Cycles 1-6)
Rituximab: 375 mg/m2 (Day 1, Cycle 1) 
500 mg/m2 (Day 1, Cycles 2-6)
Follow up 
for OS
Arm Avenetoclax and rituximab (venetoclax R); Arm Bbendamustine and rituximab (BR); 
1 cycle28 days; CLLchronic lymphocytic leukemia; OSoverall survival; PDprogressive 
disease; PO per os, orally; QDonce daily.
* Patients will receive venetoclax starting on Day 1 (venetoclax dose ramp-up period) as 
delineated in Section 4.3.2.1.1. Venetoclax will then be self-administered at 400 mg per day for 
a maximum of 2 years from Cycle 1 Day 1 or until disease progression (whichever occurs first).  
Combination therapy consisting of 6 cycles of rituximab and daily venetoclax dosing will start 
after completion of the venetoclax ramp-up period.
All patients will have baseline tumor assessment and will be assessed for response to 
treatment by the investigator using standard clinical and laboratory examinations and 
computed tomography (CT) scans according to iwCLL guidelines (Hallek et al. 2008) at 
the following timepoints (selected to mirror those used in current Phase III CLL protocols 
[CLL10, CLL11]):

Clinical response assessment only on Day 1 of every cycle of combination therapy

Full response assessment, including CT scans, at interim response assessment
(within 14 days of Cycle 4 Day 1)

Clinical response assessment only at completion of combination therapy 
(4 weeks 7 days after Day 1 of the last cycle of venetoclax+R [Arm A] or BR 
[Arm B] or Day 1 of the last treatment cycle in case of early termination)


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
Full response assessment, including CT scans, at 812 weeks after combination 
therapy (defined as 812 weeks after Day 1 of Cycle 6 or 812 weeks after Day 1 of 
the last cycle for early termination)
Following 6 cycles of combination therapy, patients in both arms will be followed 
clinically every 3 months through Year 3 from initiation of combination therapy (Cycle 1 
Day 1).  Patients will then be followed every 6 months until PD, study withdrawal, or 
end of study, whichever occurs first.  At each follow-up visit, patients will be assessed 
for response/progression by clinical assessment only.  After PD, patients will enter 
survival follow-up and be followed for OS. Information on new anti-CLL therapy will 
also be collected at survival follow-up.  This survival follow-up may be conducted by 
telephone.  If eligible, patients randomized to either Arm A or Arm B who have PD, are 
in need of therapy (per iwCLL), and have not received new anti-CLL therapy have the 
option to enter the R/C Substudy with venetoclax R (see Section 3.1.3).
At any time during the study when clinical or laboratory findings suggest that the 
response may have improved from stable disease (SD) to PR or from PR to CR, imaging
should be performed to confirm the response.  Sites are allowed to do imaging any 
time during the treatment period to confirm a CR.  Imaging is not routinely required to 
determine PD because objective evidence of PD is most often documented by 
measurement of elevated peripheral CLL cells.  However, when PD cannot be 
documented by increasing peripheral blood lymphocyte count, imaging is required 
to document PD detected by physical examination or suspected on the basis of 
symptoms.  A bone marrow biopsy may also be conducted at any time during the study 
to confirm a CR.
A bone marrow aspirate should be obtained for MRD assessment in the bone marrow 
in all responders (CRPR) at the End of Combination Treatment Response Visit.  In 
addition, MRD samples in peripheral blood are collected at baseline, within 14 days 
of C4D1 (interim assessment), completion of combination therapy/early treatment
termination visit (if applicable), End of Combination Treatment Response Visit, and 
at the timepoints specified in Appendix 1 during the follow-up or at any visit during 
follow-up where a patient has a response (PR or CR status).  Samples will be measured 
at a central laboratory.
After disease progression during the follow-up period, patients will be followed for OS 
and new anti-CLL therapy every 24 weeks until end of study.  This follow-up may be 
conducted by telephone.
Patients who receive a new anti-CLL therapy any time during follow-up in the absence of 
PD will be followed on the same schedule of assessment (see Appendix 1) for PD and 
then for OS.


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Patients who discontinue all components of study therapy either prior to completion of 
planned therapy or prior to disease progression (e.g., for toxicity) will continue to be 
followed for MRD levels, PD, and OS (regardless of whether they subsequently receive 
new anti-CLL therapy).
An independent review of the responses of all patients will also be conducted to confirm 
the primary PFS endpoint, including blinded review of clinical and laboratory findings as 
well as blinded radiology review of imaging assessments (see Section 3.1.2).
Re-Treatment /Crossover Substudy (Optional at Investigator’s 
Discretion)
If eligible, patients in either Arm A or Arm B who have progressed clinically, are in 
need of therapy (per iwCLL) and have not received new anti-CLL therapy have the 
option to enter the R/C Substudy:

Patients randomized to Arm A (venetoclax R) may receive re-treatment with 
venetoclax R.

Patients randomized to Arm B (BR) may cross over from the BR arm to receive 
venetoclax R treatment. 
See Section 3.1.3 for details.
Safety will be evaluated by monitoring the nature/frequency/severity of serious adverse 
events and non-serious adverse events, premature study withdrawals, deaths, effects on 
laboratory parameters, vital signs, physical examination, venetoclax dose delays, or 
effects on other safety biomarkers.  Adverse events will be graded using NCI CTCAE, 
v4.0 (see Section 5.3.3).  Laboratory safety assessments will include regular monitoring 
of hematology, blood chemistry, and tests of immunologic parameters.
QOL will be assessed using the MDASI, EORTC QLQ-C30, and CLL-16 module scoring 
manuals (see Appendix 3, Appendix 4, and Appendix 5).
A schedule of assessments is provided in Appendix 1.
3.1.1
Independent Review Committee
An IRC composed of board-certified radiologists and board-certified oncologists with 
experience in CLL will assess in a blinded manner all patients for response and 
progression on the basis of imaging results, bone marrow biopsy results, and relevant 
clinical data, guided by a charter specific to the independent review.
3.1.2
Independent Data Monitoring Committee
This trial includes an iDMC for review of safety and efficacy data collected during the 
study.  Reviews by the iDMC will be conducted according to a charter written and 
approved prior to study initiation.  Members of the iDMC will be external to the Sponsors 
and the study team and will follow a charter that outlines their roles and responsibilities.  


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An independent Data Coordinating Center (iDCC) that is independent of the Sponsors 
will prepare analyses for review.
At the beginning of the study, intensive monitoring and analysis of all clinically significant 
safety events will be performed.  The iDMC will assemble to review a safety analysis of 
significant safety events approximately 1 month after the first patient is enrolled 
depending on the rate of initial patient enrollment, then approximately every 2 months 
until 40 patients have completed 2 cycles of treatment (with approximately 20 patients in 
each arm).  Thereafter, the iDMC will meet approximately every 6 months and 
subsequently at a frequency determined by the iDMC and the Sponsors according to the 
emerging safety profile.  In addition, either the Sponsors or the iDMC can request ad hoc 
iDMC meetings at any time that potential safety concerns arise.  The iDMC will evaluate 
efficacy and safety at one formal interim analysis.
3.1.3
Re-Treatment/Crossover Substudy (Optional at Investigator's 
Discretion)
This is a R/C Substudy to the main GO28667 study that allows treatment with 
venetoclax R in patients who have progressed clinically regardless of treatment arm
are in need of therapy (per iwCLL). Participation is at the discretion of the investigator
and optional; therefore, new written informed consent must be obtained for 
participation in the R/C Substudy before performing any specific tests or evaluations 
for re-treatment or crossover.  Refusal to participate in the R/C Substudy will not affect 
a patient’s ongoing participation in the follow-up phases in the Study GO28667 as 
described in Section 3.1.
Approximately 30 patients from Arm A and 30 patients from Arm B who have 
progressed clinically, are in need of therapy (per iwCLL), and have not received new 
anti-CLL therapy may be treated with venetoclax R in the R/C Substudy.  The 
enrollment period will be approximately 21 months after the enrollment of the first 
patient in the R/C Substudy.
An R/C Substudy Screening (Screening-R/C) evaluation should be performed within 
28 days prior to study treatment initiation to confirm that patients meet all eligibility 
criteria.  Results of standard-of-care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to initiation of study treatment may be used; 
such tests do not need to be repeated for Screening-R/C evaluation.
Note: All visit names in the R/C Substudy will be appended with "R/C" 
(e.g., Cycle 1R/C Day 1) to differentiate from the main study.  
Inclusion Criteria
Patients must meet the following criteria to be eligible for the R/C Substudy:

Signed R/C Substudy Informed Consent Form


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
Patients randomized to Arm A or Arm B with a confirmed disease progression of 
CLL per iwCLL criteria 

Patients who have not received new anti-CLL therapy following disease progression
in Arm A or Arm B

Adequate renal and hepatic function per laboratory reference range (see 
Section 4.1.1)
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible for the R/C Substudy:

Transformation of CLL to aggressive NHL (e.g., Richter’s transformation, 
prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL

Evidence of other clinically significant uncontrolled condition(s) including, but 
not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)

Development of other malignancy since enrollment into the study, with the 
exception of curatively treated basal cell carcinoma or squamous cell carcinoma of 
the skin or carcinoma in situ of the cervix

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

History of severe (i.e., requiring permanent discontinuation of prior rituximab 
therapy) prior allergic or anaphylactic reactions to rituximab

Known HIV positivity

Positive test results for chronic hepatitis B infection (defined as positive hepatitis B 
surface antigen [HbsAg] serology) 
Patients with occult or prior hepatitis B infection (defined as positive total 
hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if 
hepatitis B virus [HBV] DNA is undetectable.  These patients must be willing 
to undergo monthly polymerase chain reaction (PCR) HBV DNA testing. 

Positive test results for hepatitis C virus (HCV; HCV antibody serology testing)
Patients positive for HCV antibody are eligible only if PCR is negative for 
HCV RNA.

Requires the use of warfarin (due to potential drugdrug interactions that may 
potentially increase the exposure of warfarin)
Patients may be eligible if able to be taken off warfarin and started on an 
alternative anticoagulant.

Has not recovered to less than Grade 2 clinically significant adverse 
effect(s)/toxicity(ies) of any previous therapy

Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and 
clarithromycin) within 7 days prior to the first dose of study treatment (see 
Appendix 9)


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
Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, 
St. John’s wort) within 7 days prior to the first dose of study treatment (see 
Appendix 9)

Consumed grapefruit or grapefruit products, Seville oranges (including marmalade 
containing Seville oranges), or star fruit within 3 days prior to the first dose of 
study treatment

A cardiovascular disability status of New York Heart Association Class 3
Class 3 is defined as cardiac disease in which patients are comfortable at rest 
but have marked limitation of physical activity due to fatigue, palpitations, 
dyspnea, or anginal pain.

A significant history of renal, neurologic, psychiatric, endocrine, metabolic, 
immunologic, cardiovascular, or hepatic disease that, in the opinion of the 
investigator, would adversely affect the patient’s participation in this study or 
interpretation of study outcomes

Major surgery within 30 days prior to the first dose of study treatment

A patient who is pregnant or breastfeeding

Malabsorption syndrome or other condition that precludes enteral route of 
administration

Known allergy to both xanthine oxidase inhibitors and rasburicase

Vaccination with a live vaccine within 28 days prior to randomization
R/C Substudy Design
Patients entering the R/C Substudy will have a 5-week venetoclax dose ramp-up period 
to reach the target dose of 400 mg QD (see Section 4.3.2.1.1).  Following the venetoclax
ramp-up period, patients will receive 6 cycles of rituximab consisting of a single 
infusion on the first day of each 28-day cycle.  Patients will continue to take their daily 
dose of venetoclax during the rituximab cycles.  Patients who have not progressed 
following the completion of the 6 cycles will continue to receive venetoclax
monotherapy until disease progression or for a maximum of 2 years from Cycle 1R/C
Day 1 of the R/C Substudy.
An EOCTR-R/C Visit will be scheduled 12 weeks after Cycle 6R/C Day 1 or at disease 
progression, whichever occurs first.  After the EOCTR-R/C Visit, patients who have 
not progressed will be followed clinically every 24 weeks (Follow-Up R/C Visits).  
Follow-Up R/C Visits will continue until completion of venetoclax treatment at 2 years 
from Cycle 1R/C Day1 (Completion of Venetoclax Treatment Response in the 
Re-treatment/Crossover Substudy[COVTR-R/C] Visit) or PD, whichever occurs first.  
If patients discontinue early due to toxicity or at disease progression, EOCTR-R/C
Visit will be scheduled immediately.  After the COVTR-R/C Visit or disease 
progression, patients should be followed for OS, PD (if not progressed already), and 
new anti-CLL therapy. These Survival Follow Up Visits will be captured every 
24 weeks until the end of study and may be conducted by telephone.


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Figure 3
Re-Treatment/Crossover Substudy Schema
Arm A venetoclax and rituximab (venetoclax R); Arm B bendamustine and rituximab 
(BR); 1 cycle 28 days; OS overall survival; PD progressive disease; PO per os, orally; 
QD once daily; R/C Re-Treatment/Crossover.
* In the R/C Substudy, patients will receive venetoclax starting on Day 1 (venetoclax dose 
ramp-up period) as delineated in Section 4.3.2.1.1. Venetoclax will then be 
self-administered at 400 mg QD for a maximum of 2 years from Cycle 1R/C Day 1 or until 
disease progression, whichever occurs first.  Combination therapy consisting of 6 cycles of 
rituximab and daily venetoclax dosing will start after completion of the venetoclax ramp-up 
period.
A full tumor assessment is required at Screening-R/C and EOCTR-R/C Visits by the 
investigator using standard clinical and laboratory examinations, bone marrow 
evaluation and CT scans according to iwCLL guidelines (Hallek et al. 2008).  The 
EOCTR-R/C Visit is to be scheduled 12 weeks (7 days) after Cycle 6R/C Day 1. 
Following the EOCTR-R/C Visit, patients will be followed clinically every 24 weeks in 
Follow-Up R/C Visits until the COVTR-R/C Visit. Patients will also have a clinical 
response assessment at the COVTR-R/C Visit to be scheduled at the completion of 
venetoclax monotherapy (i.e., 2 years from Cycle 1R/C Day 1). If patients discontinue 
prior to completion of venetoclax treatment, COVTR-R/C Visit will be scheduled 
immediately.  Additional response assessments may be performed according to 
institutional guidelines and recorded in eCRFs.  Additional CT scan evaluations should 
be performed during Follow-Up R/C or COVTR-R/C Visits to confirm a suspected 
change in response status, that is, SD to PR or PR to CR/CRi. If a patient’s response 
improves to a CR or CRi during Follow-Up R/C or COVTR-R/C Visits, a bone morrow 
biopsy must be performed to confirm the CR.
A bone marrow aspirate should be obtained for MRD assessment in the bone marrow in 
all patients at Screening-R/C and in all responders (CR or PR) at the EOCTR-R/C
Visit.  In addition, MRD samples in peripheral blood will be collected for all patients at 
Screening-R/C, EOCTR-R/C, Follow-Up R/C, and COVTR-R/C Visits.  Samples will 
be analyzed at a central laboratory.
Arm B
BR
Arm A
Venetoclax + R
PD
PD
Crossover Arm B-R/C
(N~30)
Re-treatment Arm A-R/C
(N~30)
Re-treatment/Crossover (R/C) Substudy
Venetoclax + R
Venetoclax:400 mg PO (QD Cycles 1R/C-6R/C)
(5 week dose ramp-up period prior to Cycle 1R/C)*
Rituximab: 375 mg/m2 (Day1, Cycle 1R/C)
500 mg/m2 (Day 1, Cycles 2R/C-6R/C)
optional
Venetoclax 400 mg PO QD
to PD or 2 years from start
of combination therapy
(Cycle 1RC, Day 1); Follow
up for OS and PD


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Investigators should report deaths, serious adverse events, adverse events Grade 3, 
adverse events of special interest throughout the treatment duration and 28 days 
after the last dose of venetoclax and 90 days after the last dose of rituximab (see 
Sections 5.3.1 and 5.2.3), second primary malignancies, and adverse events leading to 
treatment discontinuation on the Adverse Event eCRF. Adverse events will be graded 
using NCI CTCAE, v4.0 (see Section 5.3.3). 
A schedule of assessments for the R/C Substudy is provided in Appendix 14.
3.2
END OF STUDY
The end of the study will be approximately 81 months after the last patient is enrolled
in the main study, allowing for the collection of long-term safety, PFS, and OS data.  
This will also allow for completion of the maximum duration of planned therapy in the 
R/C Substudy (in the absence of disease progression) as well as at least 1 month of 
follow-up for all patients in the R/C Substudy.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Combination Therapy (Experimental Group)
Rituximab has been shown to be an effective treatment for low-grade, CD20-positive 
B-cell malignancies and is commonly used both as a single agent and in combination 
with cytotoxic chemotherapy (Maloney et al. 2002; Cheson 2006).
Although the exact mechanism of action of rituximab remains unclear, it is known to 
induce cell death through several pathways, including CDC, ADCC, and apoptosis
(Maloney et al. 2002).  In vitro, rituximab-resistant lymphoma clones have been shown to 
up-regulate pro-survival Bcl-2 family members relative to wild-type cells and to exhibit a 
higher degree of resistance to numerous chemotherapeutic agents.  Cutaneous Bcell 
lymphoma samples obtained after clinical relapse from rituximab treatment also 
exhibited a strong up-regulation of Bcl-2 compared with those before therapy, potentially 
linking anti-apoptotic Bcl-2 proteins to therapy resistance (Wobser at al. 2007).  These 
data suggest that by lowering the apoptotic threshold, a Bcl-2 antagonist may act 
synergistically with rituximab in a variety of settings.
In a xenograft model of NHL (DoHH-2), venetoclax dosed as monotherapy caused 
significant tumor growth delay compared with the vehicle.  Combining rituximab and 
bendamustine with venetoclax resulted in significantly improved tumor inhibition 
compared with rituximab and bendamustine alone (Souers et al. 2013).  Therefore, this 
combination may hold promise in the treatment of CD20-positive lymphoid malignancies.
3.3.1.1
Rationale for Venetoclax Dosage
Venetoclax dosing for this study was based on the experience from the single-agent 
Phase I dose-escalation Study M12-175 examining single-agent venetoclax in relapsed 
and refractory CLL patients.  That study established a ramp-up schedule over several 
weeks in order to safely administer venetoclax, reducing the risk for TLS by more 


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gradually reducing the leukemia cell burden prior to administration of the full target dose.  
The starting dose of venetoclax is 20 mg.  In M12-175, the absence of laboratory 
evidence of TLS, the 20-mg dose is followed by 50 mg venetoclax QD for 1 week, 
followed by weekly increases in dose levels to a maximum dose of 600 mg.  However, 
the dose to be used in combination with rituximab and other agents has been 
determined to be 400 mg for CLL.  Preliminary data from Study M12-175 show that the 
400 mg venetoclax dose as a single agent results in exposure that causes 80% 
reduction in lymphocyte counts, tumor size, and bone marrow infiltrates in most patients.  
These results were considered in selecting the dose for this study.  
Based on recent analysis of 58 patients enrolled in different venetoclax trials and as part 
of modifications to the tumor lysis syndrome prophylaxis measures, starting dosing with 
20 mg every day for 1 week for all patients is chosen (see Section 1.2.2.3.2). 
3.3.1.2
Rationale for Rituximab Dosage
The approved body surface area (BSA)adjusted dosing regimen of rituximab in 
combination with chemotherapy for front-line or relapsed CLL will be used in this study:  
375 mg/m2 at Cycle 1 followed by 500 mg/m2 at Cycles 26 at intervals of 4 weeks.  
Evaluation of a potential PK interaction from the combination of venetoclax and rituximab
is incorporated into the PK assessment plan in an ongoing study (M13-365).
3.3.1.3
Rationale for Duration of Therapy
The number of cycles of dosing (6 28-day cycles) is designed to provide a duration of 
treatment consistent with other therapies for CLL that have been shown to be sufficient 
to provide durable responses.  Patients randomized to Arm A (venetoclaxR) who have 
not had disease progression after 6 cycles of therapy will continue on daily venetoclax
monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Day 1.  
In the single-agent Phase I dose-escalation Study M12-175, responses to single-agent 
venetoclax have been seen to improve over time as treatment continues without a fixed 
stopping point; thus, early termination of venetoclax treatment may prevent patients from 
reaching their maximal response.  Treatment to progression is being evaluated in the 
Phase I studies of venetoclax; so far, no evidence of unexpected late toxicities has 
emerged from continued treatment with venetoclax beyond 6 months.
3.3.2
Rationale for Control Group
BR is considered a relevant comparator arm, because other available recommended 
and/or approved therapies in this setting are either associated with high toxicity 
(e.g., FCR, allogeneic stem cell transplantation [ASCT], high-dose steroid combinations, 
and alemtuzumab) or have limited effectiveness (e.g., ofatumumab, rituximab 
monotherapy, or chlorambucil) (Eichhorst et al. 2011).  Furthermore, BR is 
recommended as a second-line therapy for fit or elderly patients experiencing short 
durations of initial treatment response.  In a Phase II trial examining the efficacy of BR 
in relapsed/refractory CLL, median OS was 34 months and median PFS was 15 months 
(Fischer et al. 2011).  Alemtuzumab is recommended for treatment of patients with the 
17p deletion per the NCCN Practice Guidelines in Oncology (v3.2012); however, it 
has been withdrawn from commercial availability in the United States and the 


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European Union and will be available only under a compassionate use program for 
appropriate patients.  Moreover, alemtuzumab is less effective for eradication of bulky 
disease (Fiegl et al. 2006; Keating et al. 2002).  Although response rate to BR in 
relapsed CLL with the 17p deletion is low, more effective alternatives are not universally 
available.
3.3.2.1
Rationale for BR Dosage
Two Phase II single-arm studies have investigated BR in the previously untreated and in 
the relapsed/refractory CLL settings.  In the previously untreated CLL study, 
bendamustine was dosed for 6 cycles at 90 mg/m2 on Days 1 and 2 in combination with 
rituximab administered at 375 mg/m2 for the first cycle and 500 mg/m2 for Cycles 26
(Fischer et al. 2009).  Preliminary results indicate an OR rate of 91%, with 33% CR rate.
In the relapsed/refractory CLL study, bendamustine was dosed for 6 cycles at 70 mg/m2
on Days 1 and 2 when combined with rituximab administered at 375 mg/m2 for the first 
cycle and 500 mg/m2 for Cycles 26 (Fischer et al. 2011).  In that study with 78 patients, 
the most common Grade 3/4 adverse events observed included neutropenia (23%), 
thrombocytopenia (28%), and anemia (17%).  Grade 3 infections occurred in 13% of 
patients; dose reductions were required in 37% of patients, and 23% and 44% of 
patients did not receive at least 3 or all 6 cycles of treatment, respectively, most often 
because of toxicity.  Even with this safety profile, which is not unusual with 
chemoimmunotherapy regimens in this patient population, BR was demonstrated to 
have meaningful clinical activity with an OR rate of 59% and PFS of 15 months.
In the Phase II study in relapsed/refractory CLL, rituximab was dosed at 375 mg/m2 for 
the first cycle and at 500 mg/m2 during Cycles 26 (Fischer et al. 2011).  Because this 
schedule resulted in meaningful clinical activity, the same schedule will be used in the 
BR arm for this study.
BR chemoimmunotherapy has been shown to be associated with toxicity 
(e.g., myelosuppression) that can necessitate dose delays, dose reductions, and early 
discontinuation in patients with NHL and CLL (Fischer et al. 2011).  Consensus 
recommendations for bendamustine dose are 70 mg/m2 in relapsed/refractory patients 
either as a single agent or in combination with rituximab (Cheson et al. 2010).  Patients 
participating in this study will be treated according to this recommendation and will 
therefore receive 70 mg/m2 bendamustine on Days 1 and 2 of the cycle for 6 cycles.
3.3.3
Rationale for Patient Population
Survival in CLL patients is highly variable, ranging from less than 2 years to 20 years or 
more (Binet et al. 1981).  Intermediate-risk (Rai Stages I and II) patients, who account 
for 61% of all CLL patients, have a median survival of 79 years.  High-risk (Rai 
Stages III and IV) patients, who account for 8% of all CLL patients, have a median 
survival of 5 years.


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Treatment is usually initiated when the patient becomes symptomatic or progresses to 
late-stage CLL.  First-line treatment of CLL has evolved from single-agent therapy to 
combination chemoimmunotherapy (Keating et al. 1993; Johnson et al. 1996; 
Rai et al. 2000; Leporrier et al. 2001; Eichhorst et al. 2006; Catovsky et al. 2007;
Flinn et al. 2007; Hillmen et al. 2007; Hallek et al. 2010).  The choice of front-line therapy 
is guided by patient age, comorbidity, and Performance Status.  The lack of a standard 
regimen for front-line patients results in a heterogeneous population of second-line 
patients that has been documented in other studies in the relapsed/refractory setting 
(Fischer et al. 2011).
For relapsed patients, single- and multi-agent therapies are options, but relapsed
disease is associated with a median survival between 15 and 44 months and is highly 
dependent on CLL risk status and choice of regimen (Lamanna et al. 2006; 
Wierda et al. 2010; Fischer et al. 2011).  Furthermore, the NCCN and ESMO guidelines 
list several options for treatment of relapsed patients (see Appendix 8), which take into 
account the duration of initial response because response duration has been shown to 
be prognostic of long-term outcome (Tam et al. 2008).  ASCT is the only potentially 
curative treatment option for CLL patients; however, transplantation is appropriate only 
for a small number of younger patients and is associated with high morbidity and 
mortality.
In this study, eligible patients must have been treated with at least one but no more than 
three previous lines of therapy (a line of therapy is defined as completing 2 cycles of 
treatment for a given line of therapy) including at least one prior standard 
chemotherapy-containing regimen according to current guidelines.  Multiple standard 
and experimental treatments are available for CLL and vary by geographic region.  
Therefore, relapsed/refractory CLL patients represent a heterogeneous group especially 
as the number of prior therapies increases.  In the present study, the number of previous 
therapies is limited to three in order to limit this heterogeneity.
Data from clinical trials of fit individuals treated with FCR chemotherapy in the front-line 
setting have demonstrated long-term durable responses (Tam et al. 2008;
Hallek et al. 2010).  As previously noted, similar responses for relapsed/refractory 
patients have not been observed.  Therefore, novel approaches are needed to improve 
the outcome of this subset of CLL patients.
In almost all cases, CLL remains an incurable disease.  Moreover, treatment options are 
limited in the largely elderly patient population.  A chemotherapy-free regimen 
(e.g., venetoclaxR) may have fewer side effects and represent a novel strategy for 
improving response rates and the morbidity and mortality of patients with 
relapsed/refractory CLL.


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3.3.4
Rationale for Including Patients with 17p Deletion
CLL patients with the 17p deletion (resulting in loss of the p53 tumor suppressor allele) 
have a poor prognosis characterized by suboptimal responses to first-line and 
subsequent therapies.  Defects in p53 are found in approximately 10%15% of CLL 
patients requiring front-line therapy (Pettitt et al. 2012).  Among patients with 
chemotherapy-refractory CLL, the frequency increases to almost 50% (Zenz et al. 2009).
There are currently no treatments approved specifically to meet the need of the 
17p deletion population.  For relapsed/refractory 17p deletion patients ineligible for 
allogeneic transplant or clinical trial, outcomes following standard therapy are 
significantly worse than for patients without abnormalities at 17p (Pettitt et al. 2012).
Among patients with relapsed CLL treated with FCR, those with the 17p deletion showed 
poorer outcomes than the overall study population.  PFS and OS were 5 months and 
10 months, respectively, in patients with 17p deletion, compared with 21 months and 
47 months in the entire cohort.  The corresponding response rates were also lower in 
patients with the 17p deletion (Badoux et al. 2011).
Pettitt et al. (2012) recently described the outcome of patients with the 17p deletion 
treated in the front-line setting or at relapse with alemtuzumab.  Among the 22 relapsed 
patients, an OR rate of 77% was observed with a median PFS of 6.5 months 
(Pettitt et al. 2012).  However, alemtuzumab and other approved therapies are 
associated with significant toxicity, limiting their use in older populations.
The mechanism of action of venetoclax is independent of the TP53 pathway.  Early 
results from the ongoing single-agent Phase I dose-escalation Study M12-175 have 
demonstrated activity in 14 of 16 relapsed/refractory CLL patients with the 17p deletion.  
These encouraging preliminary data indicate that venetoclax may be beneficial in this 
unique high-risk patient population and may also represent a less toxic option when 
venetoclax is used in combination with rituximab.
3.3.5
Rationale for Biomarker Assessments
Venetoclax inhibits the ability of cancer cells to evade cell death, or apoptosis, by 
blocking the activity of the anti-apoptotic protein Bcl-2 (Korsmeyer 1999; 
Cory and Adams 2002; Borner 2003; Cory et al. 2003).  Nonclinical studies have 
demonstrated a pattern of response to venetoclax based on the levels of Bcl-2 family 
proteins. High levels of Bcl-2 and low levels of Mcl-1 are generally predictive of 
response to this drug in vitro (unpublished data, Genentech, Inc.).  In addition, high 
levels of at least one pro-apoptotic “sensor” such as Noxa or Bim are required.  
Furthermore, nonclinical studies have suggested that acquired rituximab resistance may 
occur as a result of the up-regulation of Bcl 2 (Byrd et al. 2002).  Measurement of 
relevant RNAs, miRNAs, tumor-associated DNA alterations (such as p53 and Notch1 
mutations), and proteins (including those in the Bcl-2 family) in CLL cells will be 
examined pretreatment, during treatment, and at the time of progression for putative 


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stratification markers and correlation with efficacy. Genomics is increasingly informing 
researchers' understanding of disease pathobiology. Next-generation sequencing (NGS) 
assays, including whole exome sequencing (WES) that provides a comprehensive 
characterization of the exome, and RNA sequencing (RNA-seq), which provides a 
comprehensive characterization of the transcriptome, along with clinical data collected 
in this study, may increase the opportunity for developing new therapeutic approaches. 
Exploratory biomarker research may include, but will not be limited to, analysis of 
genes or gene signatures associated with apoptosis and cell survival and may involve 
extraction of DNA and/or RNA, analysis of somatic mutations, and use of WES, 
RNA-seq, or NGS. Bone marrow aspirates and/or peripheral blood samples will be 
analyzed through use of NGS approaches (WES and RNA-seq) to identify somatic 
mutations and/or gene expression signatures that are predictive of response to study 
drugs, are associated with progression to a more severe disease state, are associated 
with acquired resistance to study drug, or can increase the knowledge and 
understanding of disease biology. In addition, blood samples will be collected to 
determine in vitro sensitivity of CLL cells to venetoclax (EC50) to evaluate whether 
response to venetoclax can be predicted in vitro.  These studies will help to identify 
responsive patient populations and to develop better therapies for patients with CLL.  
Because these biomarkers may also have prognostic value, their potential association 
with disease progression will also be explored.
3.3.6
Rationale for Patient-Reported Outcome Assessments
Patients with CLL experience a high symptom burden from the underlying disease 
process that is compounded by the side effects of currently available therapies.  These 
symptoms and treatment-related side effects can impact function and, subsequently, 
HRQoL.  If the expected clinical benefit of venetoclaxR is observed in the trial, there is 
reason to believe that patients might observe an accompanying improvement in distinct 
key symptoms of the disease (i.e., reduction in fatigue, reduction in nodular pain, and 
decrease in night sweats).  PROs will be used to capture the patients’ report of these 
symptom changes and detect change in disease symptoms.  Specifically, with PFS 
being a primary clinical endpoint, understanding the time to disease progression through 
PROs and what patients gain from disease symptoms during this time can be used to 
support PFS.
To comprehensively characterize treatment-related side effects between the two study 
arms, PROs will be used to evaluate common treatment-related side effects.  It is hoped 
that the novel treatment approach of venetoclaxR will have a reduced side-effect 
profile and improved tolerability compared with traditional chemotherapy and result in an 
improvement in HRQoL and functioning for patients with CLL while undergoing treatment.  
The reduction in both disease symptoms and treatment-related side effects combined 
with a subsequent improvement in HRQoL might serve to reduce health economic 
impact for these patients.


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3.3.7
Rationale for Re-Treatment/Crossover Substudy
The interim analysis (now primary analysis) of this study demonstrated that 
venetoclax R is superior to BR in patients with relapsed/refractory CLL.  The primary 
endpoint of investigator assessed PFS showed significant improvement with 
venetoclax R, with a hazard ratio (HR) of 0.17 (95% CI: 0.11, 0.25; p<0.0001). Key 
secondary endpoints, including OS, ORR, and CR rate, also showed consistent
clinically meaningful improvements (Seymour et al. 2018).  As the outcomes 
demonstrated with venetoclax R are significantly superior to standard of care (BR),
crossover and re-treatment will be allowed in the newly added R/C Substudy.  The 
Sponsor would now like to amend the study to investigate response in patients in Arm 
A who are re-treated with venetoclax R after progression. This is supported by Study 
M13-365 where it was demonstrated that patients have responded to re-treatment with 
venetoclax (Seymour et al. 2017) and had durable responses.  In addition, patients in 
Arm B (BR) who have progressed and are in need of further line treatment will be given 
the option to cross over and receive venetoclax R, which has demonstrated improved 
clinical outcome for patients. 
3.4
OUTCOME MEASURES 
3.4.1
Efficacy Outcome Measures
3.4.1.1
Primary Efficacy Outcome Measure
The primary efficacy outcome measure for this study is investigator-assessed PFS, 
defined as the time from randomization to the first occurrence of progression or relapse, 
determined using standard iwCLL guidelines (Hallek et al. 2008), or death from any 
cause, whichever comes first. 
While the primary efficacy endpoint is investigator-assessed PFS, PFS based on IRC 
assessments will also be analyzed to support the primary analysis.  In the United States, 
IRC-assessed PFS will be the basis for regulatory decisions.
3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are as follows:

IRC-assessed PFS in the subset of CLL patients with 17p deletion identified by 
FISH testing at a central laboratory

Investigator-assessed PFS in the subset of CLL patients with 17p deletion identified 
by FISH testing at a central laboratory

Best OR (defined as CR, CRi, nPR, and PR)rate as assessed by the investigator

OR, CR, CRi, nPR, and PR rates at end of combination treatment response visit, as 
assessed by the investigator.  Disease response will be assessed according to the 
iwCLL guidelines (Hallek et al. 2008).

OR, CR, CRi, nPR, and PR rates at end of combination treatment response visit, as 
assessed by the IRC

OS, defined as the time from randomization to death from any cause


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
EFS, defined as the time between randomization and the date of disease 
progression/relapse, death from any cause, or start of a new anti-CLL therapy  

DOR, defined for patients with a best OR of CR, CRi, nPR, or PR as the time from 
first occurrence of a CR, CRi, nPR, or PR to disease progression/relapse, as 
assessed by the investigator, or death from any cause

TTNT, defined as the time from randomization to start of new non-protocol anti-CLL 
therapy or death from any cause

MRD response rate (determined as the proportion of patients with MRD negativity)
at End of Combination Treatment Response Visit as measured at a central 
laboratory on peripheral blood and/or bone marrow samples
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of adverse events and serious adverse events

Changes in clinical laboratory results (including hematology and chemistry) during 
and following administration of study treatment

Incidence of adverse events of special interest:
Grade 3 TLS and IRRs

Measures of immune function, including serial immunoglobulin levels (IgG, IgM, IgA) 
following treatment with venetoclaxR or BR
3.4.3
Pharmacodynamic Outcome Measure
The pharmacodynamic outcome measure for this study is as follows:

Serial assessment of B- and T-cell lymphocyte subsets by flow cytometry
3.4.4
Pharmacokinetic Outcome Measures
The PK outcome measures for this study include:

Plasma venetoclax concentrations at the specified timepoints

Apparent clearance, apparent volume of distribution, and other appropriate PK 
parameters of venetoclax characterized using population PK techniques, as data 
allow
3.4.5
Patient-Reported Outcome Measures
The PRO measures for this study are as follows:

MDASI

EORTC QLQ-C30 and QLQ-CLL16
3.4.6
Health Economic Outcome Measure
The health economic outcome measure for this study is as follows:

The EQ-5D questionnaire


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3.4.7
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Evaluation of the relationship between response and PFS and various potential 
biomarkers, including Bcl-2 expression, for patients treated with venetoclax R 
or BR

Assessment of potential biomarkers that are prognostic and/or predictive of 
response and resistance to treatment with venetoclax R or BR

MRD response rate as measured at a central laboratory on peripheral blood 
samples and/or bone marrow aspirate samples at the disease response assessment 
timepoints
4.
MATERIALS AND METHODS
4.1
PATIENTS
The target population for this study is adult patients with relapsed or refractory CLL 
requiring treatment.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed informed consent

Age 18 years

Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2008).  
Patients must have peripheral blood Blymphocyte counts that clonally express 
CD5, CD19/20, and CD23 and are either kappa or lambda light-chain-restricted.  
Pro-lymphocytes may comprise no more than 55% of total circulating lymphocytes.  
At initial diagnosis of CLL (i.e., prior to front-line treatment), the peripheral 
lymphocyte count must have been 5000/mm3.  Patients must meet the following 
criteria for relapsed or refractory CLL (per the iwCLL guidelines [Hallek et al. 2008]):
Relapsed disease:  a patient who previously achieved a CR or PR but after a 
period of 6 months or more demonstrates evidence of progression
Refractory disease:  treatment failure or disease progression within 6 months 
after the last anti-leukemia therapy

Previously treated with at least one but not more than three lines of therapy (a line 
of therapy is defined as completing at least two cycles of treatment for a given line 
of therapy), including at least one prior standard chemotherapy-containing regimen 
according to current guidelines (see Appendix 8)

For patients with the 17p deletion, previously treated with at least one but not more 
than three lines of therapy, including at least one prior standard 
chemotherapy-containing regimen OR at least one prior alemtuzumab-containing 
therapy (see Appendix 8)

Patients previously treated with bendamustine only if their DOR was 24 months

Patient requires treatment in the opinion of the investigator


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
ECOG performance score of 1 (see Appendix 7)

Adequate bone marrow function independent of growth factor or transfusion support, 
within 2 weeks of screening, at screening as follows unless cytopenia is clearly due 
to marrow involvement of CLL:
Platelet count75,000/mm3; in cases of thrombocytopenia clearly due to 
marrow involvement of CLL (per the discretion of the investigator), platelet 
count should be 30,000/mm3
Absolute neutrophil count (ANC) 1000/mm3 unless neutropenia is clearly due 
to marrow involvement of CLL (per the discretion of the investigator)
Total hemoglobin 9 g/dL unless anemia is due to marrow involvement of CLL 
(per the discretion of the investigator)

Adequate renal and hepatic function, per laboratory reference range at screening, 
as follows:
Calculated creatinine clearance 50 mL/min using 24-hour creatinine clearance 
or modified Cockcroft-Gault equation (using ideal body mass [IBM] instead of 
mass):
eCCr
(140Age) IBM (kg) [0.85 if female]
72 serum creatinine (mg/dL)
Or, if serum creatinine is in mol/L:
eCCr
(140Age) IBM (kg) [1.23 if male, 1.04 if female]
serum creatinine (mol/L)
(IBM) should be used:
IBM (kg)([height in cm154]0.9)](50 if male, 45.5 if female)
AST and ALT3.0 times the upper limit of normal (ULN) of the institution's 
normal range
Bilirubin 1.5ULN.  Patients with Gilbert's syndrome may have a bilirubin level 
1.5ULN, per discussion between the investigator and the Medical Monitor
Prothrombin time (or international normalized ratio) and partial thromboplastin 
time not to exceed 1.2 times the institution’s normal range (patients with an 
elevated prothrombin time and known lupus anticoagulant may be eligible for 
participation after consulting the Medical Monitor)

Female patients must be surgically sterile, postmenopausal (for at least 1 year), or 
have negative results for a pregnancy test performed as follows:
At screening, on a serum sample obtained within 14 days prior to initiation of 
study treatment, and
Prior to dosing, on a urine sample obtained on the first day of study treatment if 
it has been 7 days since obtaining the serum pregnancy test result


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
Female patients who are not surgically sterile or postmenopausal (for at least 1 year) 
must practice at least one of the following methods of birth control throughout the 
duration of study participation and for at least 30 days after study treatment or 
12 months after completing therapy with rituximab, whichever is later:
Total abstinence from sexual intercourse
A vasectomized partner
Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that 
started at least 3 months prior to study drug administration
Double-barrier method (condomdiaphragm or cervical cup with spermicidal 
contraceptive sponge, jellies, or cream)

Non-vasectomized male patients must practice at least one of the following methods 
of birth control throughout the duration of study participation and for at least 
3 months after study treatment or 12 months after completing therapy with rituximab, 
whichever is later:
A partner who is surgically sterile or postmenopausal (for at least 1 year) or 
who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or 
transdermal) for at least 3 months prior to study drug administration
Total abstinence from sexual intercourse
Double-barrier method (condomdiaphragm or cervical cup with spermicidal, 
contraceptive sponge, jellies, or cream)
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Transformation of CLL to aggressive NHL (e.g., Richter’s transformation, 
prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL

Underwent an allogeneic stem cell transplant

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

History of intolerance to prior bendamustine treatment (defined as toxicity requiring 
permanent discontinuation of bendamustine) or other contraindication to 
bendamustine treatment

History of severe (i.e., requiring permanent discontinuation of prior rituximab therapy) 
prior allergic or anaphylactic reactions to rituximab

Known HIV positivity

Positive test results for chronic hepatitis B infection (defined as positive HBsAg 
serology) 
Patients with occult or prior hepatitis B infection (defined as positive total 
HBcAb and negative HBsAg) may be included if HBV DNA is undetectable.  
These patients must be willing to undergo monthly PCR HBV DNA testing. 


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
Positive test results for hepatitis C (HCV antibody serology testing)
Patients positive for HCV antibody are eligible only if PCR is negative for HCV 
RNA.

Requires the use of warfarin (due to potential drugdrug interactions that may 
potentially increase the exposure of warfarin).  Patients may be eligible if able to be 
taken off warfarin and started on an alternative anticoagulant.

Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of 
study treatment

Received any of the following agents within 28 days prior to the first dose of study 
treatment:
Any anti-cancer therapy including chemotherapy or radiotherapy and steroid 
therapy for anti-neoplastic intent, investigational therapy, including targeted 
small-molecule agents

Has not recovered to less than Grade 2 clinically significant adverse 
effect(s)/toxicity(ies) of any previous therapy

Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and 
clarithromycin) within 7 days prior to the first dose of study treatment (see 
Appendix 9)

Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, 
St. John’s wort) within 7 days prior to the first dose of study treatment (see 
Appendix 9)

History of prior venetoclax treatment

Consumed grapefruit or grapefruit products, Seville oranges (including marmalade 
containing Seville oranges), or star fruit within 3 days prior to the first dose of study 
treatment

A cardiovascular disability status of New York Heart Association Class 3
Class 3 is defined as cardiac disease in which patients are comfortable at rest 
but have marked limitation of physical activity due to fatigue, palpitations, 
dyspnea, or anginal pain.

A significant history of renal, neurologic, psychiatric, endocrine, metabolic, 
immunologic, cardiovascular, or hepatic disease that, in the opinion of the 
investigator, would adversely affect the patient’s participation in this study or 
interpretation of study outcomes.

Major surgery within 30 days prior to the first dose of study treatment

A patient who is pregnant or breastfeeding

History of prior other malignancy that could affect compliance with the protocol or 
interpretation of results, with the exception of the following:
Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin 
or carcinoma in situ of the cervix at any time prior to study


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Other cancers not specified above that have been curatively treated by surgery 
and/or radiation therapy from which patient is disease-free for 5 years without 
further treatment

Malabsorption syndrome or other condition that precludes enteral route of 
administration

Known allergy to both xanthine oxidase inhibitors and rasburicase

Evidence of other clinically significant uncontrolled condition(s) including but not 
limited to uncontrolled systemic infection (viral, bacterial, or fungal)

Vaccination with a live vaccine within 28 days prior to randomization
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.
Randomization will be performed by an interactive voice/Web-based system (IxRS).  
Patients will be assigned in 1:1 ratio to one of the two treatment arms through a block 
stratified randomization procedure.  The randomization scheme will ensure 
approximately equal sample sizes in the two treatment groups in regard to the following 
stratification factors:

17p deletion by local testing (yes/no)

Risk status:  high risk or low risk
High risk:  defined as harboring 17p deletion or no response to front-line 
chemotherapy-containing regimen or relapsed within 12 months after 
chemotherapy or within 24 months after chemoimmunotherapy
Low risk:  defined as relapse more than 12 months after chemotherapy or 
24 months after chemoimmunotherapy

Geographic region (United States/Canada, Australia/New Zealand, Western Europe, 
Central and Eastern Europe, Asia, or Latin America)
A unique patient number will be assigned at randomization.  This patient number will be 
used to identify the patient in the electronic data capture (EDC) system and all other 
data sources.
The iDCC and iDMC will be unblinded.  Assessments by the IRC will be blinded.
4.3
STUDY TREATMENT 
4.3.1
Formulation, Packaging, and Handling
The Sponsors will be supplying all study treatments for this study (venetoclax, rituximab, 
and bendamustine).
4.3.1.1
Venetoclax
Venetoclax (GDC-0199 [ABT-199]) is manufactured by AbbVie, Inc. and will be supplied 
as oral tablets of 10 mg, 50 mg, and 100 mg strength.  Venetoclax tablets will be 


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packaged in high-density polyethylene plastic bottles to accommodate the study design.  
Each bottle will be labeled (either single-panel or booklet) per individual country 
requirements.  Label must remain affixed to the supplies.  Venetoclax drug must be 
stored at 15C25C (59F77F).  The investigational product is for investigational use 
only and is to be used only within the context of this study.  The study drug supplied for 
this study must be maintained under adequate security and stored under the conditions 
specified on the label until dispensed for patient use or returned to the Sponsors.
For further details, see the Venetoclax Investigator’s Brochure.
4.3.1.2
Rituximab
Rituximab is manufactured by Genentech, Inc., as the licensed product Rituxanin the 
United States and Canada.  For the rest of the world, rituximab is manufactured by 
F. HoffmannLa Roche Ltd. (Roche) as the licensed product MabThera.  It is a sterile,
clear, colorless, preservative-free liquid concentrate for IV administration.  Rituximab is 
supplied at a concentration of 10 mg/mL in 100-mg (10-mL) and 500-mg (50-mL) 
single-use vials.  The product is formulated for IV administration in 9.0 mg/mL sodium
chloride, 7.35 mg/mL sodium citrate dihydrate, and 0.7 mg/mL polysorbate 80, after 
reconstitution with sterile water for Injection.  The pH is adjusted to 6.5.  Vials are for 
single use.  Each vial and carton will be labeled (either single-panel or booklet) per 
individual country requirements.  Label must remain affixed to the supplies.
Rituximab vials must be stored at 2C8C (36F46F).  Rituximab vials should be 
stored in the outer carton in order to protect them from light.  Rituximab solution for 
infusion may be stored at 2C8C (36F46F) for 24 hours and has been shown to be 
stable for an additional 12 hours at room temperature.  However, since rituximab does 
not contain a preservative, diluted solutions should be stored refrigerated (2C8C).  No 
incompatibilities between rituximab and polyvinylchloride or polyethylene bags have 
been observed.
For further details, see the local prescribing information for Rituxan/MabThera.
4.3.1.3
Bendamustine
Bendamustine HCl is marketed by Cephalon as the licensed product Treandafor the 
United States and is marketed in Germany by Mundipharma International Corporation 
Ltd, under the name Levact.  Bendamustine will be supplied in individual cartons 
containing single-use vials of 100 mg bendamustine HCl as lyophilized powder.  Each 
vial and carton will be labeled (either single-panel or booklet) per individual country 
requirements.  The label must remain affixed to the supplies.  First, dissolve contents of 
the bendamustine vial containing 100 mg of bendamustine hydrochloride in 40 mL of 
Water for Injection, while shaking.  Once a clear solution has been obtained (generally 
after 510 minutes), the total bendamustine dose is diluted immediately to a final volume 
of 500 mL.  Bendamustine is formulated for IV administration in either 0.9% sodium 
chloride injection or 2.5% dextrose/0.45% sodium chloride.  Each vial and carton will be 


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labeled (either single-panel or booklet) per individual country requirements.  Label must 
remain affixed to the supplies.
Bendamustine should be stored at 15C25C (59F77F).  It is to be retained in the 
original carton until time of use to protect from light.  Bendamustine should be prepared 
for administration as close as possible to the time of administration.  Once diluted with 
sodium chloride or dextrose/sodium chloride, the final admixture is stable for 24 hours 
if Treandais used and for 2 days if Levactis used and when stored refrigerated 
(2C8C or 36F47F) or for 3 hours when stored at room temperature (15C30C or 
59F86F) and room light.  Administration of bendamustine must be completed within 
this period.
For further details, see the local prescribing information for Treanda/Levact.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Venetoclax
Following an initial venetoclax ramp-up period (see Section 4.3.2.1.1), patients 
randomized to Arm A (venetoclax R) will take venetoclax 400 mg daily orally in 
combination with rituximab administered intravenously on Day 1 of each 28-day cycle 
for 6 cycles.  After completion of combination therapy, patients will continue to take 
venetoclax 400 mg daily orally as monotherapy until disease progression or for a 
maximum of 2 years from Cycle 1 Day 1.
4.3.2.1.1
Venetoclax Ramp-Up Period
To mitigate potential serious complications of TLS, patients will require close clinical and 
laboratory monitoring during the venetoclax ramp-up period.  See Section 4.4.1.2 for 
details of the TLS prophylaxis and monitoring guidelines.
All patients randomized to Arm A will start the study by receiving 20 mg of venetoclax
daily for at least 7 days.  Patients who demonstrate evidence of electrolyte abnormalities 
suggestive of TLS during the 24 hours following the initial 20-mg dose will receive 
appropriate treatment to resolution prior to receiving their next daily dose of venetoclax
(see Appendix 11 for Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome).
Venetoclax dose increases will then occur weekly, starting with 50 mg/day for 1 week 
followed by 100 mg/day for 1 week, 200 mg/day for 1 week, and the final dose of 
400 mg/day for 1 week.  All patients should receive any intended dose for at least 7 days 
before increasing to the next higher dose.  The duration of the venetoclax ramp-up 
period will be 5 weeks as shown in Figure 4.  Patients will then continue taking 
venetoclax 400 mg daily as directed by the investigator.


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Figure 4
Venetoclax Dosing Scheme during the Ramp-Up Period
Dday.
4.3.2.1.2
Venetoclax in Combination with Rituximab
After the patient has completed the venetoclax ramp-up period and received the target 
dose of 400 mg of venetoclax for a total of 7 days with no evidence of electrolyte 
abnormalities suggestive of LTLS or any electrolyte abnormalities resolved per protocol
Recommendations for Initial Management of Electrolyte Imbalances and Prevention of 
Tumor Lysis Syndrome (see Appendix 11), the patient will begin combination therapy 
consisting of 6 cycles of rituximab (infusions occurring on Day 1 of each 28-day cycle; 
see Section 4.3.2.2) in combination with the daily dose of venetoclax.  All patients must 
receive prophylaxis for TLS (see Section 4.4.1.2) prior to the initiation of venetoclax and 
rituximab treatment.  On days when venetoclax and rituximab are given, venetoclax will 
be taken at least 30 minutes prior to starting the rituximab infusion.
Patients will self-administer venetoclax tablets by mouth QD.  Each dose of venetoclax
will be taken with approximately 240 mL of water within 30 minutes after the completion 
of a low-fat breakfast.  Examples of a low-fat breakfast include 2 slices of white toast 
with 1 tablespoon of low-fat margarine and 1 tablespoon of jam and 8 ounces/240 mL of 
skim milk (319 calories and 8.2 g fat) or 1 cup/30 g of cereal, 8 ounces/240 mL of skim 
milk, 1 slice of toast with jam, 1 cup/240 mL of apple juice, and 1 cup/240 mL of coffee 
or tea (520 calories and 2 g fat).  If vomiting occurs within 15 minutes after taking 
venetoclax and all expelled tablets are still intact, another dose may be provided.  
Otherwise, no replacement dose is to be given.  In cases where a dose of venetoclax is 
missed or forgotten, the patient should take the dose as soon as possible, ensuring that 
the dose is taken with food within 8 hours after the missed dose.  Otherwise, the dose 
should not be taken.
Patient compliance in taking the assigned daily dose of venetoclax will be assessed by 
standard pill counts.  Bottles containing venetoclax tablets will be given to patients at 
regular scheduled visits.  Previously distributed bottles will be returned to the clinic and 
tablets counted.  Any discrepancy will be resolved with the patient at each clinic visit and 
documented in the patient record.


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Any dose modification of venetoclax should be noted on the Study Drug Administration 
electronic Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, 
or drug misuse, along with any associated adverse events, should be reported as 
described in Section 5.4.4.
Guidelines for venetoclax dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1.5.
4.3.2.2
Rituximab
Rituximab will be administered to patients in both treatment arms at 375 mg/m2 IV on 
Day 1 of Cycle 1 followed by 500 mg/m2 on Day 1 of Cycles 2 through 6 (total of six 
infusions of rituximab).  
For patients in Arm A (venetoclax R):  On days when venetoclax and rituximab are 
given, venetoclax will be taken at least 30 minutes prior to starting the rituximab infusion.
For patients in Arm B (BR):  On days when rituximab and bendamustine are to be 
administered, rituximab can be administered before or after bendamustine.  For Korean 
sites, rituximab should be administered before bendamustine.  There should be 
30 minutes between administering the two agents.
The patient’s BSA calculated at screening should be used to calculate the dose of 
rituximab throughout the study unless the patient’s weight increases or decreases by 
10% from screening.  In obese patients, there is no cap on BSA, and actual body 
weight, not adjusted weight, is recommended.  Nonetheless, empiric dose adjustment is 
permitted in obese patients (obesity defined as body mass index 30 as measured in 
kilograms divided meters squared).
During the treatment period, rituximab must be administered to patients in a clinical 
(inpatient or outpatient) setting.  Rituxan should be administered only by a healthcare 
professional with appropriate medical support to manage severe infusion reactions that 
can be fatal if they occur.
Rituximab should be administered as a slow IV infusion through a dedicated line.  
IV infusion pumps (such as the Braun Infusomat Space) should be used to control the 
infusion rate of rituximab.  Administration sets with polyvinyl chloride, polyurethane, or 
polyethylene as a product contact surface and IV bags with polyolefin, polypropylene, 
polyvinyl chloride, or polyethylene as a product contact surface are compatible and can 
be used.  Do not use an additional in-line filter because of potential adsorption.  See 
Table 1 for instructions regarding first and subsequent infusions of rituximab.
After the end of each dose of rituximab, patients should be observed for 1 hour.  If no 
adverse events occur after 1 hour, the IV line may be removed or the central venous 
catheter may be de-accessed.


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Rituximab should not be administered as an IV push or bolus.  IRRs may occur.
Premedication consisting of acetaminophen, diphenhydramine (or other suitable 
antihistamine), and a single dose of hydrocortisone (up to 100 mg or an equivalent dose 
of methylprednisolone) may also be administered beginning with the first infusion.  
Premedication may attenuate IRRs.  Because transient hypotension may occur during 
rituximab infusion, consideration should be given to withholding antihypertensive 
medications for 12 hours prior to rituximab infusion.
Table 1
Administration of First and Subsequent Infusions of Rituximab
First Infusion (Cycle 1 Day 1)
Subsequent Infusions
Begin infusion at an initial rate of 50 mg/h.
If no infusion-related or hypersensitivity 
reaction occurs, increase the infusion rate in 
50-mg/h increments every 30 minutes, to a 
maximum of 400 mg/h.
If an infusion reaction develops, stop or slow 
the infusion.  Administer infusion-reaction 
medications and supportive care in accordance 
with institutional guidelines.  If the reaction 
resolves, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate being 
used at the time that the reaction occurred).
If the patient experienced an infusion-related or 
hypersensitivity reaction during the prior 
infusion, begin infusion at an initial rate of 
50 mg/h and follow instructions for the first 
infusion.
If the patient tolerated the prior infusion well 
(defined as an absence of Grade 2 reactions 
during a final infusion rate of 100 mg/h), 
begin the infusion at a rate of 100 mg/h.
If no infusion reaction occurs, increase the 
infusion rate in 100-mg/h increments every 
30 minutes, to a maximum of 400 mg/h.
If an infusion reaction develops, stop or slow 
the infusion.  Administer infusion-reaction 
medications and supportive care in accordance 
with institutional guidelines.  If the reaction 
resolves, resume the infusion at a 50% 
reduction in rate (i.e., 50% of rate being used 
at the time that the reaction occurred).
hhour.
Note:  A fast infusion is not allowed.
Any dose modification of rituximab should be noted on the Study Drug Administration 
eCRF.  Cases of accidental overdose or medication error, along with any associated 
adverse events, should be reported as described in Section 5.4.4.
Guidelines for rituximab dosage modification and treatment interruption or
discontinuation are provided in Section 5.1.5.
4.3.2.3
Bendamustine
Patients randomized to Arm B (BR) will receive bendamustine 70 mg/m2 administered 
intravenously on 2 consecutive days of each 28-day cycle for 6 cycles, in combination 
with rituximab administered intravenously on Day 1 of each 28-day cycle for 6 cycles 
(see Section 4.3.2.2 for details of rituximab dosage and administration).


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BSA will be calculated at screening and on Day 1 of Cycle 1.  The BSA calculated at 
screening should be used to calculate the dose of bendamustine throughout the study 
unless the patient’s weight increases or decreases by 10% from screening.  In obese 
patients, there is no BSA cap and actual body weight, not adjusted weight, is 
recommended.  Nonetheless, empiric dose adjustment is permitted in obese patients 
(obesity defined as body mass index 30 kg/m2).
Bendamustine will be administered over 30 to 60 minutes on Days 1 and 2 of each 
28-day cycle for a total of 6 cycles.  On days when rituximab and bendamustine are to 
be administered, rituximab can be administered before or after bendamustine.  For 
Korean sites, rituximab should be administered before bendamustine.
Premedication with anti-emetics may be administered as per institutional guidelines (see 
Section 4.4.1).  Granulocyte colony-stimulating factor (G-CSF) may be administered as 
primary prophylaxis in each cycle of therapy, per the American Society of Clinical 
Oncology (ASCO) guidelines or each site’s institutional standards.
Any dose modification of bendamustine should be noted on the Bendamustine 
Administration eCRF.  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.4.4.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.5.
4.3.2.4
Re-Treatment/Crossover Substudy (Optional at the 
Investigator’s Discretion)
Patients entering the R/C Substudy will follow an initial venetoclax ramp-up period,
including TLS prophylaxis treatments (see Section 4.3.2.1.1), and then will take 
venetoclax 400 mg QD PO in combination with rituximab administered intravenously 
(see Section 4.3.2.1.2).  After completion of combination therapy, patients will continue 
to take venetoclax 400 mg QD PO as monotherapy until disease progression or for a 
maximum of 2 years from Cycle 1R/C Day 1 of re-treatment or crossover.
4.3.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study
(venetoclax, rituximab, bendamustine) will be provided by the Sponsors.  The 
investigational site will acknowledge receipt of IMPs, using the IxRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.
Investigational medicinal products will either be disposed of at the study site according to 
the study site’s institutional standard operating procedure or be returned to the Sponsors 
with the appropriate documentation.  The site's method of IMP destruction must be 
agreed upon by the Sponsors.  The site must obtain written authorization from the 


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Sponsors before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Venetoclax
The Sponsor will offer continued access to Roche IMP (venetoclax) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (venetoclax) after completing the study 
if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being.

There are no appropriate alternative treatments available to the patient.

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them.
A patient will not be eligible to receive Roche IMP (venetoclax) after completing the 
study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient).

The Sponsor has discontinued development of the IMP or data suggest that the 
IMP is not effective for CLL.

The Sponsor has reasonable safety concerns regarding the IMP as treatment 
for CLL.

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country.
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
Patients may be eligible to receive venetoclax + rituximab as part of the R/C Substudy, 
as described in Section 3.1.3.


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4.4
CONCOMITANT THERAPY AND FOOD
4.4.1
Permitted Therapy
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements) used by a patient from 
28 days prior to the initiation of study treatment through the end of treatment.  All 
concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use for the duration of the study or at least 
30 days after the last dose of study drug or 1 year after the last dose of rituximab, 
whichever is longer.
Necessary supportive measures for optimal medical care will be given throughout 
the study according to institutional standards, including the use of growth factors 
(e.g., erythropoietin) if clinically indicated.  G-CSF may be administered as primary 
prophylaxis in each cycle of therapy, per the ASCO guidelines (Smith et al. 2006) or 
each site’s institutional standards.
Anti-emetic therapy may be instituted for any patient if clinically indicated.  
Bendamustine has a moderate risk of emesis (Cheson et al. 2010).  It is recommended 
that bendamustine infusions be administered following premedication with a serotonin 
(5-HT3) antagonist (i.e., dolasetron, ondansetron, etc.) or per institutional practice.
4.4.1.1
Premedication before Rituximab
Premedication may attenuate IRRs.  The following premedication is required prior to 
rituximab therapy: 

Acetaminophen (6501000 mg) at least 30 minutes prior to the start of all infusions

Diphenhydramine (2550 mg) approximately 30 minutes prior to the start of the first 
infusion and mandatory for all subsequent infusions unless previous antibody 
infusions did not result in an IRR greater than NCI CTCAE Grade 1 and there was 
no interruption to the infusion.  (Another suitable antihistamine is also acceptable 
and must follow the preceding guidelines.)
A single dose of hydrocortisone (up to 100 mg or an equivalent dose of 
methylprednisolone) may also be administered with rituximab if this is the usual practice 
at the site. 
Because transient hypotension may occur during rituximab infusion, consideration 
should be given to withholding antihypertensive medications for 12 hours prior to 
rituximab infusion.


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4.4.1.2
Prophylaxis and Management of Tumor Lysis Syndrome
TLS is a risk for patients with CLL who are treated with highcell-killing agents.  Clinical 
data from CLL patients treated to date with venetoclax suggest that patients with 
baseline lymph nodes 5 cm diameter are at a greater risk for TLS than those with 
baseline lymph nodes 5 cm.  In addition, the data showed that creatinine clearance of 
80 mL/min at screening was a secondary risk factor for TLS.  A detailed description of 
risk factors for developing tumor lysis following treatment with venetoclax is available in 
the Venetoclax Investigator’s Brochure.  The section below describes the management 
of patients throughout dosing (as described in Section 4.3.2) based on their risk factors 
for developing TLS identified upon study entry. 
On the basis of the data review performed by the Sponsors, the following are three TLS
risk categories identified:
1.
TLS low-risk: the presence of all measurable lymph nodes with the largest diameter 
5 cm by radiographic assessment AND absolute lymphocyte counts 25109/L
2.
TLS medium-risk: the presence of all measurable lymph nodes with the largest 
diameter 5 cm and 10 cm by radiologic assessment OR absolute lymphocyte 
count 25109/L
3.
TLS high-risk:  the presence of any lymph node with the largest diameter 10 cm by 
radiologic assessment OR the presence of BOTH an absolute lymphocyte count 
25109/L AND a measurable lymph node with the largest diameter 5 cm by 
radiologic assessment
All patients enrolling in the study will be assessed at screening and categorized in a TLS 
risk category as described above.  
Further details of TLS prophylaxis and monitoring are presented in the following with 
summary at the end of Table 2.
Initial Doses:  20 and 50 mg
All patients, irrespective of their TLS risk category, must receive the following TLS 
prophylaxis measures prior to the initiation of the first doses of venetoclax:

Administration of an oral uric acid reducer (such as allopurinol 300 mg/day) 
beginning at least 72 hours prior to dose and continued until the first week of 
combination therapy with venetoclax and rituximab is completed

Oral hydration consisting of fluid intake of approximately 1.52 L/day starting at 
least 48 hours prior to the start of treatment and continued for at least 24 hours after 
the first dose

Serum chemistry and hematology laboratory samples must be drawn anytime within 
72 hours prior to first dose and electrolyte values should be reviewed and not 
demonstrate any clinically significant abnormalities prior to the first dose of 
venetoclax.  If clinically significant laboratory abnormalities are observed in this 
baseline laboratory assessment, first dose of venetoclax must be delayed until 


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resolution and management per the protocol Appendix 11, Recommendations for 
Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis 
Syndrome, must be initiated. If active correction of electrolytes was performed, the 
first dose of venetoclax can only be given when electrolytes have been stable 
without any more treatment for at least 24 hours.  If needed, patient should receive 
additional prophylactic treatment prior to the initiation of dosing.
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS 
risk category as follows.
TLS Low Risk

Low-risk patients will receive their initial doses of 20 and 50 mg as outpatients.

For patients unable to maintain oral hydration at 1.52 L/day starting at least 
48 hours prior to the start of treatment, IV hydration in the outpatient setting on the 
day of dosing during the clinic stay is recommended in order to assure that this full 
amount of hydration is achieved.  For patients for whom volume overload is 
considered a significant risk, hospitalization should be considered. 

Serum chemistry, hematology, and vital signs will be performed before dosing 
(defined as up to 4 hours before venetoclax dose), 8 and 24 hours after dosing 
timepoints.  Laboratory samples should be sent and analyzed immediately.  
For patients in whom the laboratory values required to be done within 72 hours 
prior to the first dose were in fact obtained within 24 hours before dosing and 
were within normal limits, results from “before dosing” laboratory values are not 
required to be available prior to initiating venetoclax treatment but rather will 
serve only as a baseline for post-dosing laboratory results comparisons. 
The 8-hour chemistry results must be reviewed before the patient leaves the 
outpatient clinic that day. 
Furthermore, the investigator or subinvestigator must review the 24-hour 
laboratory results prior to dosing on the next day.  
Additional laboratory assessments may be performed per investigator discretion.
TLS Medium Risk

Medium-risk patients who have creatinine clearance 80 mL/min will receive their 
initial doses of 20 and 50 mg as outpatients.  Patients with creatinine clearance 
80 mL/min and/or who have higher tumor burden (defined per the discretion of the 
investigator) may be handled as high-risk patients (see the High Risk section for 
details of hydration, laboratory, etc.).

In addition to oral hydration stated above, IV hydration (1.52 L) will be given in the 
outpatient setting during the clinic stay.  For patients for whom volume overload is 
considered a significant risk, hospitalization should be considered.


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
Serum chemistry, hematology, and vital signs will be performed before dosing 
(defined as up to 4 hours before venetoclax dose), 8 and 24 hours after dosing 
timepoints.  Laboratory samples should be sent and analyzed immediately.  
For patients in whom the laboratory values required to be done within 72 hours 
prior to the first dose were in fact obtained within 24 hours before dosing and 
were within normal limits, results from “before dosing” laboratory values are not 
required to be available prior to initiating venetoclax treatment, but rather will 
serve only as a baseline for post-dosing laboratory results comparisons. 
The 8-hour chemistry results must be reviewed before the patient leaves the 
outpatient clinic that day. 
Furthermore, the investigator or subinvestigator must review the 24-hour 
laboratory results prior to dosing on the next day.  
Additional laboratory assessments may be performed per investigator discretion.
TLS High Risk

High-risk patients will be hospitalized to receive their initial doses of 20 and 50 mg.  
Hospitalization will begin the evening prior to each initial dose of venetoclax and 
continue for 24 hours after.  

Upon admission, serum chemistry and hematology laboratory samples should be 
drawn and IV hydration should be started with a target of approximately 23 L per 
day or as clinically appropriate. 

Rasburicase must be administered per regional standards/institutional guidelines 
as prophylaxis prior to the first dose of venetoclax for high-risk patients with 
high uric acid levels at pre-dose (above the local laboratory ULN or Cairo-Bishop 
threshold of 476 µmol/L).  For patients with a contraindication to rasburicase 
(i.e., glucose-6-phosphate dehydrogenase deficiency), the TLS risk-mitigation plan 
must be reviewed with the Medical Monitor.  Uric acid levels following treatment with 
rasburicase must be analyzed using specific guidelines described in Section 4.5.1.7. 

Nephrology (or acute dialysis service) consultation should be considered on 
admission (per institutional standards or based on investigator discretion) for 
hospitalized patients to ensure emergency dialysis is available and the appropriate 
staff is aware and prepared to handle any necessary intervention for TLS.  
Telemetry should also be considered.

Serum chemistry, hematology, and vital signs will be performed before dosing and 
at 4 (serum chemistry only), 8, 12 (serum chemistry only), and 24 hours after dosing.  
These samples are to be sent immediately to the laboratory, and the results must be 
reviewed promptly by the investigator or subinvestigator.  The 24-hour post-dose 
laboratory results must be reviewed by the investigator or subinvestigator before the 
patient leaves the hospital or receives any additional study drug.  Additional 
laboratory assessments may be performed per investigator discretion.


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Subsequent Dose Increases during the Venetoclax Ramp-Up Period:  100, 
200, and 400 mg
All patients, irrespective of their risk category, must receive the following TLS 
prophylaxis measures prior to subsequent dose increases of venetoclax:

Continued administration of an oral uric acid reducer as indicated above.

Oral hydration consisting of fluid intake of approximately 1.52 L/day starting at 
least 48 hours prior to dosing.  IV hydration is encouraged at subsequent dose 
increases for patients unable to maintain such oral hydration.  IV hydration in the 
outpatient setting on the day of dosing during the clinic stay is recommended in 
order to assure this full amount of hydration is achieved.  For patients for whom 
volume overload is considered a significant risk, hospitalization should be 
considered.

Serum chemistry and hematology laboratory samples must be drawn within 
72 hours prior to dose and electrolyte values should be reviewed and not 
demonstrate any clinically significant abnormalities prior to each dose increase of 
venetoclax, or the patient should receive additional prophylactic treatment prior to 
dosing.  If clinically significant laboratory abnormalities are observed in this 
laboratory assessment, dose of venetoclax must be delayed until resolution, and 
management per the protocol Appendix 11, Recommendations for Initial 
Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome, 
must be initiated.  If needed, patient should receive additional prophylactic treatment 
prior to the initiation of dosing.  If active correction of electrolytes was performed, the 
first or subsequent dose of venetoclax can only be given when electrolytes have 
been stable without any more treatment for at least 24 hours.  
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS 
risk category as follows.
TLS Low Risk

Low-risk patients will receive the subsequent dose increases (100, 200, and 400 mg) 
as outpatients.

Serum chemistry, hematology, and vital signs will be performed before dosing 
(defined as up to 4 hours before venetoclax dose) and at 8 and 24 hours after 
dosing timepoints.  Laboratory samples should be sent and analyzed immediately.  
For patients in whom the laboratory values required to be done within 72 hours 
prior to the first dose were in fact obtained within 24 hours before dosing and 
were within normal limits, results from “before dosing” laboratory values are not 
required to be available prior to initiating venetoclax treatment but rather will 
serve only as a baseline for post-dosing laboratory results comparisons.
The 8-hour chemistry results must be reviewed before the patient leaves the 
outpatient clinic that day. 


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Furthermore, the investigator or subinvestigator must review the 24-hour 
laboratory results prior to dosing on the next day.  
Additional laboratory assessments may be performed per investigator discretion.
TLS Medium Risk

Medium-risk patients who have creatinine clearance ≥ 80 mL/min will receive their 
subsequent dose increases as outpatient.  Patients with creatinine clearance 
< 80 mL/min and/or who have high tumor burden (defined per the discretion of the 
investigator) may be hospitalized.

For patients who receive this subsequent dose increases as outpatient, serum 
chemistry, hematology, and vital signs will be performed before dosing (defined as 
up to 4 hours before venetoclax dose) and 8 and 24 hours after dosing timepoints.  
Laboratory samples should be sent and analyzed immediately.  
For patients in whom the laboratory values required to be done within 72 hours 
prior to the first dose were in fact obtained within 24 hours before dosing and 
were within normal limits, results from “before dosing” laboratory values are not 
required to be available prior to initiating venetoclax treatment but rather will 
serve only as a baseline for post-dosing laboratory results comparisons. 
The 8-hour chemistry results must be reviewed before the patient leaves the 
outpatient clinic that day. 
Furthermore, the investigator or subinvestigator must review the 24-hour 
laboratory results prior to dosing on the next day.  
Additional laboratory assessments may be performed per investigator discretion.

For patients hospitalized during subsequent dose increases, serum chemistry, 
hematology, and vital signs will be performed before dosing (defined as up to 
4 hours before venetoclax dose) and 4 (serum chemistry only), 8, 12 (serum 
chemistry only), and 24 hours after dosing.  These samples are to be sent 
immediately to the laboratory, and the results must be reviewed promptly by the 
investigator or subinvestigator.  The 24-hour after dosing laboratory results must be 
reviewed by the investigator or subinvestigator before the patient leaves the hospital 
or receives any additional study drug. 

IV hydration should be started with a target of approximately 23 L per day or as 
clinically appropriate for patients who are hospitalized. 
TLS High Risk

High-risk patients with creatinine clearance of ≥ 80 mL/min will receive the 
subsequent dose increases as outpatients.  Patients with creatinine clearance 
< 80 mL/min and/or high tumor burden (defined per the discretion of the investigator) 
may be hospitalized.  Hospitalization will begin the evening prior to the dose of 
venetoclax and continuing for 24 hours after.

IV hydration (1.52 L) will be given in the outpatient setting during the clinic stay.  
For patients who are hospitalized, IV hydration should be started with a target of 
approximately 23 L per day or as clinically appropriate. 


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
For patients not hospitalized, serum chemistry, hematology, and vital signs will be 
performed before dosing (defined as up to 4 hours before venetoclax dose) and 
8 and 24 hours after dosing timepoints.  Laboratory samples should be sent and 
analyzed immediately.  
For patients in whom the laboratory values required to be done within 72 hours 
prior to the first dose were in fact obtained within 24 hours before dosing and 
were within normal limits, results from “before dosing” laboratory values are not 
required to be available prior to initiating venetoclax treatment, but rather will 
serve only as a baseline for post-dosing laboratory results comparisons. 
The 8-hour chemistry results must be reviewed before the patient leaves the 
outpatient clinic that day. 
Furthermore, the investigator or subinvestigator must review the 24-hour 
laboratory results prior to dosing on the next day.  

For patients hospitalized during subsequent dose increases, serum chemistry, 
hematology, and vital signs will be performed before dosing and 4 (serum chemistry 
only), 8, 12 (serum chemistry only), and 24 hours after dosing.  These samples are 
to be sent immediately to the laboratory, and the results must be reviewed promptly 
by the investigator or subinvestigator.  The 24-hour after dosing laboratory results 
must be reviewed by the investigator or subinvestigator before the patient leaves the 
hospital or receives any additional study drug.

Additional laboratory assessments may be performed per investigator discretion.
Any patient who, at any dose, develops clinically significant electrolyte abnormalities 
must have his or her subsequent venetoclax dose held until the electrolyte abnormalities 
resolve.  Patients who develop electrolyte abnormalities should undergo aggressive 
management and further monitoring per Appendix 11, Recommendations for Initial 
Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome.  If 
active correction of electrolytes was performed, the first dose of venetoclax can only be 
given when electrolytes have been stable without any more treatment for at least 
24 hours.  Any time during the ramp-up period, if venetoclax was held for 7 days or less, 
the patient may resume venetoclax at the same dose level or at one lower dose level as 
determined by the investigator based on a risk assessment (including tumor burden 
status).  Dose must be resumed at one lower dose level if dose held more than 7 days 
with the exception of initial dose level of 20 mg (400 mg 200 mg, 200 mg 100 mg, 
100 mg 50 mg, 50 mg 20 mg).  All patients must receive the intended dose for at 
least 7 days before increasing to the next ramp-up dose.
First Rituximab Dose
All patients will have the following procedures regardless of TLS risk category:

The first dose of rituximab will be given in an outpatient setting.  Patients may be 
hospitalized for the first dose of rituximab at the investigator’s discretion following 
discussion with the Medical Monitor. 


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
Oral hydration consisting of fluid intake of approximately 1.52 L/day starting at 
least 48 hours prior to dosing.  IV hydration is encouraged for patients unable to 
maintain such oral hydration.  IV hydration in the outpatient setting on the day of 
dosing during the clinic stay is recommended in order to assure this full amount of 
hydration is achieved.  For patients for whom volume overload is considered a 
significant risk, hospitalization should be considered.
IV hydration (1.52 L) will be given in the outpatient setting during the clinic stay.  For
patients who are hospitalized, IV hydration should be started with a target of 
approximately 23 L per day or as clinically appropriate.
Venetoclax will be taken at least 30 minutes prior to starting the rituximab infusion.
Serum chemistry, hematology, and vital signs will be performed before dosing (defined 
as up to 4 hours before venetoclax dose) and 8 and 24 hours after dosing of venetoclax.  
Laboratory samples should be sent and analyzed immediately.  Results from predose 
laboratory values are not required to be available prior to initiating venetoclax treatment
provided laboratory values obtained within 24 hours before dosing were within normal 
limits.  The 8-hour laboratory results must be reviewed prior to the patient leaving the 
clinic.
The 24-hour chemistry values must be reviewed before the patient receives the next day 
dose of venetoclax.  If there is no evidence of TLS 24 hours after rituximab and 
venetoclax dose, patients can continue on venetoclax daily dosing.
Patients who develop any electrolyte changes suggestive of TLS should have his or her 
subsequent venetoclax dose held until the electrolyte abnormalities resolve and undergo 
aggressive management and further monitoring per Appendix 11, Recommendations for 
Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome.  
If active correction of electrolytes was performed, the first dose of venetoclax can only 
be given when electrolytes have been stable without any more treatment for at least 
24 hours.


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Downgrading TLS Risk Category 
Patients classified as TLS high-risk at screening due to an absolute lymphocyte count 
25 109/L AND a measurable lymph node with the largest diameter 5 cm but less 
than 10 cm by radiologic assessment may have a re- evaluation of their TLS risk 
category based on their most recent ALC for dose increases above 50 mg.  Based on 
those results, one of the following two options may be implemented:

If the patient’s ALC decreases to 25 × 109/L, the patient may be categorized as 
TLS medium- risk and follow the management guidelines for the TLS medium-risk 
category for subsequent dose increases (to 100, 200, 400 mg) of venetoclax during 
the Ramp-Up Period.

If the patient’s ALC remains 25 109/L, the patient will remain in the TLS high-risk 
category and continues to follow management guidelines for TLS high-risk patients 
for subsequent dose increases of venetoclax during the Ramp-Up Period.  
Re-assessment of the patient’s TLS risk category can occur prior to each 
subsequent dose increase. 


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Table 2
Summary of TLS Prophylaxis and Monitoring Measures
TLS Risk 
Category
Day 1 of 
Dose Level
Prophylaxis Medication
Hospitalization
Hydration a
Laboratory Assessments b, e
TLS low-risk
20, 50, 100, 
200, 400 
mg
Oral uric acid reducer (such as allopurinol 
300 mg/day) beginning at least 72 hours 
prior to dose and continued until the first 
week of combination therapy with 
venetoclax and rituximab is completed.
No
Oral hydration of 1.52 L/day 
beginning at least 48 hours 
prior to dose and continuing for 
at least 24 hours after dose.
Chemistry and Hematology within 72 hours prior to 
dose, before dosing (defined as up to 4 hours before 
venetoclax dose), 8 and 24 hours after dosing 
timepoints.
The 8-hour chemistry results must be reviewed 
before the patient leaves the outpatient clinic that 
day.
The investigator or subinvestigator must review the 
24-hour laboratory results prior to dosing on the next 
day.
TLS 
medium-risk
20 and 
50 mg
Oral uric acid reducer (such as allopurinol 
300 mg/day) beginning at least 72 hours 
prior to dose and continued until the first 
week of combination therapy with 
venetoclax and rituximab is completed.
No c, d
Oral hydration of 1.52 L/day 
beginning at least 48 hours 
prior to dose and continuing for 
at least 24 hours after dose.
In addition to oral hydration, IV 
hydration (1.52 L) will be given 
in the outpatient setting during 
the clinic stay.
Chemistry and Hematology within 72 hours prior to 
dose, before dosing (defined as up to 4 hours before 
venetoclax dose), 8 and 24 hours after dosing 
timepoints.
The 8-hour chemistry results must be reviewed 
before the patient leaves the outpatient clinic that 
day.
The investigator or subinvestigator must review the 
24-hour laboratory results prior to dosing on the next 
day.
100, 200, 
400 mg
Continue oral uric acid reducer as above.
Oral hydration of 1.52 L/day 
beginning at least 48 hours 
prior to dose and continuing for 
at least 24 hours after dose.


Table 2 Summary of TLS Prophylaxis and Monitoring Measures (cont.)
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TLS Risk 
Category
Day 1 of 
Dose Level
Prophylaxis Medication
Hospitalization
Hydration a
Laboratory Assessments b, e
TLS high-risk
20 and 
50 mg
Oral uric acid reducer (such as allopurinol 
300 mg/day) beginning at least 72 hours 
prior to dose and continued until the first 
week of combination therapy with 
venetoclax and rituximab is completed.
Rasburicase must be administered per 
regional standards/institutional guidelines 
as prophylaxis prior to the first dose of 
venetoclax for high-risk patients with high 
uric acid levels at pre-dose (above the local 
laboratory ULN or Cairo-Bishop threshold of  
476 µmol/L).  For patients with a 
contraindication to rasburicase (i.e., 
glucose 6 phosphate dehydrogenase 
deficiency), the TLS risk-mitigation plan 
must be reviewed with the Medical Monitor.  
Uric acid levels following treatment with 
rasburicase must be analyzed using 
specific guidelines described in 
Section 4.5.1.7.
Yes d
Oral hydration of 1.52 L/day 
beginning at least 48 hours 
prior to dose and continuing for 
at least 24 hours after dose.
Chemistry and Hematology within 72 hours prior to 
dose, before dosing (defined as up to 4 hours before 
venetoclax dose), 4 (serum chemistry only), 8, 12
(serum chemistry only), and 24 hours after dosing 
timepoints.
Samples are to be sent immediately to the 
laboratory, and the results must be reviewed 
promptly by the investigator or subinvestigator.
The 24-hour after dosing laboratory results must be 
reviewed by the investigator or subinvestigator 
before the patient leaves the hospital or receives any 
additional study drug


Table 2 Summary of TLS Prophylaxis and Monitoring Measures (cont.)
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TLS Risk 
Category
Day 1 of 
Dose Level
Prophylaxis Medication
Hospitalization
Hydration a
Laboratory Assessments b, e
100, 200, 
400 mg
Continue oral uric acid reducer as above
No c, d
Oral hydration of 1.52 L/day 
beginning at least 48 hours 
prior to dose and continuing for 
at least 24 hours after dose.
In addition to oral hydration, IV
hydration (1.52L) will be given 
in the outpatient setting during 
the clinic stay.
Chemistry and Hematology within 72 hours prior to 
dose, before dosing (defined as up to 4 hours before 
venetoclax dose), 8 and 24 hours after dosing 
timepoints.
The 8-hour chemistry results must be reviewed 
before the patient leaves the outpatient clinic that 
day.
The investigator or subinvestigator must review the 
24-hour laboratory results prior to dosing on the next 
day.
TLS= tumor lysis syndrome; ULN= upper limit of normal.
a
For patients unable to maintain oral hydration at 1.52 L/day starting at least 48 hours prior to the start of treatment, IV hydration in the outpatient setting on the day of dosing during 
the clinic stay is recommended (unless being hospitalized) in order to assure that this full amount of hydration is achieved.  For patients for whom volume overload is considered a 
significant risk, hospitalization should be considered.
b
Results from pre-dose laboratory values are not required to be available prior to initiating venetoclax treatment provided laboratory values obtained within 24 hours before dosing 
were within normal limits.  For laboratory samples drawn on days on study treatment, “before dosing” laboratory samples should be drawn within 04 hours before the dose.  Other 
laboratory samples occurring on the same day should be obtained within a 15‑minute window of any exact scheduled time. Any laboratory tests occurring at time intervals greater 
than or equal to 24 hours after dose should be obtained within a 2 hour window of the scheduled time.
c
Patients with creatinine clearance 80 mL/min and/or who have higher tumor burden (defined per the discretion of the investigator) may be handled as TLS high-risk patients.
d 
Nephrology (or acute dialysis service) consultation should be considered on admission (per institutional standards or based on investigator discretion) for hospitalized patients to 
ensure emergency dialysis is available and the appropriate staff is aware and prepared to handle any necessary intervention for TLS.  Telemetry should also be considered.
e
Any patient who, at any dose, develops clinically significant electrolyte abnormalities must have subsequent venetoclax dose held until the electrolyte abnormalities resolve.  Patients 
who develop electrolyte abnormalities should undergo aggressive management and further monitoring per Appendix 11.  If active correction of electrolytes is performed, the first or 
subsequent dose of venetoclax can only be given when electrolytes have been stable without any more treatment for at least 24 hours.  Any time during the ramp-up period, if 
venetoclax was held for 7 days or less, the patient may resume venetoclax at the same dose level or at one lower dose level as determined by the investigator based on a risk 
assessment (including tumor burden status).  Dose must be resumed at one lower dose level if dose held more than 7 days with the exception of initial dose level of 20 mg 
(400 mg 200 mg, 200mg 100 mg, 100 mg 50 mg, 50 mg20 mg). 


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4.4.1.3
Prophylaxis for Infections
If clinically indicated, anti-infective prophylaxis for viral, fungal, bacterial or Pneumocystis 
infections is permitted.  (Although there is a potential for drugdrug interactions, there is 
likely to be limited potential clinical effects, therefore trimethoprim sulfamethoxazole 
[Bactrim] can be considered for Pneumocystis prophylaxis with close clinical 
monitoring.)  The Medical Monitor should also be consulted regarding any consideration 
of the use of azoles as anti-fungal prophylaxis or therapy, because of the potential for 
drugdrug interactions.
4.4.1.4
Prophylaxis of Hepatitis B Reactivation
Patients in countries where prophylactic anti-viral medications for hepatitis B reactivation 
are the standard of care may be treated prophylactically.
4.4.2
Prohibited and Cautionary Therapy
Use of the following therapies is prohibited during the study treatment period:

Any therapies intended for the treatment of leukemia whether U.S. Food and Drug 
Administration (FDA)-approved or experimental (outside of this study) including:
Cytotoxic chemotherapy
Radiotherapy
Immunotherapy
Systemic steroid therapy 

Anti-retroviral medications

Hormone therapy (other than contraceptives, hormone replacement therapy, or 
megestrol acetate)

Systemic steroid therapy either during or within 7 days prior to the first dose of study 
treatment with the exception of inhaled corticosteroids for the treatment of asthma or 
chronic obstructive pulmonary disease, single infusions of hydrocortisone prior to 
rituximab infusions, topical steroids, or replacement corticosteroid therapy for an 
inherited or acquired deficiency

CYP1A2 inhibitors and inducers (because of possible interaction with bendamustine, 
a CYP1A2 substrate)
Live-virus vaccines should not be given within 28 days prior to the initiation of study 
treatment, at any time during study treatment, or following study treatment until B cell 
levels have returned to normal.


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Use of the following therapies is prohibited or cautionary during the study treatment 
period due to drug-drug interactions:

Medications prohibited during ramp-up period and cautionary at the designated dose 
of venetoclax (400 mg) include the following:
Strong and moderate CYP3A inhibitors
Prohibited during ramp-up period (consider alternative medications). If 
patient requires use of these medications at the designated dose, use with 
caution and reduce the venetoclax dose by 2-fold for moderate inhibitors 
and 4-fold for strong inhibitors during co-administration.  After 
discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose 
is increased back to the initial maintenance/target dose.
Strong and moderate CYP3A inducers
Prohibited during ramp-up period (consider alternative medications). If 
patient requires use of these medications at the designated dose, use with 
caution and contact the medical monitor for guidance.

Cautionary medications include the following:
Warfarin
Weak CYP3A inducers
Weak CYP3A inhibitors
P-gp substrates
BCRP substrates
OATP1B1 and OATP1B3 substrates
P-gp inhibitors
BCRP inhibitors
OATP1B1 and OATP1B3 inhibitors
A sample list of prohibited medications and cautionary medications due to drug-drug 
interactions can be found in Appendix 9.  It is not possible to produce an exhaustive list 
of medications that fall into these categories, so if in question, please refer to the 
appropriate product label.
4.4.3
Prohibited Food
Use of the following foods is prohibited during the study and for at least 3 days prior to 
initiation of study treatment:

Grapefruit

Grapefruit juice

Grapefruit-containing products

Seville oranges (including marmalade containing Seville oranges)

Star fruit


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4.5
STUDY ASSESSMENTS 
4.5.1
Description of Study Assessments
4.5.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, cancer history (including prior 
cancer therapies and procedures), smoking history, and all medications (e.g., 
prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 14 days prior to the screening visit.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.1.2
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the Medical History/Surgical History eCRF.  As part of tumor assessment, 
physical examinations should also include the evaluation of the presence and degree of 
enlarged lymph nodes, hepatomegaly, and splenomegaly.
Targeted physical examinations should be limited to systems of primary relevancethat 
is, cardiovascular, respiratory, those associated with symptoms, and those associated 
with tumor assessment (lymph nodes, liver, and spleen).
Changes from baseline abnormalities at subsequent visits should be recorded in patient 
notes.  New or worsened clinically significant abnormalities should be recorded as 
adverse events on the Adverse Event eCRF.
Height is to be recorded at screening only.  Weight is to be recorded in the standing 
position (if possible); please see Appendix 1.
BSA will be calculated by the formula of Mosteller (1987) or site standard formula, as 
follows:
BSA (m2) = {[Height (cm) Weight (kg)]/3600}½
BSA calculated at screening should be used to calculate the dose of rituximab and of 
bendamustine throughout the study unless the patient’s weight increases or decreases 
by 10% from screening.  In obese patients, there is no BSA cap and actual body weight, 
not adjusted weight, is recommended.  Nonetheless, empiric dose adjustment is 
permitted in obese patients (obesity defined as body mass index 30 kg/m2).
4.5.1.3
Vital Signs and ECOG Performance Status
Vital signs will include measurements of temperature, heart rate, and systolic and 
diastolic blood pressure after the patient has been in a seated position for 5 minutes.


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ECOG Performance Status (see Appendix 7) will be recorded for patients at screening 
and at subsequent visits as described in the Schedule of Assessments (Appendix 1).
4.5.1.4
Electrocardiogram
Twelve-lead resting ECGs will be obtained at screening and at subsequent visits, as 
clinically indicated.
Digital ECG recordings must be obtained at each specified timepoint.  ECGs for each 
patient should be obtained from the same machine whenever possible.  To minimize 
variability, it is important that patients be in a resting position for 10 minutes prior to 
each ECG evaluation.  Body position should be consistently maintained for each ECG 
evaluation to prevent changes in heart rate.  Environmental distractions (e.g., television, 
radio, conversation) should be avoided during the pre-ECG resting period and during 
ECG recording.  ECGs should be performed prior to any scheduled vital sign 
measurements and blood draws.
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings.  Paper copies of ECG tracings will be kept as part of the patient's 
permanent study file at the site.
4.5.1.5
Assessment of Left Ventricular Ejection Fraction
Baseline assessment of ejection fraction will be made at screening by either 
echocardiogram or multi-gated acquisition (MUGA) scan.  Subsequent evaluations of left 
ventricular ejection fraction (LVEF) will be made as clinically indicated for patients who 
develop signs of cardiac compromise.  The decision to enroll a patient with significant 
cardiac disease in the study will be made by the investigator and Medical Monitor.
4.5.1.6
Tumor and Response Evaluations
All measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response will be assessed by the investigator and by the 
IRC on the basis of physical examinations, imaging studies, laboratory results, and bone 
marrow examinations, using iwCLL response criteria for CLL (Hallek et al. 2008) (see
Appendix 10).
All patients must have clinical response assessments (including targeted physical 
examination and laboratory examinations) at screening, Day 1 of every cycle during the 
combination therapy, at interim response assessment (within 14 days of Cycle 4 Day 1), 
after combination therapy (defined as 4 weeks after Day 1 of Cycle 6 or 4 weeks after 
Day 1 of the last cycle for early termination), and at 23 months after Day 1 of the last 
cycle of combination therapy.  
All patients must have CT scans (or magnetic resonance imaging [MRI] if CT is 
contraindicated) of the neck (if clinically indicated), chest, abdomen, and pelvis with IV 
and oral contrast at screening, interim response assessment (within 14 days of Cycle 4 


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Day 1) and 23 months after completion of combination therapy (or 4 weeks after Day 1 
of the last cycle for early termination).  A follow-up scan must also be performed for 
patients who meet all clinical and laboratory criteria for an initial CR or PR at subsequent 
assessment timepoints.  Sites can do imaging to confirm a PR or CR at any time during 
the study.  The method of imaging should be consistent for each patient at subsequent 
timepoints.
Patients who have not progressed after the 6 cycles of combination therapy will then be 
followed with response assessments at every follow-up visit until progression or close of 
study, whichever occurs first.  Assessments will be based on hematological status and 
targeted physical examination.  Additional imaging evaluations should be performed to 
confirm a suspected change in response status, that is, SD to PR or PR to CR/CRi.  If a 
patient’s response improves to a CR or CRi during further follow-up, bone marrow 
examination must be performed to confirm the CR.
If at any time during the study, a patient exhibits clinical signs of possible disease 
progression (i.e., increased or de novo enlargement of liver, spleen, or lymph nodes on 
physical examination) in the absence of laboratory or histopathologic changes meeting 
the criteria for PD, then additional assessments including imaging studies and/or bone 
marrow examination (in setting of new cytopenias) must be performed within 2 weeks to 
confirm or rule out PD.
Imaging evaluation for response assessment may be limited to areas of prior 
involvement only, if required by local regulatory authorities.  Provisions will be made to 
collect and store all imaging studies for IRC review.
Bone marrow examinations should include aspirate and biopsy for morphology and 
biomarker studies, and are required at screening.  For those patients who have achieved 
a CR or CRi (including an imaging evaluation indicating a possible CR), a bone marrow 
aspirate and biopsy will be obtained to confirm the CR 23 months following the initial 
clinical assessment of the CR.  If the bone marrow is hypocellular, a repeat 
determination should be made in 4 weeks or when peripheral blood counts have 
recovered.  Any additional/unscheduled bone marrow examinations performed during 
the study will be at the discretion of the investigator.  Results of all bone marrow 
assessments should be forwarded to the Sponsors.
A bone marrow aspirate should be obtained for MRD assessment in the bone marrow in 
all responders (CRPR) at the End of Combination Treatment Response Visit.  In 
addition, MRD samples in peripheral blood will be collected at baseline, within 14 days of 
C4D1 (interim response assessment), completion of Combination Therapy/Early
Treatment Termination Visit (if applicable), End of Combination Treatment Response 
Visit, and at the timepoints specified in Appendix 1 during the follow-up or at any visit 
during follow-up where a patient has a response (PR or CR status).  Samples will be 
measured at a central laboratory.


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4.5.1.7
Laboratory Assessments
For laboratory samples drawn on days on study treatment, “before dosing” laboratory 
samples should be drawn within 04 hours before the dose.  Other laboratory samples 
occurring on the same day should be obtained within a 15‑minute window of any 
scheduled time. Any laboratory tests occurring at time intervals greater than or equal to 
24 hours after dose should be obtained within a 2‑hour window of the scheduled time.
Local Laboratory Assessments
Samples for the following standard laboratory tests will be sent to the study site's local 
laboratory for analysis:

17p deletion by FISH testing (the results will be used to determine 17p deletion 
status as positive or negative for study enrollment).  Results from a prior positive 
laboratory test may be used if available or from a negative test if testing was done 
within 8 weeks of the screen date.  In the event a local FISH test is not available, the 
result of the central test may be used by the site for randomization. 

Hematology:  complete blood count (hemoglobin, hematocrit, RBC count, WBC), 
platelet count, ANC, ALC, and percent or absolute differential counts (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells)

Quantitative immunoglobulins (IgA, IgG, IgM)

Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN or urea 
(when BUN not available), creatinine, calcium, magnesium, phosphorus, total 
bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, LDH, and uric acid  
Please note that at room temperature, rasburicase causes enzymatic 
degradation of the uric acid in blood/plasma/serum samples potentially resulting 
in spuriously low plasma uric acid assay readings.  The following special 
sample handling procedure must be followed to avoid ex vivo uric acid 
degradation in samples collected after treatment with rasburicase:
Uric acid must be analyzed in plasma. 
Blood must be collected into prechilled tubes containing heparin 
anticoagulant.  Immediately immerse plasma samples for uric acid 
measurement in an ice water bath.
Plasma samples must be prepared by centrifugation in a precooled 
centrifuge (4°C).
Finally, the plasma must be maintained in an ice water bath and analyzed 
for uric acid within 4 hours of collection.

Viral serology and detection:
Hepatitis B (HBsAg and HBcAb) 
Note:  Monitoring of HBV-DNA levels through a central laboratory is mandatory 
for patients who are positive for HBcAb and enter the study with undetectable 
HBV-DNA.  For instructions on the management of these patients, see 
Section 5.1.2.3.


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Hepatitis C virus antibody (also HCV RNA by PCR if the patient is 
HCV-antibody-positive)

Serum pregnancy test (females)

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood)

Coagulation (INR, aPTT/PTT, PT) 

Serum 2-microglobulin
Central Laboratory Assessments
Samples for flow cytometry, PK assessments, and bone marrow assessments will be 
sent to one or several central laboratories or to Genentech, Inc. for analysis.  Instruction 
manuals and supply kits will be provided for all central laboratory assessments.

CLL prognostic factors, IgVH mutational status, serum 2-microglobulin (if local test 
is unavailable), p53 mutation status, and interphase FISH for chromosomal 
abnormalities, including central confirmation of 17p deletion, 11q deletion, 13q 
deletion, and trisomy 12

Lymphocyte subset counts:  whole-blood samples will be analyzed by flow 
cytometry for B cells (CD19+) and T-cell subsets (CD3+, CD4+, CD8+) and NK cells 
(CD16+, CD56+).

MRD:  MRD measurements (in peripheral blood and in bone marrow aspirate [when 
applicable]) will be performed at a central laboratory by an accepted methodology.

Blood and bone marrow aspirate for Bcl-2 family expression (including Bcl-2:Bim 
complex) by RNA and protein

Formalin fixed bone marrow biopsy (or other tumor biopsy) for Bcl-2 family 
expression by immunohistochemistry

Peripheral blood for PK analysis, in vitro sensitivity to venetoclax and for
pharmacogenomics

HBV DNA by PCR in HBcAb positive patients at screening and then follow-up for 
patients who are positive for HBcAb and enter the study with undetectable 
HBV-DNA.  For instructions on the management of these patients, see 
Section 5.1.2.3.
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual.
4.5.1.8
Patient-Reported Outcomes
PRO data will be elicited from the patients in this study to more fully characterize the 
clinical profile of venetoclax.  The PRO instruments, translated as required in the local 
language, will be distributed by the investigator staff and completed in their entirety by 
the patient at specified timepoints during the study.  To ensure instrument validity and 
that data standards meet health authority requirements, PRO questionnaires on paper 
(EORTC QLQ-C30, EORTC CLL-16, and EQ-5D) should be self-administered at the 


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investigational site prior to the completion of other study assessments and the 
administration of study treatment.  For the MDASI questionnaire, an interactive voice 
response solution (IVRx) will be used to capture PRO questionnaire data.  The data will 
be transmitted to a centralized database at the IVRx vendor.  The data can be accessed 
by appropriate study personnel securely via the Worldwide Web.
The MDASI (Cleeland et al. 2000) is a cancer related multi-symptom, valid, and reliable 
self-report questionnaire for clinical and research use.  It consists of 19 items over two 
scales that assess symptom severity and symptom interference with different aspects of 
a patient’s life.  Thirteen items (i.e., pain, fatigue, nausea, disturbed sleep, distressed, 
shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sad, 
vomiting, and numbness or tingling) ask patients to rate how severe the symptoms were
when “at their worst” in the last 24 hours.  An additional six items ask patients to rate 
how much the symptoms have interfered with six areas of function (i.e., general activity, 
walking, work, mood, relations with other people, and enjoyment of life) in the last 
24 hours.  Additionally, the MDASI contains tumor-specific modules to assess 
disease-specific symptoms.  For this study, to specifically assess CLL symptoms and 
treatment side-effects, patients will rate six additional symptoms (night sweats, fevers 
and chills, lymph node swelling, diarrhea, bruising easy or bleeding, and constipation).  
The MDASI items are rated from 0 to 10, with 0 indicating that the symptom is either not 
present or does not interfere with the patient’s activities and 10 indicating that the 
symptom is “as bad as you can imagine” or “interfered completely” with the patient’s life.  
The MDASI takes approximately 5 minutes to complete.  The MDASI assessment will be 
conducted using IVRx at the specified timepoints in Appendix 1.
The EORTC QLQ-C30 is a validated and reliable self-report measure (Fayers et al. 1999) 
consisting of 30 questions incorporated into five functional scales (physical, role, 
cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, 
and vomiting scales), and a global health status/global quality-of-life scale.  The 
remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and 
diarrhea) assess the additional symptoms experienced by patients with cancer and the 
perceived financial burden of treatment.  The EORTC QLQ-CLL16 module is designed 
for patients with Stage 0 to Stage 4 CLL.  It is composed of 16 questions that address 
five domains of HRQoL important in CLL.  There are three multi-item scales on fatigue 
(two items), treatment side-effects and disease symptoms (eight items), and infection 
(four items), and two single-item scales on social activities and future health worries.  
The EORTC QLQ-CLL16 module is specific to CLL and is administered in addition to the 
core questionnaire (EORTC QLQ-C30).  The EORTC QLQ-C30 and QLQ-CLL16 
questionnaires take 1015 minutes to complete altogether.  A baseline assessment 
(prior to any study treatment) as well as subsequent assessements should be conducted 
as specified in Appendix 1.
The EQ-5D questionnaire is a generic, preference-based health utility measure with 
questions about mobility, self-care, usual activities, pain/discomfort, and 


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anxiety/depression that are used to build a composite of the patient’s health status.  The 
EQ-5D will be utilized in this study for economic modeling.  The EQ-5D questionnaire 
takes 5 minutes or less to complete and should be completed at the same visits as the 
EORTC QLQ-C30 and QLQ-CLL16.
4.5.1.9
Samples for Roche Clinical Repository
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities for 
the long-term storage of human biologic specimens, including body fluids, solid tissues, 
and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
Approval by the Institutional Review Board or Ethics Committee
Sampling for the RCR is contingent upon the review and approval of the exploratory 
research and the RCR portion of the Informed Consent Form by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for RCR sampling, this section 
of the protocol will not be applicable at that site.
Sample Collection
The following samples will be collected for identification of dynamic (non-inherited) 
biomarkers:

Residual tumor samples from bone marrow aspirate or lymph node biopsy for DNA, 
RNA, or protein extraction may be collected before the first study treatment.
The following samples will be collected for identification of dynamic (non-inherited) 
biomarkers and genetic (inherited) biomarkers:

Whole blood samples for DNA, RNA, or protein extraction will be collected at first 
study treatment visit (before any study treatment dosing) and at the end of treatment.


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For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the Sample Handling and Logistics Manual.  
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may only 
be disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.


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Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes using the RCR Subject Withdrawal Form and, if 
the trial is ongoing, must enter the date of withdrawal on the RCR Research Sample 
Withdrawal of Informed Consent eCRF.  The patient will be provided with instructions on 
how to withdraw consent after the trial is closed.  A patient's withdrawal from 
study GO28667 does not, by itself, constitute withdrawal of specimens from the RCR.  
Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
study GO28667.
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.5.2
Timing of Study Assessments
4.5.2.1
Screening and Pretreatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.


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Screening tests and evaluations will be performed within 28 days prior to study treatment 
initiation, unless otherwise specified.  Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 28 days prior to initiation of 
study treatment may be used; such tests do not need to be repeated for screening.  All 
screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Please see Appendix 1 for the schedule of screening and pretreatment assessments.
4.5.2.2
Assessments during Treatment
All assessments must be performed on the day of the specified visit, unless a time 
window is specified in the schedule of assessments (see Appendix 1).  Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the schedule of 
assessments.  PRO assessments should be performed prior to the completion of other 
study assessments.
See Appendix 1 for the schedule of assessments performed during the treatment period.
4.5.2.3
Assessments at Early Treatment Termination Visit
Patients who discontinue from the study treatment prior to completion of the assigned 
regimen will be asked to return to the clinic within 4 weeks after the last dose of study 
treatment for a follow-up visit.
See Appendix 1 for the schedule of assessments performed at Early Treatment 
Termination Visit.
4.5.2.4
Follow-Up Assessments
After the completion or early termination of study treatment, adverse events should be 
followed as outlined in Sections 5.5 and 5.6.
Patients who discontinue treatment in the absence of disease progression should still be 
followed for progression, new anti-CLL therapy and survival according to the protocol 
schedule. 
Patients who have disease progression during study will subsequently have follow-up 
visits for OS and new anti-CLL therapy every 24 weeks until end of study.  These survival 
follow-up visits may be conducted by telephone. Additional survival follow-up visits 
may be requested by Sponsor for regulatory or publication purposes.
See Appendix 1 for the schedule of follow-up assessments.


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4.5.2.5
Assessments at Unplanned Visits
See Appendix 1 for assessments that are required to be performed in case of an 
unplanned visit.
4.5.2.6
Re-Treatment/Crossover Substudy Assessments
All assessments must be performed on the day of the specified visit or within the
window specified in the schedule of assessments (see Appendix 14).  Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the schedule of 
assessments. Additional safety assessments may be performed per standard of care or as 
clinically indicated.
Screening-R/C evaluation will be performed within 28 days prior to study 
treatment initiation to confirm that patients meet all eligibility criteria.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent 
and within 28 days prior to initiation of study treatment may be used; such tests do not 
need to be repeated for Screening-R/C evaluation unless indicated due to clinically 
significant abnormality by the treating physician.  
An EOCTR-R/C Visit will be scheduled 12 weeks after Cycle 6R/C Day 1 or at disease 
progression, whichever occurs first.  After the EOCTR-R/C Visit, patients who have 
not progressed will be followed clinically every 24 weeks at Follow-Up R/C Visits until 
the COVTR-R/C Visit.  The COVTR-R/C Visit will be scheduled at the completion of 
venetoclax treatment at 2 years from Cycle 1R/C Day1 or at disease progression, 
whichever occurs first.  If patients discontinue early due to toxicity or at disease 
progression, EOCTR-R/C Visit will be scheduled immediately.  After the COVTR-R/C
Visit or disease progression, patients should be followed for OS, PD (if not progressed 
already), and new anti-CLL therapy. These Survival Follow Up Visits will be captured 
every 24 weeks until the end of and may be conducted by telephone.
A full tumor assessment is required at Screening-R/C and EOCTR-R/C Visits by the 
investigator using standard clinical and laboratory examinations, bone marrow 
evaluation and CT scans according to iwCLL guidelines (Hallek et al. 2008).  The 
EOCTR-R/C Visit is to be scheduled 12 weeks (7 days) after Cycle 6R/C Day 1. 
Following the EOCTR-R/C Visit, patients will be followed clinically every 24 weeks in 
Follow-Up R/C Visits until the COVTR-R/C Visit. Patients will also have a clinical 
response assessment at the COVTR-RC Visit to be scheduled at the completion of 
venetoclax monotherapy (i.e., 2 years from Cycle 1R/C Day 1).  If patients discontinue 
early during venetoclax monotherapy, COVTR-R/C Visit will be scheduled immediately.
Additional response assessments may be performed according to institutional 
guidelines and recorded in eCRFs.  Additional CT-scan evaluations should be 
performed during Follow-Up R/C or COVTR-R/C Visits to confirm a suspected change 
in response status, that is, SD to PR or PR to CR/CRi.  If a patient’s response 


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improves to a CR or CRi during Follow-Up R/C or COVTR-R/C Visits, a bone morrow 
biopsy must be performed to confirm the CR.
A bone marrow aspirate should be obtained for MRD assessment in the bone marrow in 
all patients at Screening-R/C and in all responders (CR or PR) at the EOCTR-R/C
Visit.  In addition, MRD samples in peripheral blood will be collected for all patients at 
Screening-R/C, EOCTR-R/C, Follow-Up R/C, and COVTR-R/C Visits.  Samples will 
be analyzed at a central laboratory.
See Appendix 14 for the schedule of assessments performed during the R/C Substudy.
4.6
PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or withdrawal from the study may include but are not 
limited to the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsors determine may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsors determine it is in the best interest of the patient

Patient non-compliance.
4.6.1.1
Discontinuation from Study Drug/Treatment
Patients must discontinue study treatment (venetoclax, bendamustine, rituximab) if they 
experience any of the following:

Pregnancy

Disease progression
Patients who experience toxicity that can be clearly attributed to any particular study 
drug treatment may discontinue treatment with the specific agent if the toxicity is not 
tolerable and mitigating strategies are not available or successful.  If toxicity cannot be 
clearly attributed to a single agent and is considered possibly related to the combination 
treatment, treatment with multiple agents should be discontinued.  Patients who 
discontinue treatment for reasons other than PD should remain on study and continue to 
have disease assessments per protocol.
Patients in Arm A must discontinue venetoclax permanently if they experience any 
dose delay of 4 weeks (except for hepatitis B reactivation) after the last dose (see 
Section 5.1.5, Table 3).  Patients who discontinue venetoclax for reasons other than 
disease progression should remain on the study and continue to have disease 


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assessments per protocol.  Patients in Arm A who discontinue venetoclax for any reason 
should also discontinue rituximab, although they are to continue evaluation per protocol.  
Patients in Arm A who discontinue rituximab therapy for toxicity (including anaphylaxis) 
may continue treatment with single-agent venetoclax after a discussion between the 
investigator and the Medical Monitor.
Patients in Arm B who experience an anaphylactic reaction must discontinue treatment 
with the offending agent (see Section 5.1.5 for guidelines on discontinuation of rituximab 
or dose reduction/modification and discontinuation of bendamustine).  Patients in Arm B 
who discontinue rituximab for toxicity may be eligible to continue monotherapy with 
single-agent bendamustine after a discussion between the investigator and the Medical 
Monitor.
Patients who discontinue study drug/treatment prematurely will be asked to return to the 
clinic for an Early Treatment Termination Visit (see Section 4.5.2.3) and must undergo 
follow-up assessments (see Section 4.5.2.4).  The primary reason for premature study 
drug/treatment discontinuation should be documented on the appropriate eCRF.  
Patients who discontinue study drug treatment prematurely will not be replaced.
Patients enrolled in the R/C Substudy who discontinue study drug/treatment 
prematurely during combination therapy due to toxicity or disease progression will be 
scheduled immediately for the EOCTR-R/C Visit. If venetoclax is discontinued
prematurely during the monotherapy phase, the patient will be scheduled immediately 
for the COVTR-R/C Visit. The primary reason for premature study drug/treatment 
discontinuation should be documented on the appropriate eCRF.  Patients who 
discontinue study drug treatment prematurely will not be replaced.
4.6.1.2
Withdrawal from Study
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the
appropriate eCRF.  Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study and Site Discontinuation
The Sponsors have the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsors will notify the investigator if the study is placed on hold, or if the Sponsors 
decide to discontinue the study or development program.  


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The Sponsors have the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No ongoing study activity (i.e., all patients have completed and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
5.1.1
Risks Associated with Venetoclax
Phase I/II experience with venetoclax has demonstrated that it is generally well tolerated 
and toxicities appear to be mostly manageable and/or reversible; however, clinical 
experience is limited, with 160 patients with CLL/SLL treated with single-agent 
venetoclax (study M12-175) or in combination with other agents as of 3 February 2014.  
Please see the Venetoclax Investigator’s Brochure for more information.
5.1.1.1
Tumor Lysis Syndrome
To date, the principal adverse reaction associated with venetoclax in the ongoing
single-agent Phase I dose-escalation study M12-175 has been TLS (primarily but not 
exclusively related to the first dose), and therefore the study has been modified to 
implement a ramp-up dosing scheme and rigorous TLS prophylaxis (see Section 4.4.1.2).
Experience from study M12-175 has been used to develop a dosing schedule starting at 
20 mg/day that is incrementally increased to the target dose for each cohort.  Doses that 
have been safely administered to date from Phase I studies will be used in this study.
TLS, including cases leading to clinical sequelae and death, has been observed at a 
dose of 50 mg venetoclax, and all patients enrolled in study M12-175 are required to 
receive hydration and an agent to reduce uric acid as TLS prophylaxis at least 72 hours 
prior to starting venetoclax treatment.  Laboratory testing is required after initial dosing to 
monitor for metabolic changes and will be used to assess the need for more intensive 
monitoring and treatment of metabolic abnormalities caused by rapid cell lysis.  Please 
see Section 4.3.2.1.1 and Section 4.4.1.2 for venetoclax dosing instructions and the TLS 
prophylaxis and monitoring plans, respectively.
5.1.1.2
Cytopenia
Effects on lymphocyte numbers are expected based on the mechanism of action, and 
modest reductions in neutrophils have been observed with venetoclax therapy in 
patients.  Thrombocytopenia and anemia have been reported with venetoclax in the


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ongoing single-agent Phase I dose-escalation Study M12-175 and M13-365 that is being 
conducted in heavily pretreated CLL patients.  In certain cases, the condition was 
preexisting.  In this study, blood counts will be monitored closely throughout treatment 
(see the Schedule of Assessments, Appendix 1).  Growth factors are permitted 
according to local practice, and patients will be monitored and treated promptly in case 
of infections.  Dose interruptions or reductions will be allowed based on toxicity.
5.1.1.3
Infectious Complications
Infections of various types have occurred in patients in the ongoing single-agent Phase I 
dose-escalation study M12-175.  CLL itself is associated with impaired immune function 
and increased infections, and it is unclear whether or how much the incidence could be 
increased due to venetoclax treatment.  Patients in this study will be closely monitored 
for infections and prompt therapy will be instituted, as necessary.  Patients are allowed 
to receive concomitant prophylactic anti-infective therapy at the investigator’s discretion.
5.1.1.4
Effects on Cardiac Function
Nonclinical studies demonstrated decreases in cardiac function of (contractility and 
cardiac output) approximately 20% in healthy laboratory animals.  No patterns of 
adverse events indicating changes in cardiac function have been reported in clinical 
studies to date.  However, the number of patients exposed and the duration of exposure 
is still relatively low.  Patients enrolled in this trial are required to have ECGs and 
assessments of LVEF at baseline and as clinically indicated afterwards.
5.1.1.5
Effects on Fertility
There is a potential for decreased spermatogenesis.  Male patients considering 
preservation of fertility should bank sperm before treatment with venetoclax and should 
agree to refrain from donating sperm during the treatment period and for at least 90 days 
after the last dose of venetoclax.  Long-term effects of venetoclax on female
reproductive potential are unknown.
5.1.1.6
Drug Interactions
Drugdrug interactions may occur with venetoclax.  Please refer to Section 4.4.2 for 
prohibited and cautionary medications.
5.1.2
Risks Associated with Rituximab Therapy
Please see the prescribing information for rituximab for full information.
5.1.2.1
Infusion-Related Reactions
Patients treated with rituximab are at risk for IRRs.  Fatal infusion reactions within 
24 hours of rituximab infusion can occur; approximately 80% of fatal reactions occurred 
with the first infusion.  Severe reactions to rituximab typically occurred during the first 
infusion with time to onset of 30120 minutes.  Rituximab-induced infusion reactions and 
sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, 


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pulmonary infiltrates, adult respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death.
5.1.2.2
Tumor Lysis Syndrome 
Patients treated with rituximab may be at risk for TLS.  With rituximab treatment, acute 
renal failure, hyperkalemia, hypocalcaemia, hyperuricemia, or hypophosphatemia from 
tumor lysis, some fatal, can occur within 1224 hours after the first infusion of rituximab 
in patients with NHL.  A high number of circulating malignant cells (25,000/mm3) or 
high tumor burden confers a greater risk of TLS.  Patients treated with venetoclax
(Arm A) will receive prophylaxis as described above and in Section 4.3.2.1.  Patients 
randomized to Arm B (BR) who develop evidence of TLS should be treated as clinically 
indicated.
5.1.2.3
Hepatitis B Reactivation
Hepatitis B reactivation with fulminant hepatitis, hepatic failure, and death can occur in 
patients with hematologic malignancies treated with rituximab.  The median time to 
diagnosis of hepatitis was approximately 4 months after the initiation of rituximab 
treatment and approximately 1 month after the last dose.
Patients with chronic hepatitis B (HBsAg-positive) viral infection are at risk for 
reactivation and will be excluded from the study.  Patients with evidence of prior 
hepatitis B exposure or who are carriers (defined as HBsAg-negative and 
HBcAb-positive) are at a lower risk for reactivation.  In a study of 51 hepatitis B carriers 
with DLBCL who received rituximab, 12% of patients developed evidence of reactivation 
(Skrabs et al. 2002).
Screen all patients for HBV infection by measuring HBsAg and anti-HBcAb.  Patients 
with occult or prior hepatitis B infection (defined as positive total HBcAb and negative 
HBsAg) may be included if HBV DNA is undetectable when conducted at a central 
laboratory.  These patients must be willing to undergo monthly HBV DNA testing during 
therapy and for at least 12 months after the last dose of rituximab.  A baseline blood 
sample followed by monthly testing will be collected to conduct HBV DNA testing at a 
central laboratory using an assay with a sensitivity of at least 10 IU/mL.
If the HBV-DNA assay becomes positive and is above the World Health Organization’s 
(WHO) cutoff of 100 IU/mL, treatment with venetoclax or R venetoclax will be held and 
the patient should be treated (for at least 1 year after the last dose of treatment drug) 
with an appropriate nucleoside analogue and immediately referred to a 
gastroenterologist or heptologist for management.  Patients may resume venetoclax or 
venetoclax R once HBV-DNA levels have decreased to undetectable levels 
(29 IU/mL). 
If the HBV-DNA assay becomes detectable and is 29100 IU/mL, the patient should be 
re-tested within 2 weeks.  If the assay is still positive, treatment with venetoclax or 


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venetoclaxR will be held and the patient should be treated with an appropriate 
nucleoside analogue (for at least 1 year after the last dose of study treatment) and 
immediately referred to a gastroenterologist or heptologist for management.  Patients 
may resume treatment once the HBV-DNA levels decrease to undetectable levels.  At 
the discretion of the investigator, patients may start nucleoside analogue and be referred 
to a gastroenterologist or hepatologist while the second test in pending.
If a patient’s HBV-DNA level exceeds 100 IU/mL while the patient is receiving anti-viral 
medication, treatment will be discontinued (see Section 5.1.5, Table 4).
HBV reactivation has been reported up to 24 months following completion of rituximab 
therapy.  In patients who develop reactivation of HBV while on rituximab, immediately 
discontinue rituximab and any concomitant chemotherapy and institute appropriate 
treatment (see Section 5.1.5 and Table 4).  Insufficient data exist regarding the safety of 
resuming rituximab in patients who develop HBV reactivation.
Patients who demonstrate evidence of reactivation while receiving an appropriate 
anti-viral therapy will discontinue study treatment.
5.1.2.4
Progressive Multifocal Leukoencephalopathy
Rare cases of progressive multifocal leukoencephalopathy (PML) have also been 
reported in patients treated with rituximab alone or in combination with other 
immunosuppressive medications (Goldberg et al. 2002; Calabrese et al. 2007;
Carson et al. 2009).  In a review of 57 patients who developed PML after rituximab 
administration, all patients had received prior therapies with alkylating agents, 
corticosteroids, purine analogs, or drugs to prevent allogeneic stem cell or solid-organ 
graft rejection.  The diagnosis of PML in any patient treated with rituximab is extremely 
rare but should be suspected in any patient who develops new-onset neurologic 
manifestations.  The majority of patients with hematologic malignancies diagnosed with 
PML received rituximab in combination with chemotherapy or as part of a hematopoietic 
stem-cell transplant.  Most cases of PML were diagnosed within 12 months of the 
patients’ last infusion of rituximab.
5.1.2.5
Cardiac Toxicity
Angina and cardiac arrhythmias have occurred with rituximab treatment and can be life 
threatening.  To evaluate baseline risks, patients will be required to undergo 
assessments of LVEF prior to enrolling in this study.  Clinical evidence of cardiac 
decompensation will be evaluated and managed by the treating physician.  The decision 
to continue a patient on study after developing clinically significant cardiac 
decompensation will be made by the investigator and the Medical Monitor.
5.1.2.6
Infection
Serious infections, including fatal bacterial, fungal, and new or reactivated viral infections, 
can occur during and up to 1 year following completion of rituximab-based therapy.  New 


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or reactivated viral infections include cytomegalovirus, herpes simplex virus, 
parvovirus B19, Varicella zoster virus, West Nile virus, and hepatitis B and C.
5.1.2.7
Severe Mucocutaneous Reactions
Severe reactions, including fatal mucocutaneous reactions, can occur in patients 
receiving rituximab.  These reactions include paraneoplastic pemphigus, 
Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic 
epidermal necrolysis (TEN).  The onset of these reactions in patients treated with 
rituximab has varied from 1 to 13 weeks following rituximab exposure.
5.1.2.8
Bowel Obstruction and Perforation
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can 
occur in patients receiving rituximab in combination with chemotherapy.  In 
post-marketing reports of rituximab, the mean time to documented gastrointestinal 
perforation was 6 days (range, 177 days) in patients with NHL.
5.1.3
Risks Associated with Bendamustine
For bendamustine safety monitoring, see Section 4.3.2.3 for monitoring plans and 
instructions for dose delay and modification of bendamustine.  Please see the 
prescribing information for bendamustine for full information.
5.1.3.1
Myelosuppression
Patients treated with bendamustine are likely to experience myelosuppression.  Patients 
who experience Grade 3 or 4 neutropenia or thrombocytopenia should be monitored 
until neutrophil and platelet values return to at least Grade 2.  The use of myeloid growth 
factors for the primary and secondary prevention of febrile neutropenia is permitted.
5.1.3.2
Infection
Infection, including pneumonia and sepsis, has been reported.  Patients with 
myelosuppression following treatment with bendamustine are more susceptible to 
infections.  The study physician will treat patients with clinical evidence of infection 
appropriately.  See Section 4.3.2.3 for monitoring plans and instructions for dose delay 
and modification of bendamustine.
5.1.3.3
Infusion Reactions
Infusion reactions to bendamustine have occurred commonly in clinical trials.  Symptoms 
include fever, chills, pruritus, and rash.  In rare instances, severe anaphylaxis and 
anaphylactoid reactions have occurred.
5.1.3.4
Tumor Lysis Syndrome
TLS has been reported in association with bendamustine.  Preventive measures include 
maintaining adequate volume status and close monitoring of blood chemistry, 
particularly potassium and uric acid levels.  Allopurinol has also been used during the 
beginning of bendamustine therapy.  However, there may be an increased risk of severe 


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skin toxicity when bendamustine and allopurinol are administered concomitantly.  
Allopurinol may be held on days of bendamustine administration.  Patients randomized 
to Arm B (BR) who develop evidence of TLS should be treated as clinically indicated.
5.1.3.5
Cutaneous Reactions
A number of skin reactions have been reported with bendamustine treatment, including 
rash, toxic skin reactions, and bullous exanthema.  In a study of bendamustine in 
combination with rituximab, one case of TEN occurred.  TEN has been reported for 
rituximab.  Cases of Stevens-Johnson syndrome and TEN, some fatal, have been 
reported when bendamustine was administered concomitantly with allopurinol and other 
medications known to cause these syndromes.
5.1.3.6
Long-Term Stem-Cell Toxicity
Premalignant and malignant diseases, including MDS, myeloproliferative disorders, AML, 
and bronchial carcinoma, have developed in patients treated with bendamustine.
5.1.3.7
Extravasation of Bendamustine
Erythema, marked swelling, and pain from bendamustine extravasation have resulted in 
hospitalization.
5.1.3.8
Transfusion-Associated Graft versus Host Disease
Rare cases of transfusion-associated graft versus host disease have been reported 
following treatment of low-grade B-cell malignancies with purine analogues 
(i.e., fludarabine or cladribine).  The situation with newer purine antagonists such as 
bendamustine is unclear.  Transfusions, if required, should be performed according to 
national guidelines.
5.1.3.9
Drug Interactions
Certain medications may interact with bendamustine.  Caution should be used or 
alternative treatments should be considered if concomitant treatment with CYP1A2 
inhibitors or inducers is needed.  Please see Appendix 9 for a list of medications that are 
to be excluded or used with caution in patients receiving bendamustine or venetoclax.
5.1.4
Risks Associated with Venetoclax and Rituximab Combination 
Therapy
Preliminary safety (see Section 1.2.2.3.1) and activity (see Section 1.2.2.3.3) data from 
the ongoing Study M13-365 venetoclax R supports the risk/benefit assessment for 
combination therapy.  Common hematological and GI toxicities appear to be tolerable 
and were adequately managed.  These common toxicities did not result in any study 
discontinuation.


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5.1.5
Management of Specific Adverse Events
The evaluation of potential treatment-induced toxicity in patients with advanced CLL may 
be quite difficult and require careful consideration of both the manifestations of the 
underlying disease, as well as adverse reactions to the therapy under study.  Some of 
the conventional criteria for toxicity are not applicable, especially under circumstances of 
progressive bone marrow failure from the CLL itself. 
Dose modifications for hematologic toxicity in patients with CLL must be made with 
consideration of the increased frequency of hematologic compromise at the initiation of 
therapy.  Therefore, the standard criteria used for solid tumors are difficult to be applied 
directly; many patients would be considered to have Grade 24 hematologic toxicity at 
presentation.
As a consequence, dose modification decisions for patients with cytopenia (below the 
lower limit of the normal range) at baseline will be based on the National Cancer 
InstituteWorking Group (NCI-WG) CLL grading scale (see Appendix 12).  For patients 
with a normal neutrophil count, platelet count, and/or hemoglobin value at baseline, the 
NCI CTCAE, v4.0 will be used.


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Guidelines for Dosage Modification and Treatment Interruption or 
Discontinuation
Venetoclax Rituximab Dosage Modifications
Table 3
Dose Modifications for Hematologic Toxicity during the Combination 
Therapy Period (Venetoclax Rituximab) and/or Venetoclax
Monotherapy
Hematologic toxicity
Event(s)
Dose Delay or Modification
Grade 3 or 4 neutropenia, 
without infection or fever, 
and/or Grade 3 or 4 
thrombocytopenia, first 
episode

Hold venetoclax (and rituximab if neutropenia occurs during 
Cycles 16) 

When counts recover to Grade 2 resume previous doses of 
venetoclax and rituximab

Administer G-CSF or growth factors for neutropenia as 
indicated 

If patient was not previously receiving prophylactic G-CSF, 
initiate prophylactic G-CSF for current and all subsequent 
cycles
Grade 3 or 4 neutropenia 
with infection and/or fever, 
first episode

Hold venetoclax (and rituximab if neutropenia occurs drug 
Cycles 16) until fever and/or infection resolves

Administer G-CSF or growth factors for neutropenia as 
indicated 

When counts recover to Grade 2 and infection has been fully 
treated, resume previous doses of venetoclax and rituximab

If patient not previously receiving prophylactic G-CSF, initiate 
prophylactic G-CSF for current and all subsequent cycles
Recurrent Grade 3 or 4 
neutropenia with/without 
fever and infection despite 
G-CSF 

Hold venetoclax (and rituximab if neutropenia occurs during 
Cycles 16) for at least 7 days

Administer G-CSF or growth factors for neutropenia as 
indicated 

When counts recover to Grade 2 and/or platelets are 
75 109/L resume venetoclax at one dose level reduction 
(Table 5)

Reinitiate rituximab at previous dose


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Table 3
Dose Modifications for Hematologic Toxicity during the Combination 
Therapy Period (Venetoclax Rituximab) and/or Venetoclax
Monotherapy (cont.)
Hematologic toxicity (cont.)
Event(s)
Dose Delay or Modification
Grade 4 thrombocytopenia 
and/or symptomatic 
bleeding

Hold venetoclax (and rituximab if event occurs during 
Cycles 16) for Grade 4 thrombocytopenia (platelets 
25,000/L) or presence of symptomatic bleeding until 
resolution of bleeding

Platelets may be transfused at the discretion of the 
investigator

When platelet level rises toGrade 2 without transfusional 
support for 5 consecutive days, restart venetoclax and 
rituximab at previous doses

For a second episode of severe thrombocytopenia and/or 
symptomatic bleeding, hold venetoclax (and rituximab if event 
occurs during Cycles 16).  When platelet level rises to 
Grade 2 without transfusional support for 5 consecutive 
days, restart venetoclax at one dose level reduction (Table 5).  
Rituximab may be restarted at the previous dose.

For subsequent episodes of severe thrombocytopenia, hold 
venetoclax (and rituximab if event occurs during Cycles 16).  
When platelet level rises toGrade 2 without transfusional 
support for 5 consecutive days, restart venetoclax at one dose 
level reduction.  Rituximab may be restarted at the previous 
dose.

For recurrent severe thrombocytopenia in spite of dose 
reduction and/or symptomatic bleeding, consult the Medical 
Monitor regarding continuation on protocol 
ANCabsolute neutrophil count; G-CSFgranulocyte colony-stimulating factor.


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Table 4
Dose Modifications for Non-Hematologic Toxicity during the 
Combination Therapy Period (Venetoclax Rituximab) and/or 
Venetoclax Monotherapy
Non-hematologic toxicity
Event(s)
Dose Delay or Modification
Grade 4 IRR
Grade 3 IRR, first dose
Grade 3 IRR, 
subsequent episodes
Discontinue rituximab permanently.  Patients may continue 
venetoclax. 
To be managed at investigator’s discretion, please note that dose 
reductions of rituximab are prohibited.  
Discontinue rituximab permanently.  Patients may continue 
venetoclax. 
Grades 12 IRR, first 
and subsequent 
episodes
To be managed at investigator’s discretion, please note that dose 
reductions of rituximab are prohibited.  Rituximab may be 
discontinued for patients experiencing recurrent Grades 12 IRR. 
Grade 3 or 4 tumor 
lysis syndrome (first 
episode and subsequent 
episodes)
Hold all study treatments (venetoclax and rituximab) until TLS 
resolves.  The patient’s next dose may be delayed for up to 28 days. 
Following complete resolution of tumor lysis syndrome and after 
electrolyte values have been stable without any more treatment for at 
least 24 hours, if venetoclax was held for 14 days or less, venetoclax
(and rituximab if event occurs during Cycles 16) may be restarted at 
the same dose or at one lower dose level as determined by the 
investigator based on a risk assessment (including tumor burden 
status) in conjunction with prophylactic hydration and uricosuric 
agent; hospitalization for restarting the venetoclax dose may be 
considered at the discretion of the investigator.  Dose must be 
resumed at one lower dose level if interruption lasted more than 
14 days (see Table 5).
Grade 3 or 4 
non-hematologic toxicity 
not specifically 
described above
Delay venetoclax (and rituximab if event occurs during Cycles 16) for 
a maximum of 28 days.
First episode:  If improvement to Grade 1 or baseline, resume 
previous doses of venetoclax and rituximab.
For subsequent episodes:  If improvement to Grade 1 or baseline, 
restart venetoclax at one dose level reduction (Table 5). 
Grade 2 
non-hematologic toxicity
Delay treatment with venetoclax (and rituximab if event occurs during 
Cycles 16) until resolution to Grade 1 (or baseline status) for a 
maximum of 28 days.  After resolution, resume full dose of venetoclax
and rituximab.
Grade 1 
non-hematologic toxicity
No dose reduction or delay.


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Table 4
Dose Modifications for Non-Hematologic Toxicity during the 
Combination Therapy Period (Venetoclax Rituximab) and/or 
Venetoclax Monotherapy (cont.)
Non-hematologic toxicity (cont.)
Hepatitis B reactivation 
(as evidenced by 
new detectable 
HBV-DNA levels)
Detectable HBV-DNA levels between WHO-recommended range of 
29 and 100 IU/mL:  Re-test within 2 weeks.  If still positive, hold 
venetoclax, or venetoclax and rituximab (if event occurs during 
Cycles 16) and treat patient with an appropriate nucleoside 
analogue.  Immediately refer patient to a gastroenterologist or 
hepatologist.  At the discretion of the investigation, patients may start 
the nucleoside analogue and be referred to a gastroenterologist or 
hepatologist while the second test is pending.
HBV-DNA levels at WHO-recommended cutoff of 100 IU/mL:  hold 
venetoclax or venetoclax and rituximab (if event occurs during 
Cycles 16) and treat patient with an appropriate nucleoside 
analogue.  Immediately refer patient to a gastroenterologist or 
hepatologist.
Rising HBV-DNA viral load while on an appropriate anti-viral therapy:  
Discontinue patient from venetoclax and rituximab permanently and 
refer patient to a gastroenterologist or hepatologist immediately.
IRRinfusion-related reaction; WHOWorld Health Organization.
Table 5
Venetoclax Dose Reduction
Venetoclax Current Dose Level
Venetoclax Dose Reduction
400 mg
200 mg
200 mg
100 mg
100 mg
Discontinue venetoclax and rituximab
Gradual dose increase following resolution of toxicity leading to a dose reduction may be 
considered if the patient is stable for 2 weeks on the lower dose; however, if the toxicity 
recurs, the patient may continue treatment on the lower dose.
Patients who discontinue venetoclax for toxicity should also discontinue rituximab, 
although they are to continue evaluation per protocol.
Rituximab Dosage Modifications
There will be no rituximab dose modifications in this study.  Patients at high risk for IRRs 
may, at the investigator’s discretion, receive their initial dose of rituximab split over 2 
consecutive days (e.g., 125 mg/m2 on Cycle 1 Day 1 and 250 mg/m2 on Cycle 1 Day 2).
Rituximab may be temporarily held.  Any NCI CTCAE, v4.0 toxicity Grade 3 in severity 
that is deemed related to rituximab treatment will require interruption of study treatment 
until resolution to Grade 1. 


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Patients in Arm A (venetoclax R) who discontinue rituximab for rituximab-related 
toxicity may continue to receive venetoclax.  Patients who discontinue venetoclax for 
toxicity should also discontinue rituximab, although they are to continue evaluation per 
protocol as described in Section 4.6.1.1.
Patients in Arm B (BR) who discontinue rituximab for rituximab-related toxicity may 
continue to receive bendamustine as a single agent for the full 6 cycles if deemed to be 
in the best interest of the patient as assessed by the investigator.  Patients who 
discontinue both bendamustine and rituximab are to continue evaluation per protocol as 
described in Section 4.6.1.1.
Bendamustine Dosage Modifications
On the first day of each new treatment cycle and before each bendamustine dose, the 
patient will be evaluated for possible toxicities that may have occurred after the previous 
dose(s).  The following dose-reduction rules for bendamustine should be followed (see 
Table 6 and Table 7).
If toxicities occurred at 70 mg/m2, reduce dose to 50 mg/m2; if toxicity occurred at 
50 mg/m2, discontinue bendamustine.  If the dose of bendamustine is reduced due to 
toxicity, it will not be re-escalated later in the study.
Table 6
Bendamustine Dose Reduction
Bendamustine Current Dose Level
Bendamustine Dose Reduction
70 mg/m2
50 mg/m2
50 mg/m2
Discontinue bendamustine
If a patient has disease-related splenomegaly or significant bone marrow involvement as the 
etiology of cytopenias at enrollment, treatment may be continued without meeting the 
hematologic criteria for subsequent cycles of induction chemotherapy.  In such cases, the 
decision to continue dosing of bendamustine at the current dose is at the investigator’s 
discretion.


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Table 7
Dose Modification Guidelines for Bendamustine
NCI CTCAE 
category
Severity
Dose Modification
Hematologic a
Neutrophil 1000/L
on Day 1 of 
Cycles 26
Initiation (Day 1) of Cycles 26 should be 
delayed until the neutrophil count is 1000/L (or 
returns to baseline level obtained at screening) 
and the platelet count is 75,000/L.a  If Day 1 is 
delayed by more than 2 weeks, then 
bendamustine should be resumed at the next 
lower dose level.
Platelets 75,000/L 
on Day 1 of 
Cycles 26
Grade 4 neutropenia 
with fever/infection
Initiation (Day 1) of Cycles 26 should be 
delayed until the neutrophil count is 1000/L 
without evidence of fever or infection and the 
platelet count is 75,000/L.a  Bendamustine 
should then be resumed at the next lower dose 
level.
Grade 4 neutropenia 
lasting 7 days
Grade 4 platelets for 
7 days or a platelet 
count 10,000/L at 
any time
Nausea, emesis, 
or diarrhea in the 
absence of 
maximal 
prophylaxis
Grade 3
Continue treatment, but with institution of 
maximum prophylactic therapy, including a 5-HT3
antagonist for nausea and emesis, and 
loperamide, or a comparable antidiarrheal agent, 
for diarrhea.  Events of Grade 4 toxicity require 
holding treatment until resolution of toxicity to 
Grade 2 with use of maximum prophylaxis.
Nausea, emesis, 
or diarrhea with 
maximal 
prophylaxis
Grade 3
Hold bendamustine for up to 2 weeks or until the 
toxicity returns to Grade 2, and restart at the 
next lower dose.  If treatment is delayed by more 
than 2 weeks, treatment with bendamustine must 
be discontinued.
All other toxicities 
related to 
bendamustine
Grade 3
5-HT35-hydroxytryptamine 3; NCI CTCAENational Cancer Institute Common Terminology 
Criteria for Adverse Events.
a If patients have disease-related splenomegaly or significant bone marrow involvement as 
the etiology of cytopenias at enrollment, treatment may be continued without meeting the 
hematologic criteria for subsequent cycles of induction chemotherapy.  In such cases, the 
decision to continue dosing of bendamustine at the current dose is at the investigator’s 
discretion.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study.


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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Fatal (i.e., the adverse event actually causes or leads to death)

Life-threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)


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The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to NCI CTCAE 
criteria; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsors 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsors immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2 for reporting instructions).  Adverse events of special 
interest for this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.3.5.6

Suspected transmission of an infectious agent by the study drug

Grade 3 TLS and IRR
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsors in 
accordance with instructions provided in this section and in Sections 5.4, 5.5, and 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies).


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After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 28 days after the last dose of study drug, or 90 days after last 
dose of rituximab, whichever is longer.  After this period, investigators should report any 
deaths, serious adverse events, or other adverse events of concern that are believed to 
be related to prior study drug treatment (see Section 5.6).  All grades of second primary 
malignancies (serious and non-serious) should be reported during and after the end of 
adverse event reporting period.
Re-Treatment/Crossover Study
After initiation of study drug in the R/C Substudy, investigators should report any 
deaths, serious adverse events, adverse events Grade 3, adverse events of special 
interest (see Section 5.2.3), second primary malignancies, and adverse events leading to 
treatment discontinuation. Adverse event reporting period specified above will be 
followed for re-treated and crossover patients.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE, v4.0 will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 8
Adverse Event Severity Grading Scale
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the NCI CTCAE, v4.0), which can be found at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  (last 
accessed: 22 April 2013)
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatmentrelated factors that are known to be associated with the 
occurrence of the event


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For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after rituximab and/or bendamustine 
infusion and that are judged to be related to the respective infusion should be captured 
as a diagnosis rather than individual signs and symptoms (e.g. “infusion-related reaction” 
or “injection-site reaction” or “anaphylactic reaction") on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as "systemic reaction."  If a patient experiences 
both a local and systemic reaction to the same dose of study drug, each reaction should 
be recorded separately on the Adverse Event eCRF as individual signs and symptoms 
rather than a diagnosis of allergic reaction or infusion reaction.
Other Adverse Events
For all other adverse events, a diagnosis (if known) should be recorded on the Adverse 
Event eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events Occurring Secondary to Other Events
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF.  For example:

If vomiting or diarrhea results in mild dehydration with no additional treatment in a 
healthy adult, only vomiting should be reported on the eCRF

If vomiting or diarrhea results in severe dehydration, both events should be reported 
separately on the eCRF


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
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens.  If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
In this study, certain abnormal values may not qualify as adverse events.  Hematologic 
parameters should be evaluated as described in Table 3 and Table 4 and in 
Appendix 12.  G-CSF used as prophylaxis would not be considered an adverse event 
but should be reported as a concomitant medication.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5ULN associated with cholecystitis), only the 
diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium" as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.”
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded 
on the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  


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Therefore, investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsors immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2).
5.3.5.7
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of CLL should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other deaths during the adverse event 
reporting period, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  An 
independent monitoring committee will monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
During follow-up visits occuring after the adverse event reporting period, deaths 
attributed to progression of CLL should be recorded only on the Study Completion/Early
Discontinuation eCRF.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the Medical History/Surgical History.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors (e.g., 
“more frequent headaches”).


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5.3.5.9
Lack of Efficacy or Worsening of CLL
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease (such as transformation to more aggressive histology) should not be 
recorded as adverse events.  These data will be captured as efficacy assessment data 
only.  If there is any uncertainty as to whether an event is due to disease progression, it 
should be reported as an adverse event.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for monitoring for potential 
TLS)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not suffered an adverse event

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization for outpatient care outside of normal clinic operating hours that is
required per protocol or per local standard of care.
5.3.5.11
Patient-Reported Outcome Data
Paper or electronic questionnaires may be used for this study.  In the event paper is 
used, instructions on the PRO questionnaires will include a disclaimer to let patients 
know that the site staff will not be reviewing the answers to the questionnaire and 
therefore patients should alert the site staff about any problems they are having.  Site 
staff will review PRO questionnaires for completeness ONLY.  If it is noted that the 
patient has written any words on the PRO instrument that is not a predefined response 
(e.g., comments in the margin of the questionnaire or comments in an open text field), 
site staff will alert the investigator, who will determine if the criteria for an adverse event 
have been met and will document the outcome of this assessment in the patient's 


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medical record per site practice.  If the event meets the criteria for an adverse event, it 
will be reported on the Adverse Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsors to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsors immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsors within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events

Non-serious adverse events of special interest

Pregnancies

Overdoses, medication errors, drug abuse, or drug misuse (see Section 5.4.4 for 
details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsors immediately (i.e., no more than 24 hours after becoming aware of the
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor (Roche Medical Responsible) Contact Information (North, 
Latin, and South America)
Medical Monitor:
, Ph.D.
Telephone No.:
Alternate Telephone No.:
IQVIA Medical Responsible Contact Information (Rest of World)
Medical Advisor-based in Russia:
, M.D.
Telephone No.:


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Medical Advisor-based
in Singapore:
, M.D.
Telephone No.:
IQVIA Medical Emergency 
Contact Center:
1 (973) 659-6677
Alternate Telephone No.:
1 (570) 819-8565
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Contact, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
For reports of serious adverse events and non-serious adverse events of special interest, 
investigators should record all case details that can be gathered immediately (i.e., within 
24 hours) on the Adverse Event eCRF and submit the report via the EDC system.  A 
report will be generated and sent to AbbVie/Roche Safety Management by the EDC 
system.
In the event that the EDC system is unavailable, a paper Serious Adverse Event 
Reporting Form and fax cover sheet should be completed and faxed directly to IQVIA
(AbbVie/Roche Safety Management designee) immediately (i.e., no more than 24 hours 
after learning of the event), using the fax numbers provided to investigators (see 
"Protocol Administrative and Contact Information & List of Investigators").  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 28 days after the last 
dose of study drug (or within 90 days of the last dose of rituximab).  A Pregnancy Report 
eCRF should be completed by the investigator immediately (i.e., no more than 24 hours 
after learning of the pregnancy) and submitted via the EDC system.  A pregnancy report 
will automatically be generated and sent to AbbVie/Roche Safety Management.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 


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conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.
In the event that the EDC system is unavailable, a Clinical Trial Pregnancy Reporting 
Form and fax cover sheet should be completed and faxed faxed directly to IQVIA
(AbbVie/Roche Safety Management designee) immediately (i.e., no more than 24 hours 
after learning of the pregnancy), using the fax numbers provided to investigators (see 
"Protocol Administrative and Contact Information & List of Investigators").
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
90 days after completing treatment with venetoclax or 180 days after the last dose of 
rituximab.  Male patients who received study treatment should not attempt to father a 
child until end of study or for 1 year after the last dose of rituximab.  A Pregnancy Report 
eCRF should be completed by the investigator immediately (i.e., no more than 24 hours 
after learning of the pregnancy) and submitted via the EDC system.  Attempts should be 
made to collect and report details of the course and outcome of any pregnancy in the 
partner of a male patient exposed to study drug.  The pregnant partner will need to sign 
an Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  Once the authorization has been signed, the investigator 
will update the Pregnancy Report eCRF with additional information on the course and 
outcome of the pregnancy.  An investigator who is contacted by the male patient or his 
pregnant partner may provide information on the risks of the pregnancy and the possible 
effects on the fetus, to support an informed decision in cooperation with the treating 
physician and/or obstetrician.
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1.
5.4.3.3
Abortions
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsors consider spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2).
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a serious adverse 
event, recorded on the Adverse Event eCRF, and reported to the Sponsors immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).


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5.4.4
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is 
higher than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is 
higher than the assigned dose}

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with venetoclax, rituximab, and bendamustine, 
regardless of whether they result in an adverse event, should be recorded on the Adverse 
Event eCRF and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event).  Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box. If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and 
"accidental overdose" as the event term.  Check the "Accidental overdose" and 
"Medication error" boxes.  Enter a description of the error in the additional case 
details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.


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
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug 
misuse" box.
For venetoclax, rituximab, and bendamustine, each adverse event associated with a 
special situation should be recorded separately on the Adverse Event eCRF.  If the 
associated adverse event fulfills seriousness criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  For venetoclax, rituximab, and bendamustine, adverse events associated 
with special situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose and 
one to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked on both eCRF pages.


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5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1.
5.5.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information (e.g., 
from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (see 
Section 5.3.1) if the event is believed to be related to prior study drug treatment. All 
grades of second primary malignancies (serious and non-serious) should be reported 
during and after the end of adverse event reporting period.
The investigator should report these events directly to the Sponsor or its designee on the 
Adverse Event eCRF. If the Adverse Event eCRF is no longer available, the investigator 
should report the event directly to IQVIA (AbbVie/Roche Safety Management or 
designee) using the paper Serious Adverse Event Reporting Form and fax cover sheet 
(see "Protocol Administrative and Contact Information & List of Investigators").


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsors will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsors will 
assess the expectedness of these events using the following reference documents:

Venetoclax Investigator's Brochure

Local prescribing information for rituximab

Local prescribing information for bendamustine
The Sponsors will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsors as needed.
Certain adverse events (e.g., know consequences of the underlying disease or common 
co-morbidities in the study population) are anticipated to occur in the study population 
(CLL) at some frequency independent of drug exposure and will be excluded from 
expedited reporting by the Sponsor to applicable health authorities.  Although exempt 
from expedited reporting to certain health authorities and ECs/IRBs as individual cases, 
these Serious Adverse Events and Adverse Events of Special Interest, as defined in 
Section 5.4.2, must be reported by the site/investigator expeditiously to the Sponsors 
within 24 hours of the site becoming aware of the event.  These events are listed in 
Appendix 13. These adverse events may occur alone or in various combinations and are 
considered expected for reporting purposes for this protocol.  The list of Medical 
Dictionary for Regulatory Activities (MedDRA) preferred terms associated with these 
events.
The iDMC will monitor the safety events in this study.  Any recommendation from the 
iDMC during the study that do not favor the test product will be submitted to health 
authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Details of the analyses presented in this section will be provided in the Statistical 
Analysis Plan.


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6.1
DETERMINATION OF SAMPLE SIZE
The primary endpoint of PFS was used to determine the sample size for the study.  
Estimates of the number of events required to demonstrate efficacy with regard to PFS 
are based on the following assumptions:

Two-sided log-rank test at the 0.05 level of significance

80% power to detect an HR for venetoclax R versus BR of 0.66, corresponding to 
an approximate median improvement of 15.2 months to 23 months (34% reduction 
in risk of a PFS event)

Exponential distribution of PFS

An annual dropout rate of 5%

One interim analysis for efficacy
With these assumptions, 186 PFS events are required to achieve 80% power for the 
primary analysis of PFS in all patients for detecting a trend in favor of venetoclax R 
arm over BR arm (HR 0.66).  In total, it is planned to enroll approximately 370 patients 
across 2 arms, randomized with 1:1 ratio.  It is expected that, after a 9-month enrollment 
ramp-up, 24 patients per month will be recruited, and the total enrollment is expected to 
take approximately 20 months. 
An interim analysis is planned when approximately 140 investigator-assesed PFS events 
have occurred in both treatment arms combined (75% of the 186 events required for the 
final primary efficacy analysis
The minimum detectable difference at the final analysis approximately corresponds to a 
HR of 0.75.  
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, eligibility violations, study drug administration, and patient disposition will be 
summarized by treatment arm in all randomized patients and by 17p deletion status.  A 
summary of patient disposition will include whether treatment was completed or 
discontinued early and the reason for early treatment discontinuation.  Descriptive 
statistics will be used in evaluating the conduct of the study.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics, such as age, sex, race/ethnicity, and 
baseline ECOG Performance Status, will be summarized by treatment arm in all 
randomized patients.  Descriptive statistics will be used in evaluating treatment group 
comparability.
6.4
EFFICACY ANALYSES
The primary and secondary efficacy analyses will include all randomized patients, with 
patients grouped according to the treatment assigned at randomization.


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6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is investigator-assessed PFS, defined as the time from 
randomization to the first occurrence of progression or relapse (determined using 
standard iwCLL guidelines [Hallek et al. 2008]), or death from any cause, whichever 
comes first.  For patients who have not progressed, relapsed, or died at the time of 
analysis, PFS will be censored on the date of the last disease assessment.  If no 
disease assessments were performed after the baseline visit, PFS will be censored at 
the time of randomization 1 day.  Although the primary efficacy endpoint is 
investigator-assessed PFS, PFS based on IRC assessments will also be analyzed to 
support the primary analysis.  In the United States, IRC-assessed PFS will be the basis 
of regulatory decisions.
The primary analysis of the study will test the equality of PFS distributions for the 
venetoclax and rituximab combination (venetoclax R, Arm A) and the bendamustine 
and rituximab combination (BR; Arm B), as follows:
H0: PFSvenetoclax R = PFSBR
versus
H1: PFSvenetoclax R ≠PFSBR
Treatment comparison will be made using a two-sided stratified log-rank test 
(0.05 significance level, appropriately adjusted for an interim analysis) stratified by 
17p deletion status (yes or no), risk status (high or low risk), and geographic region 
(United States/Canada, Australia/New Zealand, Western Europe, Central and Eastern 
Europe, Asia, or Latin America).  If the null hypothesis is rejected and the observed HR 
is favorable for the venetoclax R combination, then it is shown that venetoclax R has
a statistically significantly longer PFS than BR.  The KaplanMeier curve will provide a 
visual description of the differences across treatment arms.  Estimates of the treatment 
effect will be expressed as HRs through use of a stratified Cox proportional-hazards 
analysis, including 95% confidence intervals.
The following sensitivity analyses for PFS will also be performed:

An unstratified log-rank test will be performed.

PFS analyses will be performed with censoring at the initiation of 
non-protocolspecified anti-CLL therapy to assess potential confounding of the 
treatment effect estimates by subsequent therapy.

PFS analyses will be performed with censoring death or disease progression after 
more than one missed response assessment at the date of the last adequate 
response assessment.
Details will be outlined in a Statistical Analysis Plan.


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6.4.2
Secondary Efficacy Endpoints
If the study meets its primary endpoint of prolonging PFS assessed by the investigator in 
all randomized patients, then formal statistical tests of specific key secondary efficacy 
endpoints will be performed. To adjust for multiple testing of the primary and key 
secondary efficacy endpoints, thereby controlling the overall type I error rate at a 2-sided 
significance level of 0.05, a fixed sequence testing procedure will be used (Westfall and 
Krishen 2001). Additional secondary endpoints will not be tested formally. Further details of 
the fixed sequence testing will be described in the Statistical Analysis Plan.
Secondary efficacy outcome measures include:

Investigator-assessed PFS in patients with 17p deletion per central laboratory Fish 
test 

IRC-assessed PFS in patients with 17p deletion per central laboratory detection

Investigator-assessed best OR rate, CR, CRi, nPR, and PR rates

IRC-assessed best OR rate, CR, CRi, nPR, and PR rates

OR, CR, CRi, nPR, and PR rates at end of combination treatment response visit as
assessed by the investigator

OR, CR, CRi, nPR, and PR rates at end of combination treatment response visit, as 
determined by the IRC

OS, defined as the time from the date of randomization to the date of death from 
any cause.  Patients who were not reported as having died at the time of the 
analysis will be censored at the date when they were last known to be alive as 
documented by the investigator.

EFS, defined as the time between date of randomization and the date of disease 
progression/relapse, death, or start of a new anti-CLL treatment. If the specified event 
(disease progression/relapse, death, start of a new anti-CLL treatment) does not occur, 
patients will be censored at the date of last tumor assessment.  For patients without an event 
who have not had post-baseline tumor assessments, EFS will be censored at the time of 
randomization.

DOR, defined for patients with a best OR of CR, CRi, nPR, or PR as the time from 
first occurrence of a documented CR or PR to disease progression/relapse as 
assessed by the investigator or death from any cause. For patients achieving a 
response who have not progressed, relapsed, or died at the time of analysis, DOR will be 
censored on the date of last response assessment.  Patients who have never had responded 
will not be included in this analysis.

TTNT, defined as the time from randomization to start of new non-protocol anti-CLL 
therapy or death from any cause. For patients who have not received the next anti-CLL 
treatment or died at the time of analysis, TTNT will be censored at the date when the patient 
was last known to be alive without having received additional anti-lymphoma treatment.


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
MRD response rate (determined as the proportion of patients with MRD negativity) 
at End of Combination Treatment Response Visit as measured at a central 
laboratory on peripheral blood and/or bone marrow samples 
Time-to-event endpoints such as OS, EFS, and TTNT will be analyzed using the same 
statistical methods described for the primary analysis of PFS.
Time-to-event analysis of DOR will incorporate data only from the subset of patients in 
both treatment arms that achieved a CR, CRi, nPR, or PR status.  As this a 
nonrandomized comparison, a formal statistical test will not be conducted, and the 
results will only be summarized by the treatment arm estimates and confidence intervals.
Response rates in the treatment groups will be compared using stratified 
CochranMantelHaenszel (CMH) tests.  Stratification factors are identical to those used 
for the primary endpoint.  Rates and 95% confidence intervals will be reported for each 
treatment group.
6.5
SAFETY ANALYSES
Safety endpoints include adverse events, serious adverse events, and adverse events of 
special interest.  The safety analyses will include all randomized patients who received 
at least one dose of study treatment (venetoclax, rituximab, or bendamustine), with 
patients grouped according to the treatment actually received.
Treatment exposure will be summarized, including the number of cycles received by 
each patient, and the cumulative dose will be summarized by treatment arm.
Verbatim descriptions of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms.  All adverse events occurring during or 
after the first treatment will be summarized by treatment arm and NCI CTCAE grade.  In 
addition, all serious adverse events will be summarized.  
Deaths reported during the study treatment period and those reported after treatment 
completion/discontinuation will be summarized by treatment arm.
Adverse events leading to early treatment discontinuation and early study withdrawal will 
be summarized by arm and reason.
Laboratory data with values outside of the normal ranges will be identified.  Additionally, 
select laboratory data will be summarized by treatment arm and grade using the 
NCI CTCAE.  Of note, abnormal laboratory data that are clinically significant will be 
reported as adverse events and summarized in the adverse event tables.
Vital signs and other physical findings will be summarized by treatment arm.


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6.6
PHARMACODYNAMIC ANALYSES
The pharmacodynamics endpoint in this study is serial assessment of B- and T-cell 
lymphocyte subsets by flow cytometry.
The exploratory pharmacodynamic biomarker analyses will include patients with at least 
one predose and/or one post-dose biomarker assessment, with patients grouped 
according to the treatment actually received.
Blood samples for biomarker assessments will be assayed using analytically qualified 
methods (e.g., immunohistochemistry, ELISA, quantitative real-time PCR, and 
fluorescence-activated cell sorting).
6.7
PHARMACOKINETIC ANALYSES
Individual plasma concentrations of venetoclax will be tabulated after appropriate 
grouping, summarized (e.g., mean, standard deviation, coefficient of variation, median, 
minimum, and maximum), and plotted. 
Population PK methods will be used to characterize the pharmacokinetics of venetoclax 
in this study in conjunction with appropriate historical data.  Apparent clearance, 
apparent volume of distribution, and other appropriate PK parameters of venetoclax may 
be calculated and summarized as data allow.
Potential correlations of exposure with dose, demographics, pharmacodynamic variables, 
safety, and efficacy outcomes may be explored as warranted by the data.  The results 
from the population PK analysis may be reported separately from the Clinical Study 
Report.
At the discretion of the Sponsor, all analyses may be extended to include relevant 
biotransformation products of venetoclax.
6.8
PATIENT-REPORTED OUTCOME ANALYSES
The PRO endpoints in this study are:

To compare interference and tolerability of treatment-related symptoms in patients 
treated with venetoclaxR versus BR using the MDASI questionnaire

To evaluate changes from baseline disease-related symptom scores using the 
MDASI and EORTC QLQ-C30 and QLQ-CLL16 questionnaires

To evaluate time to disease-related symptom progression using EORTC QLQ-C30 
and QLQ-CLL16

To evaluate interference of treatment and disease-related symptoms on QoL using 
the MDASI questionnaire
Scoring for the MDASI, EORTC QLQ-C30, and EORTC QLQ-CLL16 questionnaires will 
be based on their corresponding user manuals (Fayers et al. 1999; Cleeland et al. 2000).  


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For the MDASI, EORTC QLQ-C30, and EORTC QLQ-CLL16 scales with more than 50% 
of the constituent items completed, a pro-rated score will be computed consistent with 
the scoring manuals and validation papers.  For subscales with less than 50% of the 
items completed, the subscale will be considered as missing. 
Summary statistics of the MDASI, EORTC QLQ-C30, and EORTC QLQ-CLL16 scales 
and their changes from baseline will be calculated at each assessment timepoint for both 
study arms.  Analysis details of these patient-reported outcomes will be provided in the 
Statistical Analysis Plan.
Disease-related symptom progression will be measured by EORTC QLQ-C30 and 
EORTC QLQ-CLL questionnaires.  Time-to-event KaplanMeier analysis on CLL 
symptoms will be used to demonstrate the time from first treatment to worsening in 
disease-related symptoms.  An event is a change in symptom score by 10 points or 
more as defined as being clinically important.
6.9
HEALTH ECONOMIC ANALYSIS
Health economic data, as assessed by the EQ-5D, will be evaluated for patients with a 
baseline assessment and at least one post-baseline EQ-5D assessment that generate a 
score.  Scores at baseline and change from baseline scores for each timepoint will be 
quantified using descriptive statistics.
The results from the health economic data analysis may be reported separately from the 
Clinical Study Report.
6.10
EXPLORATORY ANALYSES
Relationship between various baseline markers and clinical outcome parameters in 
patients from both arms of the study (including CLL prognostic markers, pro- and 
anti-apoptotic RNAs and proteins in CLL cells, somatic mutations and/or gene 
expression signatures, and pharmacogenomics variables) will be assessed using 
appropriate laboratory measures.
6.11
INTERIM ANALYSES
One interim analysis is planned during the conduct of the study to assess efficacy and 
safety of venetoclax R compared with BR and to allow for release of the results earlier 
than the planned final analysis in case of significant difference in treatment effect in favor 
of venetoclax R.  
The interim analysis will be performed when approximately 140 investigator-assessed 
PFS events have occurred in both treatment arms combined (75% of the 186 events 
required for the final primary efficacy analysis).  The stopping boundary follows a unified 
family with parameter of P 2 (Kittelson and Emerson 1999).  Based on 140 events, the 
duration of PFS will be tested at the interim analysis, approximately corresponding to a 


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2-sided p-value of 0.0026 (HR of 0.60).  If the number of events is not exactly 140 by the 
time of the analysis, then the boundary will be updated to reflect the number of events
The iDMC will evaluate efficacy and safety data at the interim analysis and recommend if 
the study result should be released early.  Summaries and analyses will be prepared by 
the iDCC and presented by treatment arm for the iDMC’s review (see Section 4.1.2).
Both investigator-assessed PFS analysis and a corresponding analysis on the basis of 
IRC-assessed PFS will be conducted in this interim analysis.  The same stratification 
factors as specified in the primary efficacy endpoint analysis will be used.  If the p-value 
of the stratified 2-sided log-rank test is 0.0026 (approximately corresponding to a HR 
of 0.60) for both investigator- and IRC-assessed PFS analysis and the observed HR is 
favorable for the venetoclaxR combination treatment, the study will have shown 
statistically significantly longer duration of PFS in the venetoclax R arm and will have 
met its primary efficacy endpoint.  The results are expected to be presented to the health 
authorities for potential registrational purposes. 
The final primary efficacy analysis will be performed when approximately 
186 investigator-assessed PFS events have been observed, where PFS will be tested at 
the significance level of approximately 0.0498 (two-sided), corresponding to detecting an 
HR of 0.75 or less.  If necessary, the statistical test level will be adjusted to incorporate 
the alpha spent at the interim analysis so that the overall type I error rate will be 
maintained at the 2-sided 0.05 level.
6.12
RE-TREATMENT/CROSSOVER SUBSTUDY ANALYSIS
Exploratory analyses will be performed to determine the efficacy of venetoclax R for 
patients who have clinically progressed on prior venetoclax R or BR regimens when
all patients who entered the R/C Substudy complete the EOCTR-R/C Visit and at the 
end of the study.  
6.12.1
Efficacy Analyses for Re-Treatment/Crossover Substudy
The efficacy population will be defined as all patients who entered the R/C Substudy
and received at least one dose of study treatment (venetoclax or rituximab), with 
patients grouped according to the prior venetoclax R (re-treatment) or BR (crossover)
regimens. Disease response will be assessed according to the iwCLL guidelines (Hallek 
et al. 2008). Newer iwCLL guidelines may be utilized in addition if published prior to 
start of enrollment in the R/C Substudy.
Efficacy endpoints for the R/C Substudy include:

OR, CR, CRi, nPR, and PR rates at EOCTR-R/C Visit as assessed by the 
investigator

OS, defined as the time from first treatment exposure in the R/C Substudy to death 
from any cause


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
MRD response rate as measured at a central laboratory on peripheral blood samples 
and bone marrow aspirate samples at each sampling timepoint as well as Best MRD 
negativity in the R/C Substudy
6.12.2
Safety Analyses for Re-Treatment/Crossover Substudy
The safety analyses will include all patients who entered the R/C Substudy and received 
at least one dose of study treatment (venetoclax or rituximab), with patients grouped 
according to the prior venetoclax R or BR regimens. Safety endpoints include deaths, 
serious adverse events, adverse events Grade 3, select adverse events (TLS, Grade 3 
neutropenia, Grade 3 infections), second primary malignancies, Richter’s 
transformation, and adverse events leading to treatment discontinuation. Treatment 
exposure will be summarized, including the number of cycles received by each patient,
dose modification, treatment discontinuation and the cumulative dose by the prior 
venetoclax R or BR regimens.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsors will supply electronic eCRF specifications for this study.  A contract 
research organization (CRO) will be responsible for data management of this study, 
including quality checking of the data.  Data entered manually will be collected via EDC 
using eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event 
of discrepant data, the CRO will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Central laboratory data and any other electronic data will be sent 
directly to the CRO, using the CRO’s standard procedures to handle and process the 
electronic transfer of these data.
The Sponsors will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsors, and the Sponsors’ 
standard procedures will be used to handle and process the electronic transfer of these 
data.  
Electronic CRFs and correction documentation will be maintained in the EDC system’s 
audit trail.  System backups for data stored at the CRO and records retention for the
study data will be consistent with the CRO’s standard procedures. 
Electronic patient-reported outcome (ePRO) data will be collected using an electronic 
device provided by an ePRO vendor.  The device is designed for entry of data in a way 
that is attributable, secure, and accurate, in compliance with U.S. FDA regulations for 
electronic records (21 CFR Part 11).  The ePRO device data are available for view 


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access only via secure access.  Only identified and trained users may view the data, and 
their actions become part of the audit trail.  The Sponsors will have view access only.  
System backups for data stored by the Sponsors and records retention for the study 
data will be consistent with the Sponsors’ standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
Electronic CRFs are to be completed using a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsors and should be handled in 
accordance with instructions from the Sponsors.
All eCRFs should be completed by designated, trained site staff.  Electronic CRFs 
should be reviewed and electronically signed and dated by the investigator or a 
designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patients will use an ePRO device to capture PRO data.  The data will be transmitted via 
internet automatically after entry to a centralized database at the ePRO vendor.  The 
data can be reviewed by site staff via secure access to an internet server.
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required.  In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.


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Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsors.  Written 
notification should be provided to the Sponsors prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 


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ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsors’ sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsors or their designee must review and approve any proposed 
deviations from the Sponsors’ sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature.
The Informed Consent Forms must be signed and dated by the patient or the patient’s 
legally authorized representative before his or her participation in the study.  The case 
history or clinical records for each patient shall document the informed consent process 
and that written informed consent was obtained prior to participation in the study.
An additional Re-treatment/Crossover Substudy (R/C) Informed Consent Form will be 
provided to address the optional participation in the R/C Substudy.  The investigator or 
authorized designee wil explain to the patient the objectives, requirements, and risks of 
participation. This substudy informed consent must be signed and dated by the 
patient’s legally authorized reprensentative before his or her participation in the study.
The Informed Consent Forms should be revised whenever there are changes to study 
procedures or when new information becomes available that may affect the willingness
of the patient to participate.  The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Informed Consent 
Forms (or to a significant new information/findings addendum in accordance with 
applicable laws and IRB/EC policy) during their participation in the study.  For any 


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updated or revised Informed Consent Forms, the case history or clinical records for each 
patient shall document the informed consent process and that written informed consent 
was obtained using the updated/revised Informed Consent Forms for continued 
participation in the study.
A copy of each signed Informed Consent Form must be provided to the patient or the 
patient’s legally authorized representative.  All signed and dated Informed Consent 
Forms must remain in each patient’s study file or in the site file and must be available for 
verification by study monitors at any time.
For sites in the United States, each Informed Consent Form may also include patient 
authorization to allow use and disclosure of personal health information in compliance 
with the U.S. Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the 
site utilizes a separate Authorization Form for patient authorization for use and 
disclosure of personal health information under the HIPAA regulations, the review, 
approval, and other processes outlined above apply except that IRB review and approval 
may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsors maintain confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 


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authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsors with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsors to submit complete and 
accurate financial certification or disclosure statements to the appropriate health 
authorities.  Investigators are responsible for providing information on financial interests 
during the course of the study and for 1 year after completion of the study.
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of  Good Clinical Practice guidelines and 
require reporting to health authorities.  As per the Sponsor's standard operating 
procedures, prospective requests to deviate from the protocol, including requests to 
waive protocol eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.


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9.4
ADMINISTRATIVE STRUCTURE
Approximately 150 international centers will participate in this study to enroll up to 
approximately 370 patients.  Data will be recorded via an EDC system from Medidata 
Solutions (New York, NY) using electronic Case Report Forms (eCRFs; see Section 6.6).  
Central laboratories will be used for the analyses of and/or management of 
pharmacodynamic, genotyping, and tissue samples.  An IxRS will be used for patient 
registration, patient number, and dose assignment.
This trial is being conducted globally under a collaboration agreement between 
F. HoffmannLa Roche, Ltd. and AbbVie, Inc.  F. HoffmannLa Roche, Ltd. and 
AbbVie, Inc. will act as co-sponsors of the trial in the United States.  AbbVie GmbH & Co. 
KG (Germany) will act as the sponsor of the trial for participating countries in the 
European Union.  In countries where an AbbVie entity is the sole sponsor, Genentech 
and a CRO will manage the study and carry out certain sponsor responsibilities 
delegated to Genentech by AbbVie, in accordance with applicable laws/regulatory 
requirements.
AbbVie, Inc. is the holder of the U.S. IND under which this study is being conducted.  
AbbVie will file all clinical trial applications for this study outside of the United States.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsors 
prior to submission.  This allows the Sponsors to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the investigator.
The Sponsors will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsors will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.


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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsors.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Assessments
Table 1
Patients Randomized to Arm A (VenetoclaxR)
Arm A
(Venetoclax
R)
Screen.
Venetoclax Ramp-Up Period
Combination (VenetoclaxR) Therapy
Venetoclax Monotherapy/Follow-Up
Cycle 1
Cycles 23
Interim Response 
Assessment a
C46 Comp. of 
Comb. 
Therapy b
Early 
Treatment 
Term. c
End of Comb. 
Treatment 
Response 
Visit d
Follow-Up
Visits e
Survival 
Follow-Up
Visits f
Day
28 
to 1
1
8
15
22
29
1
2
8
15
1
8
15
1
Visit Window
(days)
1
1
1
1
1
1
0
1
1
3
1
1
3
7
7
7
7
30
Informed consent
X
Demographic 
data g
X
General medical 
history and 
baseline conditions
X
Concomitant 
medications, 
adverse events, 
and compliance 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
X
X
Vital signs h
X
X h
X h
X h
X h
X h
X
X
X
X
X
X
X
X
X
X
X


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
162/Protocol GO28667, Version 9
Arm A
(Venetoclax
R)
Screen.
Venetoclax Ramp-Up Period
Combination (VenetoclaxR) Therapy
Venetoclax Monotherapy/Follow-Up
Cycle 1
Cycles 23
Interim Response 
Assessment a
C46 Comp. of 
Comb. 
Therapy b
Early 
Treatment 
Term. c
End of Comb. 
Treatment 
Response 
Visit d
Follow-Up
Visits e
Survival 
Follow-Up
Visits f
Day
28 
to 1
1
8
15
22
29
1
2
8
15
1
8
15
1
Visit Window
(days)
1
1
1
1
1
1
0
1
1
3
1
1
3
7
7
7
7
30
Height (at 
screening only), 
weight, calculation 
of BSA
X
X
X
X
X
X
X
X
X
X
X
Height (at 
screening only), 
weight, calculation 
of BSA
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination i
X
Targeted physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of
LVEF j
X
X
X
CLL response 
assessment k
X
X
X
X
X
X
X
X
X
CT (or MRI) scan k
X
X k
X k
(X)


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
163/Protocol GO28667, Version 9
Arm A
(Venetoclax
R)
Screen.
Venetoclax Ramp-Up Period
Combination (VenetoclaxR) Therapy
Venetoclax Monotherapy/Follow-Up
Cycle 1
Cycles 23
Interim Response 
Assessment a
C46 Comp. of 
Comb. 
Therapy b
Early 
Treatment 
Term. c
End of Comb. 
Treatment 
Response 
Visit d
Follow-Up
Visits e
Survival 
Follow-Up
Visits f
Day
28 
to 1
1
8
15
22
29
1
2
8
15
1
8
15
1
Visit Window
(days)
1
1
1
1
1
1
0
1
1
3
1
1
3
7
7
7
7
30
Bone marrow 
aspirate and 
biopsy (including 
flow cytometry or 
IHC) l, m
X
(X)
(X)
(X)
(X)
(X)
Pregnancy test n
X
X
X
X
X
X
X
Viral serologies o
X
HBV DNA on PCR 
(for applicable 
patients) p
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Hospitalization q
(X)
(X)
(X)
(X)
(X)
(X)
Hematology r
X
X t
X t
X t
X t
X t
X t
X
X
X
X
X
X
X
X
X
Coagulation
X
Serum chemistry s
X
X t
X t
X t
X t
X t
X t
X
X
X
X
X
X
X
X
X
B, T, and 
NKcell markers 
(flow cytometry) u
X
X
X
X
X
X
Urinalysis v
X


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
164/Protocol GO28667, Version 9
Arm A
(Venetoclax
R)
Screen.
Venetoclax Ramp-Up Period
Combination (VenetoclaxR) Therapy
Venetoclax Monotherapy/Follow-Up
Cycle 1
Cycles 23
Interim Response 
Assessment a
C46 Comp. of 
Comb. 
Therapy b
Early 
Treatment 
Term. c
End of Comb. 
Treatment 
Response 
Visit d
Follow-Up
Visits e
Survival 
Follow-Up
Visits f
Day
28 
to 1
1
8
15
22
29
1
2
8
15
1
8
15
1
Visit Window
(days)
1
1
1
1
1
1
0
1
1
3
1
1
3
7
7
7
7
30
Serum QIG w
X
X
X
X
X
X
CLL prognostic 
factors (including 
CLL FISH for 17p) x
X
MRD on peripheral 
blood y
X
X
X
X
X
X y
Blood and bone 
marrow samples 
for Bcl-2 family 
(RNA, flow 
cytometry) z
X
X z
X z
X z
(X z)
Blood sample for 
in vitro sensitivity 
to venetoclax z
X
Blood sample for 
Bcl-2: Bim 
analysis z
X


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
165/Protocol GO28667, Version 9
Arm A
(Venetoclax
R)
Screen.
Venetoclax Ramp-Up Period
Combination (VenetoclaxR) Therapy
Venetoclax Monotherapy/Follow-Up
Cycle 1
Cycles 23
Interim Response 
Assessment a
C46 Comp. of 
Comb. 
Therapy b
Early 
Treatment 
Term. c
End of Comb. 
Treatment 
Response 
Visit d
Follow-Up
Visits e
Survival 
Follow-Up
Visits f
Day
28 
to 1
1
8
15
22
29
1
2
8
15
1
8
15
1
Visit Window
(days)
1
1
1
1
1
1
0
1
1
3
1
1
3
7
7
7
7
30
Tumor cells for Bcl-
2 family by IHC 
(formalin fixed 
tissue) aa
X
Optional Roche 
Clinical Repository 
samples bb
(X)
(X)
(X)
Venetoclax cc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rituximab dd
X
(X)
X
X
MDASI ee
X
X
X
X
X
X
X
EORTC QLQ-30 
and CLL-16 ff
X
X
X
X
X
X
X
X
EQ-5D ff
X
X
X
X
X
X
X
X
ECG gg
X
PK sampling hh
X
X hh
B Symptoms
X
X
X
X
X
X
X
X
X
X
MRD in bone 
marrow ii
X l
(X)
(X)


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
166/Protocol GO28667, Version 9
Arm A
(Venetoclax
R)
Screen.
Venetoclax Ramp-Up Period
Combination (VenetoclaxR) Therapy
Venetoclax Monotherapy/Follow-Up
Cycle 1
Cycles 23
Interim Response 
Assessment a
C46 Comp. of 
Comb. 
Therapy b
Early 
Treatment 
Term. c
End of Comb. 
Treatment 
Response 
Visit d
Follow-Up
Visits e
Survival 
Follow-Up
Visits f
Day
28 
to 1
1
8
15
22
29
1
2
8
15
1
8
15
1
Visit Window
(days)
1
1
1
1
1
1
0
1
1
3
1
1
3
7
7
7
7
30
Anti-CLL therapy jj
X
X 
X 
Survival status/ 
disease 
progression
X
BSAbody surface area; Ccycle; CLLchronic lymphocytic leukemia; Comb. Combination; Comp. Completion; CRcomplete response; CTcomputed tomography; Dday;
ECOGEastern Cooperative Oncology Group; EORTC QLQ C-30/CLL16European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30/ 
Chronic Lymphocytic Leukemia Module 16 questionnaires; EQ-5DEuroQol's EQ-5D questionnaire; FISHfluorescence in situ hybridization; HBcAbserum immunoglobulin G 
antibody directed at hepatitis B core antigen; HBsAghepatitis B virus surface antigen; IgG anti-Hep C Abserum antibody directed against hepatitis C virus; 
IHCimmunohistochemistry, IVintravenous; IVRxinteractive voice response solution; LVEFleft ventricular ejection fraction; MDASIM. D. Anderson Symptom Inventory; 
MRDminimal residual disease; MRI magnetic resonance imaging; NKnatural killer cell; PDprogressive disease; PKpharmacokinetic; POper os, orally; PRpartial 
response; PROpatient-reported outcome; QIGquantitative immunoglobulin (including serum levels of IgA, IgG and IgM); Rrituximab; Screen. Screening; Term. Termination; 
TLStumor lysis syndrome.
Note:  (X) indicates assessments that may be performed but are not required, as determined by the investigator.
a
Interim response assessment is within 14 days of Cycle 4 Day 1.
b
Completion of combination therapy occurs 4 weeks after Cycle 6 Day 1.
c
Early Treatment Termination Visit (if applicable) occurs 4 weeks after last dose of study treatment.
d
End of Combination Treatment Response Visit occurs 12 weeks (earliest 8 weeks) after Day 1 of last cycle of combination therapy.
e
Follow-Up Visits occur every 12 weeks until 3 years and then every 24 weeks until PD.
f
Survival Follow-Up Visits occur every 24 weeks after PD until study end.


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
167/Protocol GO28667, Version 9
g
Patient age, sex, race, self-reported ethnicity.
h
Vital signs will include measurements of temperature, heart rate, systolic and diastolic blood pressure.  Vital signs should be collected at all times of chemistry blood draws.
i
Complete physical examination is required at screening; targeted physical examination for all subsequent visits.  Complete physical examination includes all systems of the body 
as described in the body of the protocol.  Targeted physical examinations should be limited to systems of clinical relevance (i.e., cardiovascular, respiratory, lymphatics [including 
spleen], and gastrointestinal [including liver], and those associated with clinical signs/symptoms). 
j
Assessment of LVEF by either echocardiogram or multigated acquisition (MUGA) scan after screening is at the discretion of the investigator. 
k
All patients must have clinical response assessments (including targeted physical examination and laboratory examinations) at interim response assessment (within 14 days of 
Cycle 4 Day 1), and 4 weeks after Day 1 of the last cycle.  All patients must have a baseline CT scan (or MRI if CT is contraindicated) of the neck (if indicated), chest, abdomen, 
and pelvis with IV and oral contrast.  A follow-up scan must also be performed at the interim response assessment (within 14 days of Cycle 4 Day 1) visit and for final response 
assessment following completion of combination therapy or early termination (23 months after Day 1 of the last treatment cycle).  Targeted physical examination and laboratory 
examinations should be repeated to confirm that patients are still in response prior to confirmatory CT or MRI scan.  Imaging evaluations at subsequent study visits are only 
required to confirm a new response (i.e., to confirm a new PR or CR).  Imaging evaluations must be performed within 2 weeks for patients who meet the clinical criteria for PD (i.e., 
increased or de novo enlargement of liver, spleen, or lymph nodes on physical examination) in the absence of laboratory or histopathologic criteria for PD.  MRI scans of the chest, 
abdomen, and pelvis with a non-contrast CT scan of the chest may be used instead of CT scans in patients for whom CT scans with contrast are contraindicated (i.e., patients with 
contrast allergy or impaired renal clearance).  Conventional CT and MRI should be performed with contiguous cuts of 10 mm or less in slice thickness.  Spiral CT should be 
performed by use of a 5-mm contiguous reconstruction algorithm; this specification applies to the tumors of the chest, abdomen, and pelvis.  If MRIs are used instead of CT scans, 
MRIs should be used consistently throughout the study.
l
A bone marrow examination must be performed at screening.  For those patients who have achieved a CR or cytopenic CR (including a CT scan indicating a possible CR), a bone 
marrow aspirate and biopsy will be obtained to confirm the CR at least 8 weeks following the initial clinical assessment of CR.  If the CR occurs at the interim response assessment 
visit, the bone marrow aspirate and biopsy to confirm that CR should be performed around Cycle 6 (at least 8 weeks following the interim response assessment visit).  If the bone 
marrow examination confirms a CR, then a repeat bone marrow at the end of combination response visit is not needed.  Otherwise, a subsequent bone marrow aspirate and 
biopsy would be required to confirm a new CR. 
m
A bone marrow aspirate should be obtained for MRD assessment in all responding patients (CR or PR).
n
Required for all women of reproductive potential (see inclusion criteria).
o
HBsAg, IgG anti-HBcAb, and Hep C Ab serology (also HCV RNA by polymerase chain reaction if the patient is HCV antibody positive) required.
p
For hepatitis B core antibody–positive patients, the HBV DNA titer needs to be determined using real-time PCR monthly until at least 12 months after the last rituximab dose.  Note 
that during the venetoclax monotherapy/follow-up period, HBV DNA titer should be performed monthly and the results reviewed by the investigator or designee.  The patient does 
not need to have any other procedures besides this laboratory test between the 12-week follow-up visits unless clinically indicated.
q
Refer to Section 4.4.1.2  for hospitalization and prophylaxis measures for TLS. 


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
168/Protocol GO28667, Version 9
r
Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count), platelet count, absolute neutrophil count, absolute lymphocyte count, and 
percent or absolute differential counts (e.g., segmented neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils, and other cells).
s
Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen or urea (when BUN not available), creatinine, calcium, magnesium, phosphorus, total bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase, lactate dehydrogenase, and uric acid.  All scheduled blood draws may be drawn up to 72 hours prior to the next planned 
evaluation.
t
Serum hematology and chemistries should be drawn at the specific timepoints as described in detail in Section 4.4.1.2 .
u
Peripheral blood lymphocyte subpopulations (CD3, CD4, CD8, CD19, CD16, and CD56) measured by flow cytometry are required at screening, interim response assessment 
(within 14 days of Cycle 4 Day 1), early termination or end of combination treatment, 12 weeks after Day 1 of the last cycle of combination therapy, and every 12 weeks thereafter.  
v
Consists of specific gravity, pH, blood, protein, glucose, ketones, and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial cells, and bacteria).
w
QIG: quantitative immunoglobulin (including serum levels of IgA, IgG and IgM).
x
Patients will have the following samples drawn at screening: serum for 2-microglobulin, whole blood for IgVH mutational status, p53 and other prognostic mutations, and 
interphase FISH for chromosomal abnormalities including 17p-, 11q-, 13q-, and trisomy +12.  Sample will be taken for both local and central testing of 17p deletion by FISH.  In the 
event a local 17p FISH test is not available, the central test results may be used for randomization.
y
MRD samples in peripheral blood collected at baseline, within 14 days of C4D1 (interim response assessment), completion of Combination Therapy/Early Treatment Termination 
visit (if applicable), End of Combination Treatment Response Visit, and every 3 months after completion of combination therapy until 3 years and then every 24 weeks until PD.  
Samples are also collected at any visit during follow-up where a patient has a response (PR or CR status), and at PD. Samples will be measured at a central laboratory.
z
Whole blood predictive biomarker sample is required for all patients at screening and at time of progression (early termination if applicable) or at end of treatment, one tube each 
for protein and RNA analysis of Bcl-2 family members.  A predictive bone marrow aspirate sample (1 mL each for protein and RNA analysis) must be drawn for all patients at 
screening.  Aspirate samples should be split from samples obtained for International Workshop on Chronic Lymphocytic Leukemia National Cancer Institute Working Group or 
International Working Group criteria assessment whenever possible. If aspirate sample is limiting, then protein should be prioritized over RNA sample.  Please note that a bone 
marrow biopsy and aspirate is not required at the time of progression (unless it is needed to confirm or rule out PD); however, if it is performed then a predictive bone marrow 
biomarker sample should also be drawn.  Predictive biomarker sample will be used for assessment of Bcl-2 family and other relevant markers by RNA and flow in the blood and 
bone marrow.  Additional biomarker assessments will include a blood sample that will be collected at Cycle 1 Day1 predose and 4-hours post-dose for Bcl-2:Bim complex by 
protein in blood and a blood sample collected predose at Day 1 of the ramp-up period for venetoclax in vitro sensitivity.
aa If formalin fixed specimen of bone marrow biopsy (also including lymph node or other biopsies) is collected at screening by the site per standard clinical assessment of the patient, 
a sample should be provided for IHC analysis of Bcl-2 family.
bb Residual tumor specimens are requested at screening and optional blood samples are requested at Day 1 of ramp-up period and at the end of combination therapy or End of 
Combination Treatment/Early Treatment Termination Visit for collection and storage at the Roche Clinical Repository.


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
169/Protocol GO28667, Version 9
cc For patients randomized to Arm A, venetoclax will be taken daily by mouth starting on Day 1 through the end of study.  As described in Section 4.3.2.1 , there will be a 5 week 
venetoclax ramp-up period when patients will start with a 20 mg dose on Day 1 for a week.  Patients will increase to 50 mg on Day 8and subsequently increase the dose weekly to 
reach the dose of 400 mg for the study.  Patients will continue venetoclax at 400 mg PO daily with concurrent rituximab for 6 cycles of 28 days each.  Patient with no evidence of 
progression will continue single agent venetoclax (400 mg PO daily) until progressive disease, unacceptable toxicity, or for a maximum of 2 years.
dd On Day 1 of Cycle 1, patients will receive rituximab 375 mg/m2 IV followed by rituximab 500 mg/m2 IV on Day 1 of Cycles 2 through 6.  Investigators will have the option of 
administering the rituximab dose for Day 1 Cycle 1 over 2 days (e.g., 100 mg IV on Day 1, Cycle 1 followed by the remainder of the 375 mg/m2 dose on Day 2 Cycle 1).
ee The MDASI questionnaire will be completed at home on the specified days.  An interactive voice response solution (IVRx) will be used to capture the MDASI questionnaire data.
ff
Patients should complete the questionnaires prior to study drug administration and any other study assessments.  PRO assessments should be performed prior to progression, at 
the time of progression, and at the first assessment after progression.
gg An ECG is required at screening only as clinically indicated.
hh PK data will be collected for patients randomized to Arm A only.  Unscheduled PK sample will be collected from patients developing laboratory or clinical evidence of TLS.  PK 
samples are to be collected on Day 1 of Cycle 1 and on Day 1 of Cycle 4 at the timepoints described in Appendix 2.
ii
A bone marrow aspiration should be obtained for MRD assessment in the bone marrow in all responders (CRPR) at the End of Combination Treatment Response Visit or any 
time after, if the patient becomes a responder.   A sample of the bone marrow examination performed at Screening will also be used to assess MRD in the bone marrow.
jj
Assessment is required but may not be applicable.  Includes regimen name, treatment dates, best overall response and date of disease progression for new anti-CLL therapy.


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
170/Protocol GO28667, Version 9
Table 2
Patients Randomized to Arm B (BR)
Arm B
(BR)
Screen.
Combination (BR) Therapy
Observation and Follow-Up
Cycle 1
Cycles 23
Interim Response 
Assessment a
C46
Comp. of 
Comb.
Therapy b
Early 
Treatment 
Term. c
End of Comb.
Treatment 
Response 
Visit d
Follow-Up 
Visits e
Survival 
Follow-up 
Visits f
Day
28 
to 1
1
2
8
15
1
2
8
15
1
Visit Window
(± days)
1
1
1
1
3
1
1
1
3
7
7
7
7
30
Informed consent
X
Demographic data g
X
General medical 
history and baseline 
conditions
X
Concomitant 
medications, adverse 
events, and 
compliance 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Status
X
X
X
X
X
X
X
X
Vital signs h
X
X
X
X
X
X
X
X
X
X
X
X
Height (at screening 
only), weight and 
calculation of BSA
X
X
(X)
X
X
X
X
X
X
X
X
Physical 
examination i
X


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
171/Protocol GO28667, Version 9
Arm B
(BR)
Screen.
Combination (BR) Therapy
Observation and Follow-Up
Cycle 1
Cycles 23
Interim Response 
Assessment a
C46
Comp. of 
Comb.
Therapy b
Early 
Treatment 
Term. c
End of Comb.
Treatment 
Response 
Visit d
Follow-Up 
Visits e
Survival 
Follow-up 
Visits f
Day
28 
to 1
1
2
8
15
1
2
8
15
1
Visit Window
(± days)
1
1
1
1
3
1
1
1
3
7
7
7
7
30
Targeted physical 
examination
X
X
X
X
X
X
X
X
X
Assessment of LVEF 
X
CLL response 
assessment j
X
X
X
X
X
X
X
X
CT (or MRI) scan j
X
X j
X j
(X) j
Bone marrow 
aspirate and biopsy 
(including flow 
cytometry or IHC) k
X
(X)
(X)
(X)
(X)
(X)
Pregnancy test l
X
X
X
X
X
Viral serologies m
X
HBV DNA on PCR 
(for applicable 
patients) n
(X)
(X)
(X)
(X)
(X)
(X)
(X) n
(X) n
Hematology o
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
Serum chemistry p
X
X
X
X
X
X
X
X
X
X
X
X


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
172/Protocol GO28667, Version 9
Arm B
(BR)
Screen.
Combination (BR) Therapy
Observation and Follow-Up
Cycle 1
Cycles 23
Interim Response 
Assessment a
C46
Comp. of 
Comb.
Therapy b
Early 
Treatment 
Term. c
End of Comb.
Treatment 
Response 
Visit d
Follow-Up 
Visits e
Survival 
Follow-up 
Visits f
Day
28 
to 1
1
2
8
15
1
2
8
15
1
Visit Window
(± days)
1
1
1
1
3
1
1
1
3
7
7
7
7
30
B, T, and NKcell 
markers (flow 
cytometry) q
X
X
X
X
X
X
Urinalysis r
X
Serum QIG 
X
X
X
X
X
X
CLL prognostic 
factors (including CLL 
FISH for 17p) s
X
MRD on peripheral 
blood t
X
X
X
X
X
X t
Blood and bone 
marrow samples for 
Bcl-2 family (RNA, 
flow cytometry) u
X
(X)
(X)
(X)
(X)
B Symptoms  
X
X
X
X
X
X
X
X
X
Blood sample for Bcl-
2: Bim analysis u
X


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
173/Protocol GO28667, Version 9
Arm B
(BR)
Screen.
Combination (BR) Therapy
Observation and Follow-Up
Cycle 1
Cycles 23
Interim Response 
Assessment a
C46
Comp. of 
Comb.
Therapy b
Early 
Treatment 
Term. c
End of Comb.
Treatment 
Response 
Visit d
Follow-Up 
Visits e
Survival 
Follow-up 
Visits f
Day
28 
to 1
1
2
8
15
1
2
8
15
1
Visit Window
(± days)
1
1
1
1
3
1
1
1
3
7
7
7
7
30
Tumor cells for Bcl-2 
family by IHC (formalin 
fixed tissue) v
X
Optional Roche 
Clinical Repository 
samples w
(X)
(X)
(X)
Rituximab x
X
(X)
X
(X)
X
Bendamustine y
X
X
X
X
X
MDASI z
X
X
X
X
X
X
EORTC QLQ-30 and 
CLL-16 aa
X
X
X
X
X
X
X
EQ-5D aa
X
X
X
X
X
X
X
ECG bb
X
MRD in bone 
marrow cc
X
(X)
(X)
Anti-CLL therapy dd
X
X
X
Survival status/ 
disease progression
X


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
174/Protocol GO28667, Version 9
BSAbody surface area; Ccycle; CLLchronic lymphocytic leukemia; Comb. Combination; Comp. Completion; CRcomplete response; CTcomputed tomography; Dday; 
ECOGEastern Cooperative Oncology Group; EORTC QLQ C-30/CLL16European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30/ 
Chronic Lymphocytic Leukemia Module 16 questionnaires; EQ-5DEuroQol's EQ-5D questionnaire; FISHfluorescence in situ hybridization; HBcAbserum immunoglobulin G 
antibody directed at hepatitis B core antigen; HBsAghepatitis B virus surface antigen; IgG anti-Hep C Abserum antibody directed against hepatitis C virus; 
IHCimmunohistochemistry, IVintravenous; IVRxinteractive voice response solution; LVEFleft ventricular ejection fraction; MDASIM. D. Anderson Symptom Inventory; 
MRDminimal residual disease; MRImagnetic resonance imaging; NKnatural killer cell; PDprogressive disease; PKpharmacokinetic; POper os, orally; PROpatient-
reported outcome; QIGquantitative immunoglobulin (including serum levels of IgA, IgG and IgM); Rrituximab; Screen. Screening; Term. Termination; TLStumor lysis 
syndrome. 
Note:  (X) indicates assessments that may be performed but are not required, as determined by the investigator.
a
Interim response assessment is within 14 days of Cycle 4 Day 1.
b
Completion of combination therapy occurs 4 weeks after Cycle 6 Day 1.
c
Early Treatment Termination Visit (if applicable) occurs 4 weeks after last dose of study treatment.
d
End of Combination Treatment Response Visit occurs 12 weeks (earliest 8 weeks) after Day 1 of last cycle of combination therapy.
e
Follow-Up Visits occur every 12 weeks until 3 years and then every 24 weeks until PD.
f
Survival Follow-Up Visits occur every 24 weeks after PD until study end.
g
Patient age, sex, race, self-reported ethnicity.
h
Vital signs will include measurements of temperature, heart rate, systolic and diastolic blood pressure.
i
Complete physical examination is required at screening; targeted physical examination for all subsequent visits.  Complete physical examination includes all systems of the body as 
described in the body of the protocol.  Targeted physical examinations should be limited to systems of clinical relevance (i.e., cardiovascular, respiratory, lymphatics [including 
spleen], and gastrointestinal [including liver], and those associated with clinical signs/symptoms).  
j
All patients must have clinical response assessments (including targeted physical examination and laboratory examinations) at interim response assessment (within 14 days of Cycle 
4 Day 1), and 4 weeks after Day 1 of the last cycle.  All patients must have a baseline CT scan (or MRI if CT is contraindicated) of the neck (if indicated), chest, abdomen, and pelvis 
with IV and oral contrast.  A follow-up scan must also be performed at the interim response assessment (within 14 days of Cycle 4 Day 1) visit and for final response assessment 
following completion of combination therapy or early termination (23 months after Day 1 of the last treatment cycle).  Targeted physical examination and laboratory examinations 
should be repeated to confirm that patients are still in response prior to confirmatory CT or MRI scan.  Imaging evaluations at subsequent study visits are only required to confirm a 
new response.  Imaging evaluations must be performed within 2 weeks for patients who meet the clinical criteria for PD (i.e., increased or de novo enlargement of liver, spleen, or 
lymph nodes on physical examination) in the absence of laboratory or histopathologic criteria for PD.  MRI scans of the chest, abdomen, and pelvis with a non-contrast CT scan of 
the chest may be used instead of CT scans in patients for whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy or impaired renal clearance).  
Conventional CT and MRI should be performed with contiguous cuts of 10 mm or less in slice thickness.  Spiral CT should be performed by use of a 5-mm contiguous reconstruction 
algorithm; this specification applies to the tumors of the chest, abdomen, and pelvis.  If MRIs are used instead of CT scans, MRIs should be used consistently throughout the study.


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
175/Protocol GO28667, Version 9
k
A bone marrow examination must be performed at screening.  For those patients who have achieved a CR or cytopenic CR (including a CT scan indicating a possible CR), a bone 
marrow aspirate and biopsy will be obtained to confirm the CR at least 8 weeks following the initial clinical assessment of CR.  A bone marrow aspirate should be obtained for MRD 
assessment to confirm a molecular CR.  Bone marrow examination should be performed as needed within 2 weeks for patients who show clinical suspicion for PD (i.e., increased or 
de novo enlargement of liver, spleen, or lymph nodes on physical examination) in the absence of laboratory or histopathologic criteria for PD.  Any additional/unscheduled bone 
marrow examinations performed during the study will be at the discretion of the investigator.
l
Required for all women of reproductive potential (see inclusion criteria).
m
HBsAg, IgG anti-HBcAb, and Hep C Ab serology (also HCV, and RNA by polymerase chain reaction if the patient is HCV antibody positive) required.
n
For hepatitis B core antibody–positive patients, the HBV DNA titer needs to be determined using real-time PCR monthly until at least 12 months after the last rituximab dose.  Note 
that during the follow-up period, HBV DNA titer should be performed monthly and the results reviewed by the investigator or designee.  The patient does not need to have any other 
procedures besides this laboratory test between the 12-week follow-up visits unless clinically indicated.
o
Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count), platelet count, absolute neutrophil count, absolute lymphocyte count, and percent 
or absolute differential counts (e.g., segmented neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils, and other cells).  
p
Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen or urea (when BUN not available), creatinine, calcium, magnesium, phosphorus, total bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase, lactate dehydrogenase, and uric acid.  
q
Peripheral blood lymphocyte subpopulations (CD3, CD4, CD8, CD19, CD16, and CD56) measured by flow cytometry are required at baseline, interim response assessment (within 
14 days of Cycle 4 Day 1), early termination or end of treatment, 12 weeks after Day 1 of the last cycle of combination therapy, and every 12 weeks thereafter.  
r
Consists of specific gravity, pH, blood, protein, glucose, ketones, and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial cells, and bacteria).
s
Patients will have the following samples drawn at screening: serum for 2-microglobulin, whole blood for IgVH mutational status, p53 and other prognostic mutations, and interphase 
FISH for chromosomal abnormalities including 17p-, 11q-, 13q-, and trisomy +12.  Sample will be taken for both local and central testing of 17p deletion by FISH.  In the event a local 
17p FISH test is not available, the central test results may be used for randomization.
t
MRD samples collected at baseline, within 14 days of C4D1 (interim response assessment), completion of Combination Therapy/Early Treatment Termination Visit (if applicable), End 
of Combination Treatment Response Visit, and every 3 months after completion of combination therapy until 3 years and then every 24 weeks until PD.  Samples are also collected 
any time a patient has a response (PR or CR status) and at PD.  Samples will be measured at a central laboratory.
u
Predictive biomarker sample will be used for assessment of Bcl-2 family and other relevant markers by RNA and flow in the blood and bone marrow.  Whole blood predictive biomarker 
sample is required for all patients at screening and at time of progression (early termination if applicable) or at end of treatment, one tube each for protein and RNA analysis of Bcl-2 
family members.  A predictive bone marrow aspirate sample (1 mL each for protein and RNA analysis) should be drawn for all patients at screening.  Aspirate samples should be split 
from samples obtained for International Workshop on Chronic Lymphocytic Leukemia National Cancer Institute Working Group or International Working Group criteria assessment 
whenever possible.  If aspirate sample is limiting then protein should be prioritized over RNA sample.  Please note that a bone marrow biopsy and aspirate is not required at the time 
of progression (unless it is needed to confirm or rule out PD); however, if it is performed then a predictive bone marrow biomarker sample should also be drawn.  A sample for Bcl-
2:Bim complex by protein in blood will be collected for Arm B patients before dosing on Cycle 1 Day 1.


Appendix 1
Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
176/Protocol GO28667, Version 9
v
If formalin fixed specimen of bone marrow biopsy is collected at screening by the site per standard clinical assessment of the patient, a sample should be provided for IHC analysis of 
Bcl-2 family.
w
Residual tumor specimens are requested at screening and optional blood samples are requested at C1D1 and at the end of combination therapy visit or End of Combination 
Treatment/Early Treatment Termination Visit for collection and storage at the Roche Clinical Repository.
x
Rituximab will be administered at 375 mg/m2 IV on Day 1 of Cycle 1 followed by 500 mg/m2 IV on Day 1 of Cycles 2 through 6.  Investigators will have the option of administering the 
rituximab dose for Day 1 of Cycle 1 over 2 days (e.g., 100 mg IV on Day 1 of Cycle 1 followed by the remainder of the 375 mg/m2 dose on Day 2 of Cycle 1).
y
Bendamustine will be administered at 70 mg/m2 IV on Days 1 and 2 of Cycles 1 through 6.
z
The MDASI questionnaire will be completed at home on the specified days.  An interactive voice response solution (IVRx) will be used to capture MDASI questionnaire data.
aa Patients should complete the questionnaires prior to study drug administration and any other study assessments.  PRO assessments should be performed prior to progression, at the 
time of progression, and at the first assessment after progression.
bb An ECG is required at screening only and as clinically indicated for subsequent visits.
cc A bone marrow aspirate should be obtained for MRD assessment in the bone marrow in all responders (CRPR) at the End of Combination Treatment Response Visit or any time 
after, if the patient becomes a responder.  A sample of the bone marrow examination performed at Screening will also be used to assess MRD in the bone marrow.
dd Assessment is required but may not be applicable.  Includes regimen name, treatment dates, best overall response and date of disease progression for new anti-CLL therapy.


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
177/Protocol GO28667, Version 9
Appendix 2
Schedule of Pharmacokinetic Assessments
Patients Randomized to Arm A (VenetoclaxR)
Blood samples to assess venetoclax concentrations will be collected at the following 
timepoints:
Visit
Timepoint
Sample Type
Cycle 1 Day 1
Pre-venetoclax dose
Plasma
4 h (1 h) post-venetoclax dose
Cycle 4 Day 1
Pre-venetoclax dose
Plasma
4 h (1 h) post-venetoclax dose
hhour.
Note:  An unscheduled PK sample will be collected if TLS is observed.  An unscheduled PK 
sample will be collected in case of early termination.


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
178/Protocol GO28667, Version 9
Appendix 3
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
EORTC QLQ-C30 (Version 3)
We are interested in some things about you and your health.  Please answer all 
of the questions yourself by circling the number that best applies to you.  There 
are no "right" or "wrong" answers.  The information that you provide will remain 
strictly confidential.
Patient’s identification number:–––––––––––––––––––––
Patient’s date of birth (Day, Month, Year):
–––––––––––––––––––––
Today's date (Day, Month, Year):
–––––––––––––––––––––
______________________________________________________________________
_
During the past week:
Not at
A
Quite
Very
All
Little a Bit Much
1.
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a short walk outside of the house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the day?
1
2
3
4
5.
Do you need help with eating, dressing, washing 
yourself, or using the toilet?
1
2
3
4
During the past week:
Not at
A
Quite Very
All
Little a Bit Much
6.
Were you limited in doing either your work or other daily activities?
1
2
3
4
7.
Were you limited in pursuing your hobbies or other
leisure time activities?
1
2
3
4
8.
Were you short of breath?
1
2
3
4
9.
Have you had pain?
1
2
3
4


Appendix 3
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
179/Protocol GO28667, Version 9
10. Did you need to rest?
1
2
3
4
11. Have you had trouble sleeping?
1
2
3
4
During the past week:
Not at
A
Quite Very
All
Little a Bit Much
12. Have you felt weak?
1
2
3
4
13. Have you lacked appetite?
1
2
3
4
14. Have you felt nauseated?
1
2
3
4
15. Have you vomited?
1
2
3
4
16. Have you been constipated?
1
2
3
4
During the past week:
Not at
A
Quite Very
All
Little a Bit Much
17. Have you had diarrhea?
1
2
3
4
18. Were you tired?
1
2
3
4
19. Did pain interfere with your daily activities?
1
2
3
4
20. Have you had difficulty in concentrating on things,
like reading a newspaper or watching television?
1
2
3
4
21. Did you feel tense?
1
2
3
4
22. Did you worry?
1
2
3
4
23. Did you feel irritable?
1
2
3
4
24. Did you feel depressed?
1
2
3
4
25. Have you had difficulty remembering things?
1
2
3
4
26. Has your physical condition or medical treatment
interfered with your family life?
1
2
3
4
27. Has your physical condition or medical treatment
interfered with your social activities?
1
2
3
4
28. Has your physical condition or medical treatment
caused you financial difficulties?
1
2
3
4


Appendix 3
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
180/Protocol GO28667, Version 9
For the following questions please circle the number between 1 and 7 that best applies 
to you.
29.
How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
30.
How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent

Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
181/Protocol GO28667, Version 9
Appendix 4
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire (EORTC QLQ-CLL16)


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
182/Protocol GO28667, Version 9
Appendix 5
M.D. Anderson Symptom Inventory (MDASI) Questionnaire


Appendix 5
M.D. Anderson Symptom Inventory (MDASI) Questionnaire (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
183/Protocol GO28667, Version 9


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
184/Protocol GO28667, Version 9
Appendix 6
EQ-5D (U.S. Version)


Appendix 6
EQ-5D (U.S. Version) (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
185/Protocol GO28667, Version 9


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
186/Protocol GO28667, Version 9
Appendix 7
ECOG Performance Status Scale
Grade
Description
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, e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of 
waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair
5
Dead


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
187/Protocol GO28667, Version 9
Appendix 8
Treatment Options for CLL (Adapted from NCCN Version 4.2014 
and 2011 ESMO Clinical Practice Guidelines)
CLL Treatment Options per NCCN Guidelines (v 4.2014)
Treatment Options for Patients WITHOUT the 17p deletion
Front-line
Frail patients with significant 
comorbidities
Age70 or younger with 
significant comorbidities
Age70 or older patients 
without significant 
comorbidities

Chlorambucil GA101

Chlorambucil rituximab

Single agent rituximab

Pulsed corticosteroids

Chlorambucil

Chlorambucil 
Obinutuzumab

Chlorambucil rituximab

Bendamustinerituximab

Cyclophosphamide, 
prednisone rituximab

Single agent rituximab

Fludarabine rituximab

Cladribine

Chlorambucil

Chemoimmunotherapy
o
FCR
o
FR
o
PCR
o
BR
o
Chlorambucil 
Obinutuzumab
Relapsed/Refractory Disease
Long duration of response 
(18-36 months)
Short response and age70 
Short response for age70 or 
older patients without 
significant comorbidities

Re-treat with first line 
therapy

Ibrutinib

Idelalisibrituximab

Reduced dose FCR or 
PCR

BR

HDMP rituximab

Chlorambucil rituximab

Ofatumumab

Alemtuzumab rituximab

Lenalidomide rituximab

Dose dense rituximab 
(cat 2B)

Ibrutinib

Idelalisibrituximab

Chemoimmunotherapy 
(e.g., FCR, PCR, BR, 
fludarabine alemtuzum
ab, RCHOP, OFAR

Ofatumumab

Lenalidomide rituximab

Alemtuzumab rituximab

HDMP rituximab


Appendix 8
Treatment Options for CLL (Adapted from NCCN Version 4.2014
and 2011 ESMO Clinical Practice Guidelines) (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
188/Protocol GO28667, Version 9
CLL Treatment Options per NCCN Guidelines (v 4.2014) (cont.)
Treatment Options for Patients WITH the 17p deletion
Front-line

FCR

FR

HDMPrituximab*

Alemtuzumabrituximab

Obinutuzumabchlorambucil

Ibrutinib
Relapsed/Refractory Disease

Alemtuzumab rituximab

RCHOP

CFAR

HDMPrituximab

Ibrutinib

Idelalisibrituximab

Lenalidomiderituximab

Ofatumumab

OFAR
* For the purpose of this trial, HDMP rituximab cannot be the only previous line of therapy.


Appendix 8
Treatment Options for CLL (Adapted from NCCN Version 4.2014
and 2011 ESMO Clinical Practice Guidelines) (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
189/Protocol GO28667, Version 9
CLL Treatment Options per ESMO Guidelines (adapted from Eichhorst et al. 2011)
Treatment Options for Patients WITHOUT the 17p deletion
Front-line
Good PS
Poor PS

FCR

Chlorambucil
Relapsed/Refractory Disease
Early Relapse (< 12-24 months to relapse after monotherapy or < 24-36 months to relapse after 
chemoimmunotherapy)
Good PS after 
chemoimmunotherapy
Good PS after monotherapy
Poor PS 

Alemtuzumab 
fludarabine or BR 
followed by ASCT

FCR

FCR

bendamustine

alemtuzumab

ofatumumab

HDMP rituximab
Late Relapse (12-24 months after monotherapy or 24-36 months after chemoimmunotherapy)
Any PS:  repeat first–line therapy
Treatment Options for Patients WITH the 17p deletion
Frontline
Good PS
Poor PS

FCR or aletuzumab fludarabine followed 
by ASCT

Alemtuzumab
Relapsed/Refractory Disease
Good PS 
Poor PS

Alemtuzumab fludarabine followed by 
ASCT

Alemtuzumab
ASCT allogeneic stem cell transplantation; BRbendamustine, rituximab; 
CFARcyclophosphamide, fludarabine, alemtuzumab, rituximab; CHOPcyclophosphamide, 
doxorubicin, vincristine, prednisone; CLLchronic lymphocytic leukemia; ESMO European 
Society for Medical Oncology; FCRfludarabine, cyclophosphamide, rituximab; 
FRfludarabine, rituximab; HDMPhigh-dose methylprednisolone; NCCNNational 
Comprehensive Cancer Network; OFARoxaliplatin, fludarabine, cytarabine, rituximab; 
PCRpentostatin, cyclophosphamide, rituximab; PSPerformance Status.


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
190/Protocol GO28667, Version 9
Appendix 9
Sample List of Prohibited and Cautionary Medications
Type
Example Medications
Prohibited during ramp-up period and cautionary at the designated dose (400mg)
Strong CYP3A inducers
Avasimibe,carbamazepine (Tegretol), cyproterone, 
efavirenz, enzalutamide, etravirine, hyperforin, mitotane, 
modafinil, nevirapine, oxcarbazepine, phenobarbital, 
phenytoin (Dilantin), rifampin (Rifadin), and St. John's 
Wort
Moderate CYP3A inducers
Bosentan, efavirenz, etravirine, modafinil, and nafcillin,
Strong CYP3A inhibitors b
Boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, diltiazem, elvitegravir/ritonavir, 
idelalisiba, indinavir, itraconazole, ketoconazole, 
mibefradil, lopinavir/ritonavir, nefazodone, nelfinavir, 
ritonavir, paritaprevir/ritonavir combinations, 
posaconazole, saquinavir, telaprevir, tipranavir/ritonavir, 
telithromycin, and voriconazole
Moderate CYP3A inhibitors b
Amprenavir, aprepitant, atazanavir, cimetidine, 
ciprofloxacin, clotrimazole crizotiniba, cyclosporinea, 
darunavir/ritonavir, dronedarone,erythromycin, 
fluconazole, fosamprenavir, imatiniba, isavuconazole, 
tofisopam and verapamil
Cautionary throughout the study
Warfarin

Weak CYP3A inducers
Amprenavir, aprepitant, armodafinil, 
clobazamechinacea, pioglitazone, prednisone, 
rufinamide, and vemurafeniba
Weak CYP3A inhibitors
Alprazolam, amiodarone, amlodipine, atorvastatin, 
bicalutamidea, chlorzoxazone, cilostazol, fluoxetine, 
fosaprepitant, ginkgo, goldenseal, isoniazid, istradefylline, 
ivacaftor, lomitapide, oral contraceptives, pazopaniba, 
ranitidine, ranolazine, tacrolimus, ticagrelor, and zileuton
P-gp substrates
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, 
digoxin, everolimusa, fexofenadine, lapatiniba, 
loperamide, maraviroc, nilotiniba, ranolazine, saxagliptin, 
sirolimusa, sitagliptin, talinolol, tolvaptan, and topotecana
BCRP substrates
Methotrexatea, mitoxantronea, irinotecana, lapatiniba, 
rosuvastatin, sulfasalazine, topotecana
OATP1B1/1B3 substrates
Atrasentan, atorvastatin, ezetimibe, fluvastatin, 
glyburide, rosuvastatin, simvastatin acid, pitavastatin, 
pravastatin, repaglinide, telmisartan, valsartan, and 
olmesartan
P-gp inhibitors
Amiodarone, azithromycin, captopril, carvedilol, 
felodipine, quercetin, quinidine, ronalzine, and ticagrelor


Appendix 9
Sample List of Prohibited and Cautionary Medications (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
191/Protocol GO28667, Version 9
Type
Example Medications
BCRP inhibitors
Gefitinib a
OATP1B1/B3 inhibitors
Gemfibrozil, eltrombopag, , and tipranavir
BCRPbreast cancer resistance protein ; OATP1B1organic anion transporter protein 1B1; 
OATP1B3organic anion transporter protein 1B3; P-gpP-glycoprotein 1.
Note:  This is not an exhaustive list.  For an updated list, see the following link:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInte
ractionsLabeling/ucm093664.htm  In addition to the medications listed in this table, patients 
receiving venetoclax should not consume grapefruit, grapefruit products, Seville oranges 
(including marmalade containing Seville oranges), or star fruits. 
a These are anticancer agents; consult the Medical Monitor before use.
b After discontinuation of a strong or moderate CYP3A inhibitor, wait for 3 days before 
venetoclax dose is increased back to the initial maintenance/target dose.
COMMONLY USED CYP1A2 INHIBITORS AND INDUCERS (DRUGS, FOODS, 
OVER-THE-COUNTER MEDICATIONS AND SUPPLEMENTS)
Based on the USPI for bendamustine, no formal clinical assessments of 
pharmacokinetic drugdrug interactions between bendamustine and other drugs have 
been conducted.  Bendamustine's active metabolites, gamma-hydroxy bendamustine 
(M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome P450 CYP1A2.  
Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma 
concentrations of bendamustine and decrease plasma concentrations of active 
metabolites.  Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to 
decrease plasma concentrations of bendamustine and increase plasma concentrations 
of its active metabolites.
The medications listed below are not contraindicated; however, caution should be used 
or alternative treatments with medications that are not CYP1A2 inhibitors or inducers 
should be considered if concomitant treatment with CYP1A2 inhibitors or inducers is 
needed for your patient's medical condition.  This list is not exhaustive. 


Appendix 9
Sample List of Prohibited and Cautionary Medications (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
192/Protocol GO28667, Version 9
CYP1A2 Inhibitors (cautionary)
CYP1A2 Inducers (cautionary)
Amiodarone
Cruciferous vegetables (broccoli, cauliflower, 
arugula, brussel sprouts, cabbage, kale, chard, 
turnips, radishes, wasabi, bok choy, watercress, 
collard greens)
Cimetidine
Char-grilled meat
Ciprofloxacin
Enoxacin,
Beta-naphthoflavone
Fluoroquinolones
Methylcholanthrene
Fluvoxamine
Modafinil
Furafylline
Nafcillin
Interferon
Omeprazole
Methoxsalen
Mexiletine
Mibefradil
Oral contraceptives
Zafirlukast
Smoking/tobacco 
Phenytoin
Rifampin 
Ritonavir
Teriflunomide
The bendamustine USPI recommends that caution be used or alternative treatments be 
considered if treatment with one of these listed drugs or substances or another CYP1A2 
inhibitor or inducer is needed.  Please contact the study principal investigator if you have 
further questions.


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
193/Protocol GO28667, Version 9
Appendix 10
Definitions of Response and Progression for Patients with 
Chronic Lymphocytic Leukemia
Please see the “Imaging Site Operations Manual” for details of imaging acquisition and 
guidance on response assessment.
Based on iwCLL guidelines (Hallek et al. 2008)
SELECTION OF TARGET LESIONS IN IMAGING OR INDICATOR LESIONS IN 
PE
Up to six of the largest dominant nodes or tumor masses as well as 6 extra-nodal lesions 
selected according to all of the following:

Clearly measurable in at least two perpendicular dimensions at baseline
All nodal lesions must measure
1.5 cm in greatest transverse diameter (GTD) regardless of short axis 
measurement

All extranodal lesions must measure 10 mm in the GTD

Extranodal lesions within the liver or spleen must be at least 1.0 cm in two 
perpendicular dimensions

If possible, they should be from disparate regions of the body.

Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved.
Measurable extranodal disease should be assessed in a manner similar to that used 
for nodal disease. 
SELECTION OF NON-TARGET LESIONS IN IMAGING OR INDICATOR 
LESIONS IN PE
All of the sites of disease present at baseline and not classified as target lesions will be 
classified as non-target lesions, including any measurable lesions that were not chosen 
as target lesions.  Examples of non-target lesions include:

Abnromal (according to the same size criteria as target lesion) measurable lesions 
beyond the maximum number of target)

All bone lesions, irrespective of the modality used to assess them

Lymphangitis of the skin or lung

Cystic lesions

Splenomegaly and hepatomegaly (in CT only)

Measurable lesions beyond the maximum number of six

Groups of lesions that are small and numerous


Appendix 10
Definitions of Response and Progression for Patients with
Chronic Lymphocytic Leukemia (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
194/Protocol GO28667, Version 9

Pleural/pericardial effusions and/or ascites

Effusions, ascites or other fluid collections will be followed as non-target lesions.
Existing effusions/ascites:  Effusions, ascites or other fluid collections will be 
followed as non-target lesions.  At each time point, radiologists will check for the 
presence or absence of effusions/ascites.  If there is a significant volume 
increase in the absence of a benign etiology, progression can be assessed.
New effusions/ascites:  Significant new effusions, ascites or other fluid 
collections, which are radiographically suggestive of malignancy should be 
recorded as new lesions.
Non-target lesions will be qualitatively assessed at each subsequent timepoint to check 
if they are still abnormal or normalized.
REPORTING CONVENTIONS
UNABLE TO EVALUATE (UE) LESION CATEGORY
This category is reserved for target and non-target lesions that are deemed unevaluable 
because 1) subsequent (post-baseline) exams had not been performed, 2) lesions could 
not be evaluated due to poor radiographic technique or poorly defined margins, or 3) 
lesions identified at baseline were not at a subsequent time point.
Examples of UE lesions are a lung lesion in the hilum obstructing the bronchus and 
causing atelectasis of the lobe, or a hypodense liver lesion that becomes surrounded by 
fatty infiltration.  In both examples the boundaries of the lesion can be difficult to 
distinguish.  Every effort should be made to assign measurements to lesions that 
develop less distinct margins because they become much smaller.  Another example is 
the instance when lesions identified at baseline were not imaged at a subsequent time 
point unless the lesions are not imaged because of complete resolution.  Lesions that 
cannot be measured or evaluated will be classified for that time point as UE.
If a target lesion is classified as UE post-baseline, the SPD/area (whichever applies) of 
the target lesions cannot accurately be determined for that time point a response of CR, 
PR, or SD cannot be assigned for that time point and the response assessment will be 
UE unless unequivocal progression is determined on the basis of non-target or new 
lesions, or the evaluable target lesions.
PD can be determined without evaluation of all sites of disease based on the GTD, area 
or SPD for target lesions, evaluation of unequivocal progression in non-target lesions or 
observation of a new lesion within the available radiographic or clinical assessments.


Appendix 10
Definitions of Response and Progression for Patients with
Chronic Lymphocytic Leukemia (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
195/Protocol GO28667, Version 9
TOO SMALL TO MEASURE (TSTM) /BELOW MEASURABLE LIMIT (BML) 
LESION CATEGORY
Any target lesion findings identified on baseline images, which at a subsequent time 
point decreases in size to 5 mm in any dimension, should be categorized as TSTM.  
The lesion, node or mass should be assigned measurements of 5 mm5 mm (for the 
GTD and the short axis) on the Source Document for the purpose of calculating the area.  
If that lesion increases in size to 5 mm in any dimension afterwards, its true size (GTD 
and short axis) should be recorded.  The purpose of the assigned value for the 
measurement is the acknowledgment that small findings are not accurately measured.
COMPLETE RESPONSE
Complete response (CR) requires all of the following criteria as assessed no earlier than 
2 months after completion of therapy: 

Peripheral blood lymphocytes (evaluated by blood and differential count) below 
4 109/L (4000/L)

Absence of lymphadenopathy (nodes15 mm in longest diameter or any extra 
nodal disease) by physical examination and CT scan

No hepatomegaly or splenomegaly by physical examination as determined by 
measurement below the relevant costal margin

Absence of disease or constitutional symptoms (B symptoms)

Blood counts above the following values
Neutrophils 1.5109/L (1500/L) (without growth factors)
Platelets 100109/L (100 000/L) (without platelet transfusion or growth 
factors)
Hemoglobin 110 g/L (11 g/dL) (without blood transfusions or erythropoietin)

Bone marrow at least normocellular for age, with 30% of nucleated cells being 
lymphocytes.  Lymphoid nodules should be absent. Bone-marrow aspirate and 
biopsy should be performed 3 months after last treatment when clinical and 
laboratory results listed above demonstrate that a CR/cytopenic CR has been 
achieved.  If the bone marrow is hypocellular, a repeat determination should be 
made in 4 weeks or when peripheral blood counts have recovered.  A marrow 
biopsy should be compared with a pretreatment marrow if available.  Patients who 
are otherwise in a CR, but whose bone marrow nodules can be identified 
histologically, should be considered to be in partial response (PR [nodal PR]).  
Immunohistochemistry should be performed to define whether these nodules are 
composed primarily of T cells or lymphocytes other than or chronic lymphocytic 
leukemia (CLL) cells.


Appendix 10
Definitions of Response and Progression for Patients with
Chronic Lymphocytic Leukemia (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
196/Protocol GO28667, Version 9
COMPLETE RESPONSE WITH INCOMPLETE BONE MARROW RECOVERY
For patients who fulfill the criteria for CR (including bone marrow), but who have 
persistent cytopenia, the marrow evaluation described above should be performed with 
scrutiny and should not show any clonal infiltrate.
NODULAR PARTIAL RESPONSE (nPR)
In some cases, lymphoid nodules can be found, which often reflect residual disease.  
These nodules should be recorded as “nodular PR.”  Moreover, immunohistochemistry 
should be performed to define whether these nodules are composed primarily of T cells 
or lymphocytes other than CLL cells or of CLL cells. 
PARTIAL RESPONSE
To be considered PR, patients must exhibit the following features for at least 2 months. 
At least two of the following criteria must be met:

50% decrease in peripheral blood lymphocyte count from the pretreatment value.

50% reduction in lymphadenopathy (sum of longest diameter of the 6 largest 
lymph nodes by physical examination and 50% reduction in the sum of product of 
diameter of 6 largest lymph nodes measured by computed tomography [CT] scan).  
There should be no increase in any node and no new enlarged lymph node.  In 
small lymph nodes (2 cm in diameter), an increase of less than 25% is not 
considered to be significant.

50% reduction of liver and/or spleen enlargement if enlarged at baseline as 
assessed by physical examination.
In addition, at least one of the following criteria must be met:

Neutrophils 1.5 109/L (1500/L) (without growth factors) or 50% of pretreatment 
value

Platelets 100 109/L (100 000/L) (without platelet transfusion or growth factors) 
or 50% of pretreatment value

Hemoglobin 110 g/L (11 g/dL) (without blood transfusions or erythropoietin) or 
50% of pretreatment value


Appendix 10
Definitions of Response and Progression for Patients with
Chronic Lymphocytic Leukemia (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
197/Protocol GO28667, Version 9
PROGRESSIVE DISEASE
Progressive disease (PD) during or after therapy will be characterized by at least one of 
the following:

50% increase in the absolute number of circulating lymphocytes to at least 
5 109/L.  
During combination treatment, the increase should be assessed against Cycle 1, 
Day 1 (precycle) lymphocyte count and not - cycle lymphocyte counts, which may 
not be stable.
After treatment, the increase should be assessed against the lowest lymphocyte 
count assessed at the first follow-up visit after the end of combination treatment.

Appearance of new palpable lymph nodes (15 mm in longest diameter) or any 
new extra-nodal lesion (regardless of size)

50% increase in the longest diameter of any previous site of lymphadenopathy

50% increase in the enlargement of the liver and/or spleen as determined by 
measurement below the relevant costal margin or appearance of palpable 
hepatomegaly or splenomegaly that was not previously present

Transformation to a more aggressive histology (e.g., Richter syndrome or 
plasmacytoid lymphocytic lymphoma with 55% prolymphocytes); whenever 
possible, this diagnosis to be supported by lymph node biopsy
After treatment, the progression of any cytopenia (unrelated to autoimmune cytopenia), 
as documented by a decrease of hemoglobin levels by more than 20 g/L (2 g/dL) or to 
less than 100 g/L (10 g/dL) or by a decrease of platelet counts by more than 50% or to 
less than 100 109/L (100,000/L), that occurs no earlier than 3 months after end of 
therapy defines progression if the marrow biopsy demonstrates an infiltrate of clonal CLL 
cells.
STABLE DISEASE
Patients who have not achieved a CR or a PR or who have not exhibited PD will be 
considered to have stable disease.


Appendix 10
Definitions of Response and Progression for Patients with
Chronic Lymphocytic Leukemia (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
198/Protocol GO28667, Version 9
Table 1
iwCLL 2008 Criteria for Tumor Response
Parameter
Complete 
Remission (CR)
All Criteria Must 
be Meta
Partial Remission 
(PR) at Least 2 
Criteria from 
Group A AND at 
Least 1 Criterion 
from Group B 
Must be Met
Progressive 
Disease (PD) at 
Least 1 Criterion 
from Group A 
OR 1 Criterion 
from Group B 
Must be Metb
Stable Disease 
(SD) All Criteria 
Must be Met
Group A
Lymphadenopathy None1.5 cm
Decrease50%c
Increase 50%d
or any new 
LN1.5 cm
Change of 49% 
to 49%a
Blood 
Lymphocytes
4000/L
Decrease 50% 
from baseline
Increase 50% 
over baseline 
(5000 L)
Change of 49% 
to 49%
Hepatomegalyb
None
Decrease50%
Increase50%c
Change of 49% 
to 49%
Splenomegalyb
None
Decrease50%
Increase50%c
Change of 49% 
to 49%
Marrow
Normocellular,
30% 
lymphocytes, no 
B-lymphoid 
nodules; 
hypocellular 
marrow defines 
CRi
N/A
N/A
N/A
Group B
Platelet Count
100,000/Ld
100,000/L or 
increase50% 
from baselineh
Decrease 
of 50% from 
baseline 
secondary to 
CLL
Change of 49% 
to 49%
Hemoglobin
11.0 g/dLd
11.0 g/dL or 
increase50% 
from baselineh
Decrease of 
2g/dL from 
baseline 
secondary to 
CLL
Increase 
to 11.0 g/dL 
over baseline, or 
decrease2g/dL
Neutrophils
1500/Ld
1500/L or 
increase50% 
from baselineh
Decrease 
of 50% from 
baseline 
secondary to 
CLL
N/A


Appendix 10
Definitions of Response and Progression for Patients with
Chronic Lymphocytic Leukemia (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
199/Protocol GO28667, Version 9
Table 1
iwCLL 2008 Criteria for Tumor Response (cont.)
Parameter
Complete 
Remission (CR)
All Criteria Must 
be Meta
Partial Remission 
(PR) at Least 2 
Criteria from 
Group A AND at 
Least 1 Criterion 
from Group B 
Must be Met
Progressive 
Disease (PD) at 
Least 1 Criterion 
from Group A 
OR 1 Criterion 
from Group B 
Must be Metb
Stable Disease 
(SD) All Criteria 
Must be Met
Other 
Considerations
New Lesions
None
None
Appearance of 
new palpable 
lymph nodes 
(1.5 cm in 
longest 
diameter) or any 
new extra nodal 
lesion 
(regardless of 
size) or 
transformation to 
a more 
aggressive 
histology, e.g. 
Richter 
Syndromed
None
Non-Target 
Lesions
Nodes must be 
normal size as 
visually 
estimated; extra 
nodal and other 
assessable 
disease should 
be absent
No 
change/decreased
Unequivocal 
progression
No change or 
decrease or 
non-substantial 
increase


Appendix 10
Definitions of Response and Progression for Patients with
Chronic Lymphocytic Leukemia (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
200/Protocol GO28667, Version 9
Table 1
iwCLL 2008 Criteria for Tumor Response (cont.)
Parameter
Complete 
Remission (CR)
All Criteria Must 
be Meta
Partial Remission 
(PR) at Least 2 
Criteria from 
Group A AND at 
Least 1 Criterion 
from Group B 
Must be Met
Progressive 
Disease (PD) at 
Least 1 Criterion 
from Group A 
OR 1 Criterion 
from Group B 
Must be Metb
Stable Disease 
(SD) All Criteria 
Must be Met
Target Extra Nodal 
Disease
Absence of any 
nodal disease by 
physical 
examination 
(palpable, 
visualized extra 
nodal) and CT 
scan
50% decrease in 
SPD
50% increase 
in the longest 
diameter of any 
extra nodal 
lesion
Not CR, CRi, PR, 
or SD
CLLchronic lymphocytic leukemia; LNlymph nodes; N/Anot applicable; SPD sum of the 
products of diameters; CRicomplete remission with incomplete marrow recovery.
a CR also requires the lack disease-related constitutional symptoms.
b Transformation to a more aggressive histology (e.g., Richter Syndrome) would also qualify as 
a PD.
c Sum of the products of multiple LNs (as evaluated by CT scans).  Note in eCRF if by physical 
examination only.
d Increase in SPD of multiple nodes, or in greatest diameter of any previous site, or 
appearance of any new lymphadenopathy or organomegaly. Degree of change in LN or 
lymphocyte counts should be measured from nadir (lowest post-treatment) values.


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
201/Protocol GO28667, Version 9
Appendix 11
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome
FIRST DOSE OF VENETOCLAX OR DOSE INCREASE

Within the first 24 hours after either the first dose or dose increase, 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 level is a medical emergency.

Nephrology (or acute dialysis service) must be consulted/contacted on admission 
(per institutional standards to ensure emergency dialysis is available).

IV fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at least 
1 mL/kg/h rounded to the nearest 10 mL (target 150 to 200 mL/h; not < 50 mL/h).  
Modification of fluid rate should also be considered for individuals with specific 
medical needs.

Monitor for symptoms or signs of TLS (e.g., fever, chills, tachycardia, nausea, 
vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, 
paresthesias, mental status changes, confusion, and seizures).  If any clinical 
features are observed, recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour STAT.

Vital signs should be taken at time of all blood draws or any intervention.

The management recommendations below focus on the minimum initial responses 
required.  If a diagnosis of TLS is established, ongoing intensive monitoring and 
multi-disciplinary management will be per institutional protocols.
In addition to the recommendations in the table below, for patients with CLL/SLL 
receiving first dose of venetoclax:

For potassium increase 0.5 mmol/L from baseline, or any value 5.0 mmol/L, 
recheck potassium, phosphorus, uric acid, calcium, and creatinine within 1 hour 
STAT and follow guideline.

For phosphorus increase of 0.5 mg/dL AND 4.5 mg/dL, administer phosphate 
binder and recheck potassium, phosphorus, uric acid, calcium, and creatinine within 
1 hour STAT.


Appendix 11
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
202/Protocol GO28667, Version 9
Table 1
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome
Abnormality
Management Recommendations
Hyperkalemia (including rapidly rising potassium)
Potassium 0.5 mmol/L 
increase from prior value 
(even if potassium within 
normal limits [WNL])

Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour STAT.  If further 0.2 mmol/L increase in 
potassium, but still upper limit of normal (ULN), manage per 
potassium ULN. Otherwise recheck in 1 hour.

Resume per protocol testing if change in potassium is 
0.2 mmol/L, and potassium ULN, and no other evidence of 
tumor lysis.

At discretion of investigator, may recheck prior to hospitalization. 
If stable or decreased, and still WNL, hospitalization is at the 
discretion of the investigator.  Potassium, phosphorus, uric acid, 
calcium, and creatinine must be rechecked within 24 hours.
Potassium upper limit of 
normal

Perform STAT ECG and commence telemetry.

Nephrology notification with consideration of initiating dialysis

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV1.

Administer calcium gluconate 100 to 200 mg/kg IV slowly if there 
is ECG/telemetry evidence of life-threatening arrhythmias.

Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour STAT. 

If potassium ULN 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium, and creatinine 1, 2, and 4 hours later, if no 
other evidence of tumor lysis.
Potassium 6.0 mmol/L 
(6.0 mEq/L) and/or 
symptomatic
(e.g., muscle cramps, 
weakness, paresthesias, 
nausea, vomiting, 
diarrhea)

Perform STAT ECG and commence telemetry.

Nephrology assessment with consideration of initiating dialysis

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV1.

Administer insulin 0.1 U/kg IVD25 2 mL/kg IV.

Administer sodium bicarbonate 1 to 2 mEq/kg IV push.
o
If sodium bicarbonate is used, rasburicase should not be 
used as this may exacerbate calcium phosphate 
precipitation.

Administer calcium gluconate 100 to 200 mg/kg IV slowly if there 
is ECG/telemetry evidence of life-threatening arrhythmias.  Do 
not administer in same IV line as sodium bicarbonate.

Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine every hour STAT.


Appendix 11
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
203/Protocol GO28667, Version 9
Table 1
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (cont.)
Abnormality
Management Recommendations
Hyperuricemia
Uric acid 8.0 mg/dL 
(476 µmol/L)

Consider rasburicase (dose per institutional guidelines).
o
If rasburicase is used, sodium bicarbonate should not be 
used as this may exacerbate calcium phosphate 
precipitation.

Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour STAT.
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 
(0.027 mmol/L) from 
predose level

Administer rasburicase (dose per institutional guidelines).
o
If rasburicase is used, sodium bicarbonate should not be 
used as this may exacerbate calcium phosphate 
precipitation.

Consult nephrology.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT.

If uric acid 8.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium, and creatinine 2 and 4 hours 
later, if no other evidence of tumor lysis.
Hypocalcemia
Corrected calcium 
7.0 mg/dL 
(1.75 mmol/L)
OR
Patient symptomatic 
(e.g., muscle cramps, 
hypotension, tetany, 
cardiac arrhythmias) in 
the presence of 
hypocalcemia

Administer calcium gluconate 50 to 100 mg/kg IV slowly with 
ECG monitoring.

Telemetry.

Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour STAT.

If calcium normalized 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium, and creatinine 2 and 4 hours 
later, if no other evidence of tumor lysis.
Hyperphosphatemia
Phosphorus 5.0 mg/dL 
(1.615 mmol/L) with 
0.5 mg/dL 
(0.16 mmol/L) increase

Administer a phosphate binder (e.g., aluminum hydroxide, 
calcium carbonate, sevelamer hydroxide, or lanthanum 
carbonate).

Nephrology notification (dialysis required for phosphorus 
10 mg/dL)

Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour STAT.

If phosphorus 5.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium, and creatinine 2 and 4 hours 
later, if no other evidence of tumor lysis.


Appendix 11
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
204/Protocol GO28667, Version 9
Table 1
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (cont.)
Abnormality
Management Recommendations
Creatinine
Increase25% from 
baseline

Start or increase rate of IV fluids.

Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 to 2 hours STAT.
IVintravenous; ULNupper limit of normal; WNLwithin normal limits.
ONGOING DOSING OF VENETOCLAX
Management of electrolyte changes from last value at intervals 24 hours after either 
the first dose or dose increase (e.g., 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 increase (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 increase (table above).


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
205/Protocol GO28667, Version 9
Appendix 12
National Cancer InstituteSponsored Working Group 
Hematologic Adverse Event Grading Scale for Chronic 
Lymphocytic Leukemia for Patients with Baseline Abnormal 
Hematologic Laboratories
Decrease in Platelets a or Hgb b from 
Pretreatment Value
Grade
10.1.1.1.1
ANC/µL c (nadir) 
(109 cells/L)
No change10%
0
2000 (2.00)
11%24% 
1
1500 and 2000 (1.5 and 2.0)
25%49%
2
1000 and 1500 (1.0 and 1.5)
50%74%
3
500 and 1000 (0.5 and 1.0)
75%
4
500 (0.5)
Source:  Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and 
treatment of chronic lymphocytic leukemia:  a report from the International Workshop on 
Chronic Lymphocytic Leukemia updating the National Cancer InstituteWorking Group 1996 
guidelines.  Blood 2008;111:544656.
ANCabsolute neutrophil count; Hgbhemoglobin; Grades:  1 mild, 2 moderate, 
3 severe, 4 life threatening.
a If, at any level of decrease, the platelet count is 20109/L (20,000/L), this will be 
considered a Grade 4 toxicity unless a severe or life-threatening decrease in the initial 
platelet count (e.g., 20109/L [20,000/L]), was present before treatment, in which case 
the patient is not evaluable for toxicity with regard to platelets.
b Baseline and subsequent Hgb determinations must be performed before any given 
infusion.
c If ANC was 1109/L prior to therapy, the patient is not evaluable for toxicity in ANC.


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
206/Protocol GO28667, Version 9
Appendix 13
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL
DISEASE-RELATED EVENTS

Lymphadenopathy

Splenomegaly

Hepatomegaly

Leukemia cutis (macules, papules, plaques, nodules, ulcers, or blisters)

Lymphocytosis

Cytopenias (neutropenia, anemia and thrombocytopenia)

Febrile neutropenia

Autoimmune hemolytic anemia

Autoimmune thrombocytopenia

Hypogammaglobulinemia

Infections (bacterial, viral, and fungal)

Second cancers (Kaposi's sarcoma, malignant melanoma, squamous cell skin 
cancer, basal cell carcinoma, cancers of the larynx, colorectal cancer and cancers 
of the lung)

Fatigue

Weight loss

Pyrexia

Bruising

Minor hemorrhages

Pain (any type)
POPULATION-RELATED COEXISTING MEDICAL CONDITIONS:

Hypertension

Rheumatoid arthritis/osteoarthritis

Hyperlipidemia

Peptic ulcer

Inflammatory bowel disease

Coronary artery disease

Peripheral vascular disease

Cardiomyopathy

Valvular disease


Appendix 13
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
207/Protocol GO28667, Version 9

Atrial fibrillation

Diabetes mellitus

Chronic obstructive pulmonary disease

Cerebrovascular accident

Transient ischemia attack


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
208/Protocol GO28667, Version 9
Appendix 14
Re-Treatment/Crossover Substudy Schedule of Assessments
Re-Treatment or 
Crossover Substudy
Screening-R/C
Venetoclax Ramp-Up R/C Period
Combination (Venetoclax R) Therapy
Venetoclax Monotherapy/Follow-Up
(Venetoclax + R)
Cycle 1R/C
Cycles 
2R/C6R/C
EOCTR-
R/C
Visit a
Follow-Up
R/C Visits b
COVTR-R/C
Visit y
Survival FU
Visits b
Day
1
8
15
22
29
1
2
8
15
1
12 wks 
after 
Cycle 6 
Day 1
Every 24 
weeks after 
EOCTR-R/C
until
COVTR-R/C
Visit 
After 
completion of 
venetoclax 
treatment
(i.e., 2 years 
from Cycle 
1R/C Day 1)
Every 24 
weeks after 
COVTR-
R/CVisit or 
PD until 
study end
Visit Window ( days)
28 
to 1
1
1
1
1
1
1
0
1
1
3
7
7
7
30
Informed consent
X
Updated medical 
history and baseline 
conditions
X
Adverse events, 
concomitant 
medications and 
compliance 
assessment c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Status
X
X
X
X
X
X
Vital signs d
X
X d
X d
X d
X d
X d
X
X
X
X
X
X
X
X
Weight, calculation of 
BSA
X
X
X
X
X
X
X
X
Physical examination e
X
Targeted physical 
examination e
X
X
X
X
X
X
X
X
X
X
Assessment of LVEF f
X
ECG f
X
Hematology g
X
X i
X i
X i
X i
X i
X i
X
X
X
X
X
X
X


Appendix 14
Re-Treatment/Crossover Substudy Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
209/Protocol GO28667, Version 9
Re-Treatment or 
Crossover Substudy
Screening-R/C
Venetoclax Ramp-Up R/C Period
Combination (Venetoclax R) Therapy
Venetoclax Monotherapy/Follow-Up
(Venetoclax + R)
Cycle 1R/C
Cycles 
2R/C6R/C
EOCTR-
R/C
Visit a
Follow-Up
R/C Visits b
COVTR-R/C
Visit y
Survival FU
Visits b
Day
1
8
15
22
29
1
2
8
15
1
12 wks 
after 
Cycle 6 
Day 1
Every 24 
weeks after 
EOCTR-R/C
until
COVTR-R/C
Visit 
After 
completion of 
venetoclax 
treatment
(i.e., 2 years 
from Cycle 
1R/C Day 1)
Every 24 
weeks after 
COVTR-
R/CVisit or 
PD until 
study end
Visit Window ( days)
28 
to 1
1
1
1
1
1
1
0
1
1
3
7
7
7
30
Coagulation
X
Serum chemistry h
X
X i
X i
X i
X i
X i
X i
X
X
X
X
X
X
X
Urinalysis j
X
CLL response 
assessment k
X
X
X
X
B Symptoms
X
X
X
X
CT (or MRI) scan k
X
X k
(X x)
(X x)
Bone marrow aspirate 
and biopsy (including 
flow cytometry or IHC) l, 
m
X
X l
(X x)
(X x)
Pregnancy test n
X
X
X
X
X
X
X
Viral serologies o
X
HBV DNA on PCR 
(for applicable patients) 
p
(X)
(X)
(X)
(X)
(X)
(X)
Hospitalization q
(X)
(X)
(X)
(X)
(X)
(X)
MRD on peripheral 
blood r
X
X
X
X


Appendix 14
Re-Treatment/Crossover Substudy Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
210/Protocol GO28667, Version 9
Re-Treatment or 
Crossover Substudy
Screening-R/C
Venetoclax Ramp-Up R/C Period
Combination (Venetoclax R) Therapy
Venetoclax Monotherapy/Follow-Up
(Venetoclax + R)
Cycle 1R/C
Cycles 
2R/C6R/C
EOCTR-
R/C
Visit a
Follow-Up
R/C Visits b
COVTR-R/C
Visit y
Survival FU
Visits b
Day
1
8
15
22
29
1
2
8
15
1
12 wks 
after 
Cycle 6 
Day 1
Every 24 
weeks after 
EOCTR-R/C
until
COVTR-R/C
Visit 
After 
completion of 
venetoclax 
treatment
(i.e., 2 years 
from Cycle 
1R/C Day 1)
Every 24 
weeks after 
COVTR-
R/CVisit or 
PD until 
study end
Visit Window ( days)
28 
to 1
1
1
1
1
1
1
0
1
1
3
7
7
7
30
MRD in bone marrow m
X
X m
CLL prognostic factors 
(including 17p, TP53, 
IgVH) s
X
Predictive biomarker 
blood and bone marrow 
samples t
X
Venetoclax u
X
X
X
X
X
X
X
X
X
X
X
X u
Rituximab v
X
(X)
X
Anti-CLL therapy w, y
X
Disease progression b
X
Survival status y
X
BSA body surface area; C cycle; CLL chronic lymphocytic leukemia; CR complete response; CT computed tomography; D day; ECOG Eastern 
Cooperative Oncology Group; EOCTR-R/C=End of Combination Treatment Response in the Re-Treatment/Crossover Substudy; COVTR-R/C = Completion of 
Venetoclax Treatment Response in the Re-Treatment/Crossover Substudy; FU follow-up; HBcAb serum immunoglobulin G antibody directed at hepatitis B core 
antigen; HBsAg hepatitis B virus surface antigen; IgG anti-Hep C Ab serum antibody directed against hepatitis C virus; IHC immunohistochemistry, 
IV intravenous; LVEF left ventricular ejection fraction; MRD minimal residual disease; MRI magnetic resonance imaging; PD progressive disease;
PO per os, orally; PR partial response; R rituximab; R/C Re-Treatment/Crossover; RNA; RNA-seq; TLS tumor lysis syndrome; wks=weeks.
Note:  (X) indicates assessments that may be performed, as determined by the investigator.


Appendix 14
Re-Treatment/Crossover Substudy Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
211/Protocol GO28667, Version 9
a
EOCTR-R/C visit to be scheduled 12 weeks after Cycle 6R/C Day 1 or at disease progression (whichever occurs first).
b
After the EOCTR-R/C Visit, patients who have not progressed will be followed clinically every 24 weeks until the COVTR-R/C Visit. COVTR-R/C 
visit to be scheduled after completion of venetoclax treatment (i.e., 2 years from Cycle 1R/C Day1) or at disease progression (whichever occurs 
first). 
c
See Section 5.3.1 for details on adverse event reporting.
d
Vital signs will include measurements of temperature, heart rate, systolic and diastolic blood pressure.  Vital signs should be collected at all times 
of chemistry blood draws.
e
Complete physical examination is required at Screening-R/C; targeted physical examination for all subsequent visits.  Complete physical 
examination includes all systems of the body as described in the body of the protocol.  Targeted physical examinations should be limited to 
systems of clinical relevance (i.e., cardiovascular, respiratory, lymphatics [including spleen], and gastrointestinal [including liver], and those 
associated with clinical signs/symptoms). 
f
Assessment of LVEF by either echocardiogram or multigated acquisition (MUGA) scan after Baseline is at the discretion of the investigator. An 
ECG is required at Screening-R/C only as clinically indicated.
g
Includes complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count), platelet count, absolute neutrophil count, 
absolute lymphocyte count, and percent or absolute differential counts (e.g., segmented neutrophils, bands, lymphocytes, eosinophils, monocytes, 
basophils, and other cells).
h
Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen or urea (when BUN not available), creatinine, calcium, 
magnesium, phosphorus, total bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, lactate dehydrogenase, and uric acid.  All 
scheduled blood draws may be drawn up to 72 hours prior to the next planned evaluation.
i
Serum hematology and chemistries should be drawn at the specific timepoints as described in detail in Section 4.4.1.2.
j
Consists of specific gravity, pH, blood, protein, glucose, ketones, and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, and bacteria).
k
All patients must have a clinical response assessment (including targeted physical examination and laboratory examinations) at the EOCTR-R/C, 
Follow-Up R/C, and COVTR-R/C Visits.  All patients must have a Screening-R/C CT scan (or MRI if CT is contraindicated) of the neck (if indicated), 
chest, abdomen, and pelvis with IV and oral contrast.  A follow-up scan must also be performed at the EOCTR-R/C Visit.  Targeted physical 
examination and laboratory examinations should be repeated to confirm that patients are still in response prior to confirmatory CT or MRI scan.  
MRI scans of the chest, abdomen, and pelvis with a non-contrast CT scan of the chest may be used instead of CT scans in patients for whom CT 
scans with contrast are contraindicated (i.e., patients with contrast allergy or impaired renal clearance).  Conventional CT and MRI should be 
performed with contiguous cuts of 10 mm or less in slice thickness.  Spiral CT should be performed by use of a 5-mm contiguous reconstruction 
algorithm; this specification applies to the tumors of the chest, abdomen, and pelvis.  If MRIs are used instead of CT scans, MRIs should be used 
consistently throughout the study.


Appendix 14
Re-Treatment/Crossover Substudy Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
212/Protocol GO28667, Version 9
l
A bone marrow examination must be performed at Screening-R/C.  For those patients who have achieved a CR or cytopenic CR (including a CT 
scan indicating a possible CR), a bone marrow aspirate and biopsy will be obtained to confirm the CR at the EOCTR-R/C Visit. 
m A bone marrow aspirate should be obtained for MRD assessment at Screening-R/C and in all responding patients (CR or PR) at the EOCTR-R/C 
Visit.
n
Required for all women of reproductive potential prior to drug dispensation.
o
HBsAg, IgG anti-HBcAb, and Hep C Ab serology (also HCV RNA by polymerase chain reaction if the patient is HCV antibody positive) required.
p
For hepatitis B core antibody–positive patients, the HBV DNA titer needs to be determined using real-time PCR monthly until at least 12 months 
after the last rituximab dose.  Note that during the venetoclax monotherapy/follow-up period, HBV DNA titer should be performed monthly and the 
results reviewed by the investigator or designee.  The patient does not need to have any other procedures besides this laboratory test between the 
12-week follow-up visits unless clinically indicated.
q
Refer to Section 4.4.1.2  for hospitalization and prophylaxis measures for TLS. 
r
MRD samples in peripheral blood collected at Screening-R/C, EOCTR-R/C, Follow-Up R/C, and COVTR-R/C Visits.  MRD samples will be 
measured at a central laboratory.
s
Patients will have the following samples drawn at Baseline: serum for 2-microglobulin, whole blood for IgVH mutational status, p53 and other 
prognostic mutations, and interphase FISH for chromosomal abnormalities including 17p-, 11q-, 13q-, and trisomy +12.  
t Whole blood predictive biomarker sample is required for all patients at baseline, one tube for nucleic acid (e.g., mutations, Bcl-2 family expression) 
analysis.  A predictive bone marrow aspirate sample (3-4 mL for RNA [e.g., RNA-seq]) analysis must be drawn for all patients at baseline.  
Aspirate samples should be split from samples obtained for International Workshop on Chronic Lymphocytic Leukemia National Cancer Institute 
Working Group or International Working Group criteria assessment whenever possible.  Priority should be given to assessment samples when 
splitting.  Predictive biomarker sample will be used for assessment of Bcl-2 family and other relevant markers by RNA and flow in the blood and 
bone marrow.
u
Venetoclax will be taken daily by mouth starting on Day 1 through the end of study.  As described in Section 4.3.2.1 , there will be a 5 week 
venetoclax ramp-up period when patients will start with a 20 mg dose on Day 1 for a week.  Patients will increase to 50 mg on Day 8 and 
subsequently increase the dose weekly to reach the dose of 400 mg for the study.  Patients will continue venetoclax at 400 mg PO daily with 
concurrent rituximab for 6 cycles of 28 days each.  Patient with no evidence of progression will continue single agent venetoclax (400 mg PO daily) 
until progressive disease, unacceptable toxicity, or for a maximum of 2 years from Cycle 1R/C Day 1.
v
On Day 1 of Cycle 1R/C, patients will receive rituximab 375 mg/m2 IV followed by rituximab 500 mg/m2 IV on Day 1 of Cycles 2R/C6R/C.  
Investigators will have the option of administering the rituximab dose for Day 1 Cycle 1R/C over 2 days (e.g., 100 mg IV on Day 1, Cycle 1R/C 
followed by the remainder of the 375 mg/m2 dose on Day 2 Cycle 1R/C).
w Assessment is required but may not be applicable.  Includes regimen name, treatment dates, best overall response and date of disease 
progression for new anti-CLL therapy.


Appendix 14
Re-Treatment/Crossover Substudy Schedule of Assessments (cont.)
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd
213/Protocol GO28667, Version 9
x
Additional imaging evaluations should be performed during the Follow-Up R/C or COVTR-R/C Visits to confirm a suspected change in response 
status, that is SD to PR or PR to CR/CRi. If a patient’s response improves to a CR or CRi during Follow-Up R/C or COVTR-R/C Visits, bone 
morrow examination must be performed to confirm the CR. 
y
After the COVTR-R/C or disease progression patients should be followed for OS, PD (if not progressed already) and new anti-CLL therapy every 
24 weeks until the end of study.  Survival follow-up visits may be conducted by telephone.

SAP_001.pdf: 
 
Official Title: 
 
A Study to Evaluate the Benefit of Venetoclax Plus Rituximab 
Compared With Bendamustine Plus Rituximab in Participants With 
Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) 
(MURANO) 
NCT Number: 
NCT02005471 
Document Dates: SAP V1.0: 27-Jul-15 
SAP V4.0: 18-May-17 
 
 


Name
Reason for Signing
Date and Time
(UTC)
27-Jul-2015 19:42:58
Company Signatory
STATISTICAL ANALYSIS PLAN APPROVAL 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
venetoclax (GDC-0199/ABT-199)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO28667 
 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED 
STUDY IN RELAPSED/REFRACTORY PATIENTS WITH 
CHRONIC LYMPHOCYTIC LEUKEMIA TO EVALUATE THE 
BENEFIT OF VENETOCLAX (GDC-0199/ABT-199) PLUS 
RITUXIMAB COMPARED WITH BENDAMUSTINE PLUS 
RITUXIMAB 
PROTOCOL NUMBER: 
GO28667 
STUDY DRUG: 
Venetoclax (GDC-0199/ABT-199) (RO5537382) 
VERSION NUMBER: 
1 
IND NUMBER: 
110159 
EUDRACT NUMBER: 
2013-002110-12 
SPONSOR: 
F. Hoffmann-La Roche Ltd and AbbVie Inc. will act 
as co-sponsors of this trial globally. 
PLAN PREPARED BY: 
 Ph.D. 
DATE FINAL: 
See electronic date stamp below. 


 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 4 
2.1 
Protocol Synopsis.................................................................... 6 
2.2 
Outcome Measures ................................................................. 6 
2.2.1 
Primary Efficacy Outcome Measures ...................................... 6 
2.2.2 
Secondary Efficacy Outcome Measures.................................. 6 
2.2.3 
Exploratory Efficacy Outcome Measures................................. 7 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures ........................ 8 
2.2.5 
Pharmacodynamic Efficacy Outcome Measure....................... 8 
2.2.6 
Safety Outcome Measures ...................................................... 8 
2.2.7 
Health-Related Quality of Life (HRQOL) and 
Symptom Measures................................................................. 8 
2.2.8 
Health Economic Outcome Measure ....................................... 8 
2.3 
Determination of Sample Size ................................................. 8 
2.4 
Analysis Timing ....................................................................... 9 
3. 
STUDY CONDUCT....................................................................................... 9 
3.1 
Randomization Specifications.................................................. 9 
3.2 
Independent Review Committee............................................ 10 
3.3 
Independent Data Monitoring Committee .............................. 10 
4. 
STATISTICAL METHODS .......................................................................... 11 
4.1 
Analysis Population ............................................................... 11 
4.1.1 
Randomized Patients ............................................................ 11 
4.1.2 
Pharmacokinetic Evaluable Population ................................. 11 
4.2 
Analysis of Study Conduct..................................................... 11 
4.3 
Analysis of Treatment Group Comparability .......................... 11 
4.4 
Medical History...................................................................... 12 
4.5 
Previous Treatment and Concomitant 
Medications ........................................................................... 12 
4.6 
Efficacy Analysis.................................................................... 12 
4.6.1 
Primary Efficacy Endpoint...................................................... 12 
4.6.2 
Secondary Efficacy Endpoints............................................... 13 
venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO28667 
2 


4.6.3 
Exploratory Efficacy Endpoints.............................................. 15 
4.6.4 
Sensitivity Analyses............................................................... 15 
4.6.5 
Subgroup Analyses ............................................................... 15 
4.7 
Safety Analyses..................................................................... 15 
4.7.1 
Exposure to Study Medication............................................... 16 
4.7.2 
Adverse Events ..................................................................... 16 
4.7.3 
Laboratory Data..................................................................... 16 
4.7.4 
Vital Signs.............................................................................. 17 
4.8 
Missing Data.......................................................................... 17 
4.9 
Pharmacodynamic Analyses ................................................. 17 
4.10 
Pharmacokinetic Analyses..................................................... 17 
4.11 
Interim Analyses .................................................................... 18 
4.12 
References ............................................................................ 19 
 
 
LIST OF TABLES 
Table 1 
Probability of Passing Boundary at the Interim Analysis for a 
Given Hazard Ratio..................................................................... 18 
 
 
LIST OF FIGURES 
Figure 1 
Design of the Study....................................................................... 4 
Figure 2 
Venetoclax Dosing Scheme during the Ramp-Up Period ............. 5 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 20 
Appendix 2 
Schedule of Assessments........................................................... 36 
venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO28667 
3 


venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO28667 
4 
1. 
BACKGROUND 
This document is based on the Statistical Considerations and Analysis Plan section of 
the study protocol and will provide more details on the planned statistical analyses.  For 
purposes of registration, the analyses outlined in this Statistical Analysis Plan will 
supersede those specified in the protocol.  
2. 
STUDY DESIGN 
This is an open-label, international, multicenter, randomized, Phase III study to 
investigate the efficacy and safety of venetoclax (GDC-0199/ABT-199) in combination 
with rituximab (venetoclax + R) compared with bendamustine in combination with 
rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL; 
see Figure 1). 
The primary objective of the study is to evaluate the efficacy of venetoclax + R compared 
with BR in patients with relapsed or refractory CLL, as measured by 
investigator-assessed progression-free survival (PFS).  
Figure 1 Design of the Study 
 
Arm A = venetoclax (GDC-0199) and rituximab (venetoclax + R); Arm B = bendamustine and 
rituximab (BR); 1 cycle = 28 days; CLL = chronic lymphocytic leukemia; OS = overall survival; 
PD = progressive disease; PO = per os; QD = once daily. 
* Patients will receive venetoclax starting on Day 1 (venetoclax dose ramp-up period) as 
delineated in Figure 2.  Venetoclax will then be self-administered at 400 mg per day for a 
maximum of 2 years from Cycle 1 Day 1 or until disease progression (whichever is earlier).  
Combination therapy consisting of 6 cycles of rituximab and daily venetoclax dosing will start 
after completion of the venetoclax ramp-up period. 
 


Figure 2 Venetoclax Dosing Scheme during the Ramp-Up Period 
 
D = day. 
Note:  For all patients enrolled after Protocol Version 4.  Prior to Version 4, ramp up was 4 or 
5 weeks. 
 
Approximately 370 patients will be recruited and randomly assigned in 1:1 ratio to 
receive either venetoclax+R (Arm A) or BR (Arm B).  Randomization will be stratified 
according to the following 3 factors: 
• 
17p deletion:  yes or no 
• 
Risk status:  high risk or low risk 
High risk:  defined as harboring 17p deletion, no response to front-line 
chemotherapy-containing regimen, relapsed within 12 months after 
chemotherapy, or relapsed within 24 months after chemoimmunotherapy 
Low risk:  defined as relapse more than 12 months after chemotherapy or 
24 months after chemoimmunotherapy. 
• 
Geographic region:  United States/Canada, Australia/New Zealand, Western Europe, 
Central and Eastern Europe, or Asia  
 
Patients randomized to Arm A (venetoclax + R) will have a 5-week venetoclax dose 
ramp-up period to reach the target dose of 400 mg daily, followed by 6 cycles of 
rituximab consisting of a single infusion on the first day of each 28-day cycle.  Patients 
will continue to take their daily dose of venetoclax during the rituximab cycles.  Patients 
whose disease has not progressed following the completion of the 6 cycles will continue 
to receive venetoclax until disease progression or for a maximum of 2 years from 
Cycle 1 Day 1.  Patients randomized to Arm B (BR) will receive 6 cycles of BR consisting 
of a single infusion of rituximab on Day 1 and bendamustine infusions on Days 1 and 2 
of each 28-day cycle.   
After 6 cycles of combination therapy, patients in both arms will be followed clinically 
every 3 months through Year 3 from Cycle 1, Day 1, after which they will be followed 
every 6 months for an additional 2 years, until withdrawal of consent, or until end of 
study, whichever comes first. 
Patients who discontinue all components of study treatment for other reasons, or receive 
a new anti-CLL therapy at any time during follow-up in the absence of disease 
venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO28667 
5 


progression will also be followed for progression and survival according to the schedule 
defined in the protocol. 
2.1 
PROTOCOL SYNOPSIS 
The protocol synopsis of Amendment 5 is provided in Appendix 1.  For additional details, 
see the Schedule of Assessments in Appendix 2. 
2.2 
OUTCOME MEASURES 
All patients will have baseline tumor assessment at the screening visit and will be 
assessed for response to treatment at the scheduled response assessment follow-up 
visits using standard clinical and laboratory examinations and/or computed tomography 
(CT) scans according to the International Workshop on CLL (iwCLL) guidelines (Hallek 
et al. 2008). 
The assessment of response and progression by the investigator will be considered the 
primary analysis for all of the endpoints described in the study.  Response and 
progression will also be assessed by an Independent Review Committee (IRC). 
2.2.1 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is investigator-assessed PFS. 
 
 
  
Duration of PFS is defined as the time from randomization to the first occurrence of 
progression or relapse, determined using standard iwCLL guidelines, or death from any 
cause, whichever comes first.  Data from patients without disease progression, relapse, 
or death will be censored at the time of the last response assessment.  If no response 
assessments were performed after the baseline visit, the PFS date will be censored at 
the randomization date plus one day.  Patients who have initiated new anti-CLL therapy 
without documented disease progression will not be censored. 
2.2.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
IRC-assessed PFS in the subset of CLL patients with 17p deletion identified by 
fluorescence in situ hybridization (FISH) testing at a central laboratory  
• 
Investigator-assessed PFS in the subset of CLL patients with 17p deletion identified 
by FISH testing at a central laboratory  
• 
Overall response rate (ORR, which is defined as the percentage of patients with 
complete response [CR], complete response with incomplete marrow recovery [CRi], 
nodular partial response [nPR], or partial response [PR]) as assessed by the 
investigator.  In cases where no post-baseline response assessment is available, 
patients will be considered non-responders. 
venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO28667 
6 


• 
ORR, CR, CRi, nPR, and PR rates at the end of combination treatment response 
visit, as assessed by the investigator.  In cases where no post-baseline response 
assessment is available, patients will be considered non-responders. 
• 
ORR, CR, CRi, nPR, and PR rates at end of combination treatment response visit, 
as assessed by the IRC.  In cases where no post-baseline tumor assessment is 
available, patients will be considered non-responders. 
• 
Overall survival (OS), which is defined as the time from randomization to death from 
any cause.  Patients who were not reported as having died at the time of the 
analysis will be censored at the date when they were last known to be alive. 
• 
Event-free survival (EFS), which is defined as the time between date of 
randomization and the date of disease progression/relapse, death, or start of a new 
non-protocol-specified anti-CLL therapy.  If the specified event (disease 
progression/relapse, death, start of a new anti-CLL treatment) does not occur, 
patients will be censored at the date of last response assessment.  In cases where 
no post-baseline response assessment is available, patients without an event will be 
censored at the randomization date plus one day. 
• 
Duration of response (DOR), which is defined for patients with a best overall 
response of CR, CRi, nPR, or PR as the time from first occurrence of a documented 
CR/CRi/nPR/PR to disease progression/relapse, as assessed by the investigator, or 
death from any cause.  Patients with no documented progression or death after CR, 
CRi, nPR, or PR will be censored at the last date at which they are known to have 
had the CR, CRi, nPR, or PR.  Patients who have never responded will not be 
included in this analysis. 
• 
Time to next anti-CLL treatment (TTNT), which is defined as the time from 
randomization to start of new non-protocol−specified anti-CLL therapy or death from 
any cause.  Patients who were reported as not having started new non-protocol 
anti-CLL therapy or death will be censored at the last visit date for this outcome 
analysis. 
• 
Minimal residual disease (MRD) response rate at the end of combination treatment 
response visit as measured at a central laboratory on peripheral blood samples 
and/or bone marrow aspirate samples.  In cases where no post-baseline MRD 
assessment is available, patients will be considered as MRD-positive in this analysis. 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Assessment of potential biomarkers that are prognostic and/or predictive of 
response and resistance to treatment with venetoclax + R or BR 
• 
Evaluation of the relationship between clinical response and PFS and various 
potential biomarkers for patients treated with venetoclax + R or BR 
• 
MRD response rate as measured at a central laboratory on peripheral blood 
samples and/or bone marrow aspirate samples over time. 
 
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2.2.4 
Pharmacokinetic Efficacy Outcome Measures 
The pharmacokinetic (PK) outcome measures for this study are as follows: 
• 
Apparent clearance, apparent volume of distribution, and other appropriate PK 
parameters of venetoclax characterized using population PK techniques 
 
2.2.5 
Pharmacodynamic Efficacy Outcome Measure 
The pharmacodynamic outcome measure for this study is as follows: 
• 
Serial assessment of B-cell, T-cell, and NK-cell lymphocyte subsets by flow 
cytometry 
 
2.2.6 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, nature, and severity of adverse events and serious adverse events, 
including deaths 
• 
Changes in vital signs, physical findings, and clinical laboratory results (including 
hematology and chemistry) during and following administration of study treatment 
• 
Incidence of adverse events of special interest: 
Grade ≥ 3 tumor lysis syndrome (TLS) and infusion-related reactions (IRRs) 
• 
Measures of immune function, including serial immunoglobulin levels (IgG, IgM, IgA) 
following treatment with venetoclax+R or BR 
 
2.2.7 
Health-Related Quality of Life (HRQOL) and Symptom 
Measures 
The HRQOL and disease- and treatment-related symptom measures for this study are 
as follows: 
• 
MD Anderson Symptom Inventory (MDASI) (see Appendix 5 of the protocol) 
• 
European Organisation for Research and Treatment of Cancer (EORTC) Quality of 
Life Questionnaire Core 30 (QLQ-C30) and Quality of Life Questionnaire CLL 
module (QLQ-CLL16) (see Appendix 3 and Appendix 4, respectively, of the protocol) 
 
2.2.8 
Health Economic Outcome Measure 
The health economic outcome measure for this study is as follows: 
• 
The EQ-5D-5L questionnaire (see Appendix 6 of the protocol) 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
The primary endpoint of PFS was used to determine the sample size for the study based 
on the following assumptions: 
• 
Two-sided log-rank test at the 0.05 level of significance 
• 
80% power to detect a hazard ratio (HR) for venetoclax + R versus BR of 0.66, 
corresponding to an approximate median improvement of 15.2 months (Fischer et 
al. 2011) to 23 months (34% reduction in risk of a PFS event) 
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• 
Exponential distribution of PFS 
• 
An annual dropout rate of 5% 
• 
One interim analysis for efficacy at approximately 75% of total investigator-assessed 
PFS events (140 investigator-assessed PFS events). 
 
With these assumptions, 186 investigator-assessed PFS events are required to achieve 
80% power for the primary analysis of PFS in all patients.  It is planned to enroll 
370 patients across the two arms, with 1:1 randomization ratio. 
Sample size calculations, including the calculations, were performed with Insightful 
S + Seq Trial S 2.0.6. 
2.4 
ANALYSIS TIMING 
An efficacy interim analysis is planned at approximately 140 investigator-assessed PFS 
events (75% of the 186 events required for the final primary efficacy analysis) have 
occurred for both treatment arms combined (see Section 4.11).  The stopping boundary 
follows a unified family with parameter P = 2 (Kittelson et al. 1999).  Based on 140 events, 
this corresponds to approximately a 2-sided p-value of 2 × 0.0013 = 0.0026. 
If the p-value of the two-sided log-rank test is less than or equal to 0.0026, the trial will 
have met its primary efficacy endpoint (corresponding to a HR of approximately 0.60 or 
better).  Based on the assumption of HR = 0.66 (venetoclax + R arm vs. BR arm), and the 
duration of enrollment of 20 months, the interim analysis will happen at around 
26 months after first patient in.  If the study results are not released in the IA, the final 
analysis for the study will be conducted when approximately 186 PFS events based on 
the investigator assessment have occurred.  Based on the aforementioned assumptions 
of HR and the duration of enrollment, the final analysis will happen at around 32 months 
after first patient in. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION SPECIFICATIONS 
Randomization will be performed by an interactive voice/Web-based system (IxRS).  
Patients will be assigned in 1:1 ratio to one of the two treatment arms through a 
block stratified randomization procedure.  The randomization scheme will ensure 
approximately equal sample sizes in the two treatment groups in regard to a total of 
15 strata by the following stratification factors: 
• 
17p deletion by local testing (yes or no) 
• 
Risk status:  high risk or low risk 
• 
Geographic region (United States/Canada, Australia/New Zealand, Western Europe, 
Central and Eastern Europe, or Asia) 
 
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A unique patient number will be assigned at randomization.  This patient number will be 
used to identify the patient in the electronic data capture system and all other data 
sources. 
3.2 
INDEPENDENT REVIEW COMMITTEE 
An IRC composed of board-certified radiologists and board-certified oncologists with 
experience in CLL will assess all patients for response and progression on the basis of 
imaging results, bone marrow biopsy results, and relevant clinical data.  The IRC 
assessment will be blinded with respect to treatment arm and investigator assessment of 
response. 
A charter for the IRC will further describe the responsibilities, methods of response 
evaluation, and determination of progression. 
3.3 
INDEPENDENT DATA MONITORING COMMITTEE 
This trial includes an independent Data Monitoring Committee (iDMC) for periodic review 
of safety and efficacy data collected during the study.  Reviews by the iDMC will be 
conducted according to a charter written and approved prior to study initiation.  Members 
of the iDMC will be external to the Sponsors and the study team and will follow a charter 
that outlines their roles and responsibilities. 
At the beginning of the study, intensive monitoring and analysis of all clinically significant 
safety events will be performed.  The iDMC will assemble to review a safety analysis of 
significant safety events approximately 1 month after the first patient is enrolled 
depending on the rate of initial patient enrollment, then approximately every 2 months 
until 40 patients have completed 2 cycles of treatment (with approximately 20 patients in 
each arm).  Thereafter, the iDMC will meet approximately every 6 months and 
subsequently at a frequency determined by the iDMC and the Sponsors according to the 
emerging safety profile.  In addition, either the Sponsors or the iDMC can request ad hoc 
iDMC meetings at any time that potential safety concerns arise.   
An interim analysis of efficacy data will be conducted and further reviewed by the iDMC 
when approximately 140 (75%) of the 186 investigator-assessed PFS events required 
for the primary efficacy analysis have occurred.  Recommendations to release the study 
results early because of significant evidence of efficacy will be based on the specified 
interim analysis methodology. 
An independent Data Coordinating Center (iDCC), which is independent of the Sponsors, 
will prepare all summaries and analyses for the iDMC review. 
Further details about the definition, the role, as well as the responsibility of the iDMC are 
provided in a separate document, the iDMC Charter. 
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4. 
STATISTICAL METHODS 
4.1 
ANALYSIS POPULATION 
4.1.1 
Randomized Patients 
By following the intent-to-treat principle, efficacy analyses will be performed using all 
randomized patients.  Patients will be analyzed in the treatment arm that they were 
randomized to by the IxRS, regardless the actual treatment received. 
Safety analyses will include all randomized patients who received at least one dose of 
study treatment (venetoclax, rituximab, or bendamustine), with patients grouped 
according to the treatment arm as treated.  If patients in the control (BR) arm received 
venetoclax, they will be assigned to venetoclax-containing arm in the safety analysis 
population.  If patients in the venetoclax-containing arm accidentally missed some doses 
of venetoclax, they will remain in the venetoclax-containing arm in the safety analysis 
population.  
4.1.2 
Pharmacokinetic Evaluable Population 
PK analyses and the evaluable population will be defined in a separate analysis plan. 
4.2 
ANALYSIS OF STUDY CONDUCT 
The number of patients who are randomized will be tabulated by treatment group, center, 
and country.  Major eligibility violations, major protocol deviations, patient disposition, 
and reasons for study discontinuation will be summarized by treatment group for all 
randomized patients.  Duration of follow-up will also be assessed. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic characteristics, including but not limited to age, sex, race, ethnicity, 
baseline weight, height, baseline Eastern Cooperative Oncology Group (ECOG) 
Performance Status, baseline disease characteristics (e.g., disease staging at diagnosis, 
time from first diagnosis, fludarabine-refractory status, prior number of oncology 
therapies), cytogenetic abnormalities (including 17p and P53 mutation), IgVH status, 
bulky disease (nodes  ≥ 5 cm or  ≥ 10 cm), absolute lymphocyte count at baseline 
(≥ 25 × 109/L or  ≥ 50 × 109/L), stratification factors (17p deletion, risk status, and 
geographic region), and TLS risk category (low, medium, or high) identified upon study 
entry based on both case report form (CRF) and programming will be summarized by 
treatment group for all randomized patients. 
The number of non-missing observations, mean, median, standard deviations, minimum, 
and maximum values of the continuous variables will be summarized by treatment group.  
Percentages of patients within each subgroup of categorical variables will be provided.  
Number of patients with missing information will also be summarized.  
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4.4 
MEDICAL HISTORY 
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the CRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of patients with a particular 
condition/diagnosis will be summarized.  Patients reporting more than one 
condition/diagnosis within a body system will be counted only once for that body system. 
4.5 
PREVIOUS TREATMENT AND CONCOMITANT MEDICATIONS 
A prior medication is defined as any medication started and ended prior to the first dose 
of study drug.  Concomitant therapy includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal/homeopathic remedies, nutritional supplements) used by 
a patient from 28 days prior to the initiation of study treatment through the end of 
treatment.  Concomitant medication will be summarized by treatment groups. 
The number and percentage of patients who have taken medications will be summarized 
for prior medications, concomitant medications, and prior cancer therapies.  
For summaries of concomitant medications, if an incomplete start date was collected for 
a medication, the medication will be assumed to be a concomitant medication only if the 
partial date information indicates that the drug was used by a patient from 28 days prior 
to the initiation of study treatment. 
4.6 
EFFICACY ANALYSIS 
4.6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is PFS. 
 
 
 the primary efficacy endpoint is the IRC-assessed PFS, 
which is defined as the time from randomization to the first occurrence of progression or 
relapse as assessed by the IRC (determined using standard iwCLL guidelines [Hallek et 
al. 2008]) or death from any cause, whichever comes first. 
The primary analysis of the study will test the equality of PFS distributions in the 
venetoclax and rituximab combination (venetoclax + R, Arm A) and in bendamustine and 
rituximab combination (BR, Arm B) arms, as follows: 
H0: PFSvenetoclax+R = PFSBR vs. H1: PFSvenetoclax+R≠PFSBR
The treatment comparison will be performed using a two-sided stratified log-rank test (at 
the 0.05 significance level, appropriately adjusted for an interim analysis if it is 
conducted) stratified by 17p deletion status (yes or no), Risk status (high risk or low risk), 
and geographic region (United States/Canada, Australia/New Zealand, Western Europe, 
Central and Eastern Europe, or Asia).  If the null hypothesis is rejected and the observed 
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HR is favorable for the venetoclax + R combination, then it is shown that the 
venetoclax + R treatment arm has statistically significantly longer PFS than the BR arm.  
The investigator-assessed PFS will also be analyzed using the same models. 
For cases in which a patient is misrandomized with respect to a stratification factor (i.e., 
there is a discrepancy between the IxRS-recorded stratification factor level and the 
eCRF-recorded stratification factor level), the IxRS data will be used in the primary 
analysis.  Discordances between the IxRS and the eCRF data will be summarized. 
Further estimates of the treatment effect will be expressed as HRs from a stratified Cox 
proportional-hazards analysis, including 95% confidence intervals.  The stratification 
factors in the Cox model will include aforementioned stratification factors. 
The Kaplan−Meier plot will be used to provide a visual description of the differences in 
duration of PFS across treatment arms.  Median PFS for both treatment groups (if 
available) and the 95% confidence intervals will be estimated based on the method of 
Brookmeyer and Crowley (1982). 
Sensitivity analyses for PFS will also be performed as described in Section 4.6.4. 
4.6.2 
Secondary Efficacy Endpoints 
Secondary endpoints are as defined in Section 2.2.2.  Formal statistical tests of duration 
of PFS between the two arms for the population of patients determined to have 17p 
deletion by the central laboratory, the ORR based on investigator assessment as well as 
the OS will be conducted.  
To adjust for multiple testing of key secondary efficacy endpoints, thereby controlling the 
overall type I error rate at a two-sided significance level of 0.05, a fixed sequence testing 
procedure will be used (Westfall and Krishen 2001).  For registration purposes in the 
United States, the following endpoints will be tested in the order given (see also 
Section 2.2.2 for secondary endpoints not included in the fixed sequence testing 
procedure): 
• 
PFS in randomized patients based on IRC assessment 
• 
PFS based on IRC assessment in the population of patients with 17p deletion 
mutation detected based on the central laboratory FISH test results 
• 
ORR based on investigator assessment 
• 
OS  
 
Specifically, if the study meets its primary efficacy endpoint of prolonged PFS in the 
treatment arm (venetoclax + R) in all randomized patients, then a formal statistical test of 
IRC-assessed PFS between the two arms will be performed at the two-sided 
significance level of 0.05 for the patients with 17p deletion mutation detected based on 
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the central laboratory FISH test results.  An unstratified log-rank test will be used as the 
main test for treatment effect comparison.   
If the study does not meet its primary endpoint, then this test will not be performed.   
A stratified log-rank test with early or late relapse or progression after prior 
chemotherapy-containing and geographic region will also be performed as a supportive 
analysis. 
The ORR based on investigator assessment will only be tested once the test for PFS in 
the population of patients with 17p deletion mutation detected based on the central 
laboratory FISH test results has been rejected at a two-sided level significance of 0.05. 
If the test for ORR has been rejected at a two-sided significance level of 0.05, the 
duration of OS will be further tested in the final analysis (when approximately 
186 investigator-assessed PFS events have occurred) at a two-sided significance level 
of 0.05. 
This fixed-sequence testing of the duration of PFS in 17p-deleted patients, ORR by 
investigator assessment or OS maintains the type I error level at 0.05 (Alosh et al. 2010).  
No further adjustment for multiplicity will be made for the other secondary endpoints 
analyses. 
Investigator-assessed PFS will be analyzed in the subset of CLL patients with 17p 
deletion identified by central laboratory FISH testing by methods similar to those used for 
the IRC based PFS analyses for the subset of CLL patients with 17p deletion. 
ORR, CR, CRi, nPR, and PR rate at the end of combination treatment response visit as 
assessed by the investigator or by the IRC will be compared between the two arms 
using the stratified Cochran−Mantel−Haenszel (CMH) tests.  Stratification factors to be 
used are identical to those used for the primary PFS endpoint analyses.  Various 
response rates and 95% confidence intervals will be reported for each treatment group.  
Both bone marrow aspirate- and peripheral blood-based MRD response rates from the 
two treatment arms at the end of combination treatment response visit will be compared 
by using the Chi-square test.  In cases where no post-baseline MRD assessment is 
available at this time point, patients will be considered as MRD-positive in this analysis.  
Time-to-event endpoints, including OS, EFS, and TTNT, will be analyzed using the same 
statistical log-rank tests as described for the primary analysis of PFS. 
Time-to-event analysis of DOR will incorporate data only from the subset of patients in 
both treatment arms that achieved a CR/CRi/nPR/PR.  As there is no expectation for 
treatment arm balance, analyses of DOR will not incorporate stratification factors and will 
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not produce a p-value but only summarize the treatment arm estimates and confidence 
intervals. 
4.6.3 
Exploratory Efficacy Endpoints 
Relationship between various baseline biomarkers and clinical outcome parameters in 
patients from both arms of the study may be assessed using appropriate laboratory 
measures. 
The MRD response rates based on the peripheral blood/bone marrow aspirate samples 
at each disease response assessment visit will be summarized over time for both 
treatment arms.  In cases where no post-baseline MRD assessment is available at a 
specific time point, patients will be considered as MRD-positive, except for those who 
have not been followed up long enough to have MRD data collected for that timepoint. 
4.6.4 
Sensitivity Analyses 
To check robustness of the statistical models and underlying assumptions to be 
implemented in the primary endpoint analyses, the following two sensitivity analyses for 
PFS will be performed: 
• 
An unstratified log-rank test for the primary PFS comparison between treatment 
arms will be conducted. 
• 
The impact of patients’ initiation of non-protocol−specified anti-CLL therapy without 
meeting the criteria of disease progression on PFS will be assessed by censoring 
these patients at the start date of the non-protocol−specified anti-CLL treatment.  
Stopping only one component of the randomized study treatment will not be 
considered a reason for censoring patients. 
 
4.6.5 
Subgroup Analyses 
Subgroup analyses of investigator-assessed PFS, IRC-assessed PFS, and ORR will be 
performed according to prognostic factors to assess internal consistency.  The odds ratio 
of response and their 95% confidence intervals, hazard ratio of time-to-event endpoint 
and their 95% confidence intervals, as well as the sample sizes will be reported 
separately for each level of the following subgroups in forest plot: 
• 
Baseline characteristics (including, but not limited to age at randomization, sex, race, 
17p deletion status or P53 mutation status) 
• 
Stratification factors (17p deletion by local testing, risk status, geographic region) 
 
4.7 
SAFETY ANALYSES 
Safety of the study will be assessed through adverse events (AE) reporting, including 
serious adverse events (SAE) and non-serious adverse events of special interest, safety 
laboratory assessments, measurement of vital signs, and other protocol-specified tests 
that are deemed critical to the safety evaluation.  
The safety analyses will be performed based on the Treated Patients. 
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4.7.1 
Exposure to Study Medication 
Information on study drug administration such as the duration of treatment, dose 
intensity (percentage of planned dosage received) and number of dose/cycles will be 
summarized by treatment arm and by study medication by using the following statistics:  
sample size, mean, standard deviation, median, minimum, and maximum.   
Withdrawals of patients from study treatment will be reported as listings and summary 
tables by treatment arms as well. 
4.7.2 
Adverse Events 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported.  After initiation of study 
drug, all AEs will be reported until 28 days after the last dose of study drug, or 90 days 
after last dose of rituximab, whichever is longer.  Verbatim descriptions of AEs will be 
mapped to the most recent version of the Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms.   
AEs and SAEs will be summarized by treatment arm, by body system and by the 
National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI−CTCAE) 
version 4.0 grading system.  For all AEs, the most extreme intensity will be used for 
reporting.  Individual listings and summary tables will be presented by body system and 
intensity.  In tables showing the overall incidence of AEs, patients who experienced the 
same event on more than one occasion will be counted only once in the calculation of 
the event frequency.  
AEs of special interest (Grade  ≥ 3 TLS and IRR) will be summarized by treatment arm 
and listings will be provided. 
AEs leading to dose interruptions, early treatment discontinuation and early study 
withdrawal will be summarized by treatment arm. 
Summary tables of AEs by age, gender, and race will also be provided. 
Deaths reported during the study treatment period and those reported after treatment 
completion/discontinuation will be summarized by treatment arm and by AE versus 
non-AE. 
4.7.3 
Laboratory Data 
Selected laboratory measurements and change from baseline will be summarized over 
time by treatment arm, where baseline measurement is defined as the last valid 
measurement before first dose of any study medication.  For example, TLS-related lab 
measurements (including uric acid, potassium, inorganic phosphorus, and calcium) and 
changes from baseline will be summarized by treatment arm over time.  In addition, 
laboratory measurements from individual patients who developed an AE of TLS during 
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the study will be presented by listings.  Important hematology parameters, such as 
absolute lymphocyte count, absolute neutrophil count, Hg, Hct, and WBC will be 
categorized according to NCI CTCAE grading version 4.0.  Shift tables will be generated 
to cross-tabulate the number of patients grouped into each grade at baseline versus 
post-baseline observations. 
4.7.4 
Vital Signs 
Vital signs will be summarized over time for absolute values and changes from baseline 
without imputation for missing data.  Descriptive statistics will be provided by treatment 
arm. 
ECG data at the screening visit will be summarized by treatment arm for number of 
patients that fall into each category of status as collected in the CRF. 
4.8 
MISSING DATA 
For PFS, patients who do not have documented disease progression or death will have 
observations censored on the date of the last tumor assessment or, if no response 
assessments were performed after the baseline visit, at the time of randomization plus 
one day. 
For OS, patients for whom death has not been documented will have observations 
censored on the last date at which they were known to be alive. 
For response endpoints, patients with no response assessments (for any reason) will be 
considered non-responders. 
For DOR, patients with no documented progression after CR, CRi, nPR, or PR will be 
censored at the last date at which they are known to have had the CR, CRi, nPR, or PR.  
Patients who have never responded will not be included in this analysis. 
4.9 
PHARMACODYNAMIC ANALYSES 
The pharmacodynamic endpoint in this study is serial assessment of B-cell, T-cell, and 
NK-cell lymphocyte subsets by flow cytometry.  Proportions of each lymphocyte subset 
and change from baseline in the proportions will be summarized by treatment arm over 
time as warranted by the data. 
4.10 
PHARMACOKINETIC ANALYSES 
Venetoclax concentrations will be summarized by nominal visit and timepoint of 
collection in the Clinical Study Report (CSR).  Population PK methods will be used to 
characterize the PK of venetoclax in this study in conjunction with appropriate historical 
data to calculate apparent clearance, apparent volume of distribution, and other 
appropriate PK parameters of venetoclax.  Potential correlations of exposure with dose, 
demographics, pharmacodynamic variables, safety, and efficacy outcomes may be 
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explored as warranted by the data.  PK analyses will be defined in a separate PK report.  
The results from the population PK analysis may be reported separately from the CSR. 
4.11 
INTERIM ANALYSES 
One interim analysis is planned during the conduct of the study to assess the efficacy of 
venetoclax + R combination treatment compared with BR treatment, and to allow for 
release of the results earlier than the planned final analysis in case of significant 
differences. 
The interim analysis will be performed when approximately 140 investigator-assessed 
PFS events have occurred in both treatment arms combined (75% of the 186 events 
required for the final primary efficacy analysis is available).  The stopping boundary 
follows a unified family with parameter P = 2 (Kittelson et al. 1999).  Based on 140 events, 
the duration of PFS will be tested at the interim analysis, which corresponds to 
approximately a 2-sided p-value of 2 × 0.0013 = 0.0026.  If the number of events is not 
exactly 140, then the boundary will be updated to reflect the number of events.  Table 1 
summarizes the  probability of passing boundary at the planned interim analysis given a 
hazard ratio. 
Table 1 
Probability of Passing Boundary at the Interim Analysis for a 
Given Hazard Ratio  
True Hazard Ratio 
0.66 
0.42 
0.35 
Approximate 
median PFS in RV 
arm a (months) 
23.0 
36.2 
43.4 
Probability of 
passing boundary 
at interim analysis 
29% 
98% 
99% 
PFS = progression-free survival; RV venetoclax + rituximab. 
a Assumes a median duration of PFS of 15.2 months for the BR arm.  
 
Both investigator-assessed PFS analysis and a corresponding analysis on the basis of 
IRC-assessed PFS events will be conducted in this interim analysis.  The same 
stratification factors as specified in the primary efficacy endpoint analysis will be used.  If 
the p-value of the stratified two-sided log-rank test is less than or equal to 0.0026 
(approximately corresponding to a HR of 0.60) for both investigator-assessed PFS 
analysis and IRC-assessed PFS analysis and the observed HR is favorable for the 
venetoclax + R combination treatment, the trial will have met its primary efficacy endpoint.  
An iDMC will evaluate interim analysis results and provide a recommendation as to 
whether to release the trial results early.  All summaries and analyses according to 
treatment arm will be prepared by an iDCC for the iDMC review.  
 
  
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The final primary efficacy analysis will be performed when approximately 
186 investigator-assessed PFS events have been observed.  The statistical test level will 
be adjusted to incorporate the alpha spent at the interim analysis (if it was conducted) so 
that the overall type I error rate will be maintained at the two-sided 0.05 level. 
4.12 
REFERENCES 
Alosh M, Huque M. A consistency-adjusted alpha-adaptive strategy for sequential testing. 
Stat Med 2010;29:1559−71. 
Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. 
Biometrics 1982;38:29-41. 
Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients 
with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter Phase 
II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 
2011;29:3559−66. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 
1996 guidelines. Blood 2008;111:5446−56. 
Kittelson J, and Emerson S. A Unifying Family of Group Sequential Test Designs. 
Biometrics 1999;55:874-82 
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple 
testing procedures. J Stat Plan Inference 2001;99:25–40. 
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STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
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STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED 
STUDY IN RELAPSED/REFRACTORY PATIENTS WITH CHRONIC 
LYMPHOCYTIC LEUKEMIA TO EVALUATE THE BENEFIT OF 
VENETOCLAX (GDC-0199/ABT-199) PLUS RITUXIMAB 
COMPARED WITH BENDAMUSTINE PLUS RITUXIMAB 
PROTOCOL NUMBER: 
GO28667 
STUDY DRUG: 
Venetoclax (GDC-0199/ABT-199, RO5537382) 
VERSION NUMBER: 
4 
IND NUMBER: 
110159 
EUDRACT NUMBER: 
2013-002110-12 
SPONSOR: 
F. Hoffmann-La Roche Ltd and AbbVie Inc. will act 
as co-sponsors of this trial globally. 
PLAN PREPARED BY: 
 Ph.D. 
DATE FINAL: 
Version 1: 27 July 2015 
DATES AMENDED 
Version 2: 20 June 2016 
Version 3: 21 December 2016 
Version 4: See electronic date stamp below.  
Name
Reason for Signing
Date and Time
(UTC)
18-May-2017 17:23:32
Company Signatory (Clinical)


Venetoclax (GDC-0199/ABT-199)—F. Hoffmann-La Roche Ltd
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STATISTICAL ANALYSIS PLAN, VERSION 4:
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 9
2.2
Outcome Measures ................................................................. 9
2.2.1
Primary Efficacy Outcome Measures ...................................... 9
2.2.2
Secondary Efficacy Outcome Measures.................................. 9
2.2.3
Exploratory Efficacy Outcome Measures............................... 11
2.2.4
Pharmacokinetic Efficacy Outcome Measures ...................... 11
2.2.5
Pharmacodynamic Efficacy Outcome Measure..................... 11
2.2.6
Safety Outcome Measures .................................................... 11
2.2.7
Patient-Reported Outcome Measures ................................... 12
2.2.8
Health Economic Outcome Measure ..................................... 12
2.3
Determination of Sample Size ............................................... 12
2.4
Analysis Timing ..................................................................... 12
3.
STUDY CONDUCT..................................................................................... 13
3.1
Randomization Specifications................................................ 13
3.2
Independent Review Committee............................................ 13
3.3
Independent Data Monitoring Committee .............................. 13
4.
STATISTICAL METHODS .......................................................................... 14
4.1
Analysis Population ............................................................... 14
4.1.1
Randomized Patients ............................................................ 14
4.1.2
Treated Patients .................................................................... 14
4.1.3
Pharmacokinetic Evaluable Population ................................. 14
4.2
Analysis of Study Conduct..................................................... 14
4.3
Analysis of Treatment Group Comparability .......................... 15
4.4
Medical History...................................................................... 15
4.5
Previous Treatment and Concomitant 
Medications ........................................................................... 15
4.6
Efficacy Analysis.................................................................... 16
4.6.1
Primary Efficacy Endpoint...................................................... 16
4.6.2
Secondary Efficacy Endpoints............................................... 17


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4.6.3
Exploratory Efficacy Endpoints.............................................. 19
4.6.4
Sensitivity Analyses............................................................... 20
4.6.5
Subgroup Analyses ............................................................... 20
4.7
Safety Analyses..................................................................... 20
4.7.1
Exposure to Study Medication............................................... 20
4.7.2
Adverse Events ..................................................................... 21
4.7.3
Laboratory Data..................................................................... 21
4.7.4
Vital Signs.............................................................................. 22
4.8
Missing Data.......................................................................... 22
4.9
Pharmacodynamic Analyses ................................................. 22
4.10
Pharmacokinetic Analyses..................................................... 22
4.11
Patient-Reported Outcomes Analyses................................... 23
4.12
Interim Analyses .................................................................... 23
5.
REFERENCES ........................................................................................... 24
LIST OF TABLES
Table 1
Probability of Passing Boundary at the Interim Analysis for a 
Given True Hazard Ratio ............................................................ 23
LIST OF FIGURES
Figure 1
Design of the Study....................................................................... 7
Figure 2
Venetoclax Dosing Scheme during the Ramp-Up Period ............. 8
Figure 3
Diagram of Hierarchical Testing of Primary and Key 
Secondary Endpoints.................................................................. 18
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 25
Appendix 2
Schedule of Assessments........................................................... 43


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
BR
bendamustine in combination with rituximab
CLL
chronic lymphocytic leukemia
CMH
CochranMantelHaenszel
CR
complete response
CRi
complete response with incomplete marrow recovery
DOR
duration of response
eCRF
electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EFS
event-free survival
FISH
fluorescence in situ hybridization
HR
hazard ratio
HRQOL
health-related quality of life
IA
interim analysis
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IRC
Independent Review Committee
IRR
infusion-related reaction
iwCLL
International Workshop on CLL
IxRS
interactive voice/Web-based system
MDASI
MD Anderson Symptom Inventory
MRD
Minimal residual disease
NCI CTCAE
National Cancer Institute Common Terminology Criteria for adverse Events
NK
natural killer
nPR
nodular partial response
ORR
objective response rate
OS
overall survival
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
QLQ-C30
Quality of Life Questionnaire Core 30
QLQ-CLL16
Quality of Life Questionnaire CLL module
TLS
tumor lysis syndrome
TTNT
time to next anti-CLL treatment
venetoclax R
venetoclax (GDC-0199/ABT-199) in combination with rituximab


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1.
BACKGROUND
This document is based on the Statistical Considerations and Analysis Plan section of 
the study GO28667 (MURANO) protocol and will provide more details on the planned 
statistical analyses.  For purposes of registration, the analyses outlined in this Statistical 
Analysis Plan  will supersede those specified in the protocol.
2.
STUDY DESIGN
This is an open-label, international, multicenter, randomized, Phase III study to 
investigate the efficacy and safety of venetoclax (GDC-0199/ABT-199) in combination 
with rituximab (venetoclaxR) compared with bendamustine in combination with 
rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) 
(see Figure 1).
The primary objective of the study is to evaluate the efficacy of venetoclaxR compared 
with BR in patients with relapsed or refractory CLL, as measured by 
investigator-assessed progression-free survival (PFS). In the United States, 
Independent Review Committee (IRC)-assessed PFS will be analyzed to support the 
primary efficacy analysis and will be the basis for regulatory decisions. 


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Figure 1
Design of the Study
1 cycle28 days; Arm Avenetoclax (GDC-0199) and rituximab (venetoclax R); Arm Bbendamustine and rituximab (BR); CLLchronic 
lymphocytic leukemia; OSoverall survival; PDprogressive disease; PO per os; QDonce daily.
*Patients will receive venetoclax starting on Day 1 (venetoclax dose ramp-up period) as delineated in Figure 2.  Venetoclax will then be 
self-administered at 400 mg per day for a maximum of 2 years from Cycle 1 Day 1 or until disease progression (whichever is earlier).  
Combination therapy consisting of 6 cycles of rituximab and daily venetoclax dosing will start after completion of the venetoclax ramp-up period.


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Figure 2
Venetoclax Dosing Scheme during the Ramp-Up Period
Dday.
Note:  For all patients enrolled after Protocol Version 4.  Prior to Version 4, ramp up was 4 or 
5 weeks
Approximately 370 patients will be recruited and randomly assigned in 1:1 ratio to 
receive either venetoclaxR (Arm A) or BR (Arm B).  Randomization will be stratified 
according to the following 3 factors:

17p deletion:  yes or no

Risk status:  high risk or low risk
High risk:  defined as harboring 17p deletion, no response to front-line 
chemotherapy-containing regimen, relapsed within 12 months after 
chemotherapy, or relapsed within 24 months after chemoimmunotherapy
Low risk:  defined as relapse more than 12 months after chemotherapy or 
24 months after chemoimmunotherapy.

Geographic region:  United States/Canada, Australia/New Zealand, Western Europe,
Central and Eastern Europe, or Asia 
Patients randomized to Arm A (venetoclaxR) will have a 5-week venetoclax dose 
ramp-up period to reach the target dose of 400 mg daily, followed by 6 cycles of 
rituximab consisting of a single infusion on the first day of each 28-day cycle.  Patients 
will continue to take their daily dose of venetoclax during the rituximab cycles.  Patients 
whose disease has not progressed following the completion of the 6 cycles will continue 
to receive venetoclax until disease progression or for a maximum of 2 years from 
Cycle 1 Day 1.  Patients randomized to Arm B (BR) will receive 6 cycles of BR consisting 
of a single infusion of rituximab on Day 1 and bendamustine infusions on Days 1 
and 2 of each 28-day cycle.
After 6 cycles of combination therapy, patients in both arms will be followed clinically 
every 3 months through Year 3 from Cycle 1, Day 1, after which they will be followed 
every 6 months for an additional 2 years, until withdrawal of consent, or until end of 
study, whichever comes first.
Patients who discontinue all components of study treatment for other reasons, or receive 
a new anti-CLL therapy at any time during follow-up in the absence of disease 
progression will also be followed for progression and survival according to the schedule 
defined in the protocol.


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2.1
PROTOCOL SYNOPSIS
The protocol synopsis of Version 7 is provided in Appendix 1.  For additional details, see 
the Schedule of Assessments in Appendix 2.
2.2
OUTCOME MEASURES
All patients will have baseline tumor assessment and will be assessed for response to 
treatment at the scheduled response assessment follow-up visits using standard clinical 
and laboratory examinations and/or computed tomography scans according to the 
International Workshop on CLL (iwCLL) guidelines (Hallek et al. 2008).
The assessment of response and progression by the investigator will be considered the 
primary analysis for all of the endpoints described in the study.  Response and 
progression will also be assessed by an IRC.
2.2.1
Primary Efficacy Outcome Measures
The primary efficacy outcome measure for this study is investigator-assessed PFS.  
 
 
Duration of PFS is defined as the time from randomization to the first occurrence of 
progression or relapse, determined using standard iwCLL guidelines, or death from any 
cause, whichever comes first.  Data from patients without disease progression, relapse, 
or death will be censored at the time of the last adequate response assessment.  If no 
response assessments were performed after the baseline visit, PFS will be censored at 
the date of randomization.  Patients who have initiated new anti-CLL therapy prior to the 
documented disease progression will not be censored at the date of initiation of the new 
anti-CLL therapy.
An adequate response assessment visit must include the following assessments:
1.
Physical examination (nodal and extranodal disease as applicable, spleen, and liver)
2.
Hematology labs (lymphocytes, platelets, and hemoglobin).
  
 
  
 
 
2.2.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are as follows:

IRC-assessed PFS in the subset of CLL patients with 17p deletion identified by 
fluorescence in situ hybridization (FISH) testing at a central laboratory


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
Investigator-assessed PFS in the subset of CLL patients with 17p deletion identified 
by FISH testing at a central laboratory

Investigator-assessed best overall response rate (ORR), which is defined as the 
percentage of patients with the best response of complete response (CR), complete 
response with incomplete marrow recovery (CRi), nodular partial response (nPR), or 
partial response (PR), at any time point during the study as assessed by the 
investigator.  In cases where no post-baseline response assessment is available, 
patients will be considered non-responders.

IRC-assessed ORR, which is defined as the percentage of patients with the best 
response of CR, CRi, nPR, or PR at any time point during the study as assessed by 
the IRC.  In cases where no post-baseline response assessment is available, 
patients will be considered non-responders.

IRC-assessed CR rate, which is defined as the percentage of patients with the best 
response of CR or CRi at any time point during the study as assessed by the IRC.

ORR, CR, CRi, nPR, and PR rates at the end of combination treatment response 
visit, as assessed by the investigator.  In cases where no post-baseline response 
assessment is available, patients will be considered non-responders.

ORR, CR, CRi, nPR, and PR rates at end of combination treatment response visit, 
as assessed by the IRC.  In cases where no post-baseline tumor assessment is 
available, patients will be considered non-responders.

Overall survival (OS), which is defined as the time from randomization to death from 
any cause.  Patients who were not reported as having died at the time of the 
analysis will be censored at the date when they were last known to be alive.

Investigator-assessed event-free survival (EFS), which is defined as the time 
between date of randomization and the date of disease progression/relapse, death, 
or start of a new non-protocol-specified anti-CLL therapy as assessed by the 
investigator.  If the specified event (disease progression/relapse, death, start of a 
new anti-CLL treatment) does not occur, patients will be censored at the date of last 
adequate response assessment.  In cases where no post-baseline response 
assessment is available, patients without an event will be censored at the 
randomization date.

Duration of response (DOR), which is defined for patients with a best overall 
response of CR, CRi, nPR, or PR as the time from first occurrence of a documented 
CR/CRi/nPR/PR to disease progression/relapse, as assessed by the investigator, or 
death from any cause.  Patients with no documented progression or death after CR, 
CRi, nPR, or PR will be censored at the last date of adequate response assessment.  
Patients who have never responded will not be included in this analysis.

Time to next anti-CLL treatment (TTNT), which is defined as the time from 
randomization to start of new non-protocolspecified anti-CLL therapy or death from 
any cause.  Patients who were reported as not having started new non-protocol 
anti-CLL therapy or death will be censored at the last visit date for this outcome 
analysis.


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
Minimal residual disease (MRD) response rate at the end of combination treatment 
response visit as measured at a central laboratory on peripheral blood samples.
2.2.3
Exploratory Efficacy Outcome Measures
The exploratory outcome measures for this study are as follows:

Assessment of potential biomarkers that are prognostic and/or predictive of 
response and resistance to treatment with venetoclaxR or BR.

Evaluation of the relationship between clinical response and PFS and various 
potential biomarkers for patients treated with venetoclaxR or BR.

MRD response rate as measured at a central laboratory based on peripheral blood 
samples over time.

The best MRD response rate as measured by a central laboratory based on 
peripheral blood samples collected during the study. 

MRD response rate as measured by a central laboratory based on bone marrow 
aspirate samples in responders (CR/CRi, nPR/PR).
2.2.4
Pharmacokinetic Efficacy Outcome Measures
The pharmacokinetic (PK) outcome measures for this study are as follows:

Plasma venetoclax concentrations at the specified timepoints

Apparent clearance, apparent volume of distribution, and other appropriate PK 
parameters of venetoclax characterized using population PK techniques, as data 
allow
2.2.5
Pharmacodynamic Efficacy Outcome Measure
The pharmacodynamic outcome measure for this study is as follows:

Serial assessment of B-cell, T-cell, and natural killer (NK)-cell lymphocyte subsets 
by flow cytometry
2.2.6
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of adverse events and serious adverse events, 
including deaths

Mean of changes in vital signs, physical findings, and clinical laboratory results 
(including hematology and chemistry) during and following administration of study 
treatment

Incidence of adverse events of special interest:
Grade > 3 tumor lysis syndrome (TLS) and infusion-related reactions (IRRs)

Measures of immune function, including serial immunoglobulin levels (IgG, IgM, and 
IgA) following treatment with venetoclaxR or BR


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2.2.7
Patient-Reported Outcome Measures
The health-related quality of life (HRQOL) and disease- and treatment-related symptom 
measures for this study are as follows:

MD Anderson Symptom Inventory (MDASI) (see Appendix 5 of the protocol)

European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (QLQ-C30) and Quality of Life Questionnaire CLL module 
(QLQ-CLL16) (see Appendix 3 and Appendix 4, respectively, of the protocol)
2.2.8
Health Economic Outcome Measure
The health economic outcome measure for this study is as follows:

The EuroQol five-dimension five-level questionnaire (see Appendix 6 of the protocol)
2.3
DETERMINATION OF SAMPLE SIZE
The primary endpoint of PFS was used to determine the sample size for the study based 
on the following assumptions:

Two-sided log-rank test at the 0.05 level of significance

80% power to detect a hazard ratio (HR) for venetoclaxR versus BR of 0.66, 
corresponding to an approximate median improvement of 15.2 months (Fischer et 
al. 2011) to 23 months (34% reduction in risk of a PFS event)

Exponential distribution of PFS

An annual dropout rate of 5%

One interim analysis (IA) for efficacy at approximately 75% of total investigator-
assessed PFS events (approximately 140 investigator-assessed PFS events).
With these assumptions, 186 investigator-assessed PFS events are required to achieve 
80% power for the primary analysis of PFS in all patients.  It is planned to enroll 
370 patients across the two arms with 1:1 randomization ratio.
Sample size calculations were performed with Insightful SSeq Trial S 2.0.6.
2.4
ANALYSIS TIMING
An efficacy IA is planned when approximately 140 investigator-assessed PFS events 
(75% of the 186 events required for the final primary efficacy analysis) have occurred for 
both treatment arms combined (see Section 4.12).  The stopping boundary follows a 
unified family with parameter P2 (Kittelson and Emerson 1999).  Based on 140 events, 
this corresponds to approximately a 2-sided p-value of 20.00130.0026.  The exact 
crossing boundary for the IA will be determined by the actual number of events observed.
If the p-value of the two-sided log-rank test is less than or equal to the crossing 
boundary, for example, 0.0026, the trial will have met its primary efficacy endpoint 
(corresponding to a HR of approximately 0.60 or better).  Based on the assumption of 
HR0.66 (venetoclax R arm vs. BR arm), and the duration of enrollment of 20 months, 
the IA will take place approximately 26 months after first patient is enrolled.  If the study 


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results are not released in the IA, the final analysis for the study will be conducted when 
approximately 186 PFS events based on the investigator assessment have occurred.  
Based on the aforementioned assumptions of HR and the duration of enrollment, the 
final analysis will take place approximately 32 months after the first patient is enrolled.
3.
STUDY CONDUCT
3.1
RANDOMIZATION SPECIFICATIONS
Randomization will be performed by an interactive voice/Web-based system (IxRS).  
Patients will be assigned in 1:1 ratio to one of the two treatment arms through a 
block stratified randomization procedure.  The randomization scheme will ensure 
approximately equal sample sizes in the two treatment groups in regard to a total of 
15 strata by the following stratification factors:

17p deletion by local testing (yes or no)

Risk status:  high risk or low risk

Geographic region (United States/Canada, Australia/New Zealand, Western Europe, 
Central and Eastern Europe, or Asia)
A unique patient number will be assigned at randomization.  This patient number will be 
used to identify the patient in the electronic data capture system and all other data 
sources.
3.2
INDEPENDENT REVIEW COMMITTEE
An IRC composed of board-certified radiologists and board-certified oncologists with 
experience in CLL will assess all patients for response and progression on the basis of 
imaging results, bone marrow biopsy results, and relevant clinical data.  The IRC 
assessment will be blinded with respect to treatment arm and investigator assessment of 
response.
The responsibilities, methods of response evaluation, and determination of disease 
response/progression can be found in the IRC Charter.
3.3
INDEPENDENT DATA MONITORING COMMITTEE
This trial includes an independent Data Monitoring Committee (iDMC) for periodic review 
of safety and efficacy data collected during the study.  Reviews by the iDMC will be 
conducted according to a charter written and approved prior to study initiation.  Members 
of the iDMC will be external to the Sponsors and the study team and will follow a charter 
that outlines their roles and responsibilities.
At the beginning of the study, intensive monitoring and analysis of all clinically significant 
safety events will be performed.  The iDMC will assemble to review a safety analysis of 
significant safety events approximately 1 month after the first patient is enrolled 
depending on the rate of initial patient enrollment, then approximately every 2 months 
until 40 patients have completed 2 cycles of treatment (with approximately 20 patients in 


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each arm).  Thereafter, the iDMC will meet approximately every 6 months and 
subsequently at a frequency determined by the iDMC and the Sponsors according to the 
emerging safety profile.  In addition, either the Sponsors or the iDMC can request ad hoc 
iDMC meetings at any time that potential safety concerns arise.
An IA of efficacy data will be conducted and further reviewed by the iDMC when 
approximately 140 (75%) of the 186 investigator-assessed PFS events required for the 
primary efficacy analysis have occurred.  Recommendations to release the study results 
early because of significant evidence of efficacy will be based on the specified IA 
methodology.
An independent Data Coordinating Center (iDCC), which is independent of the Sponsors, 
will prepare all summaries and analyses for the iDMC review.
Further details about the definition, the role, as well as the responsibility of the iDMC are 
provided in a separate document, the iDMC Charter.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATION
4.1.1
Randomized Patients
By following the intent-to-treat principle, efficacy analyses will be performed using all 
randomized patients.  Patients will be analyzed in the treatment arm that they were 
randomized to by the IxRS, regardless of the actual treatment received.
4.1.2
Treated Patients
Safety analyses will include all randomized patients who received at least one dose of 
study treatment (venetoclax, rituximab, or bendamustine), with patients grouped 
according to the treatment arm as treated.  If patients in the control (BR) arm received 
venetoclax, they will be assigned to venetoclax-containing arm in the safety analysis 
population.  If patients in the venetoclax-containing arm accidentally missed some doses 
of venetoclax, they will remain in the venetoclax-containing arm in the safety analysis 
population.
4.1.3
Pharmacokinetic Evaluable Population
Pharmacokinetic analyses and the evaluable population will be defined separately.
4.2
ANALYSIS OF STUDY CONDUCT
The number of patients who are randomized will be tabulated by treatment group, center, 
and country.  Major eligibility violations, major protocol deviations, patient disposition, 
and reasons for study discontinuation will be summarized by treatment group for all 
randomized patients.  Duration of follow-up will also be assessed.


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4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic characteristics, including but not limited to age, sex, race, ethnicity, 
baseline weight, height, baseline Eastern Cooperative Oncology Group (ECOG) 
Performance Status, baseline disease characteristics (e.g., disease stage at diagnosis, 
time from first diagnosis, fludarabine-refractory status, prior number of oncology 
therapies), cytogenetic abnormalities (including 17p and P53 mutation), IgVH status, 
bulky disease (nodes5 cm or10 cm), absolute lymphocyte count at baseline
(25109/L or100109/L), stratification factors (17p deletion, risk status, and 
geographic region), and TLS risk category (low, medium, or high) identified upon study 
entry based on both the electronic Case Report Form (eCRF) and programming based 
on raw data will be summarized by treatment group for all randomized patients.
The number of non-missing observations, mean, median, standard deviations, minimum, 
and maximum values of the continuous variables will be summarized by treatment group.  
Percentages of patients within each subgroup of categorical variables will be provided.  
Number of patients with missing information will also be summarized.
4.4
MEDICAL HISTORY
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of patients with a particular 
condition/diagnosis will be summarized.  Patients reporting more than one 
condition/diagnosis within a body system will be counted only once for that body system.
4.5
PREVIOUS TREATMENT AND CONCOMITANT MEDICATIONS
A prior medication is defined as any medication started and ended prior to the first dose 
of study drug.  Concomitant therapy includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal/homeopathic remedies, or nutritional supplements) used 
by a patient from 28 days prior to the initiation of study treatment through the end of 
treatment.  Concomitant medication will be summarized by treatment groups.
The number and percentage of patients who have taken medications will be summarized 
for prior medications, concomitant medications, and prior cancer therapies.
For summaries of concomitant medications, if an incomplete start date was collected for 
a medication, the medication will be assumed to be a concomitant medication only if the 
partial date information indicates that the drug was used by a patient from 28 days prior 
to the initiation of study treatment.


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4.6
EFFICACY ANALYSIS
4.6.1
Primary Efficacy Endpoint
The primary efficacy endpoint of this study is PFS as assessed by investigator.  
 
 
the primary efficacy endpoint is the 
IRC-assessed PFS, which is defined as the time from randomization to the first 
occurrence of progression or relapse as assessed by the IRC (determined using 
standard iwCLL guidelines [Hallek et al. 2008]) or death from any cause, whichever 
comes first.
The primary analysis of the study will test the equality of PFS distributions in the 
venetoclax and rituximab combination (venetoclaxR, Arm A) and in bendamustine and
rituximab combination (BR, Arm B) arms, as follows:
H0: PFSvenetoclax+RPFSBR vs. H1: PFSvenetoclax+R≠PFSBR
The treatment comparison will be performed using a two-sided stratified log-rank test (at 
the 0.05 significance level, appropriately adjusted for an IA (if it is conducted) stratified 
by 17p deletion status (yes or no), risk status (high risk or low risk), and geographic 
region (United States/Canada, Australia/New Zealand, Western Europe, Central and 
Eastern Europe, or Asia).  If the null hypothesis is rejected and the observed HR is 
favorable for the venetoclaxR combination, then it has shown that the venetoclaxR
treatment arm has statistically significantly longer PFS than the BR arm.  The 
investigator-assessed PFS will also be analyzed using the same models.  
Agreement/disagreement between investigator assessment and assessment by the IRC 
will be summarized.
For cases in which a patient is misrandomized with respect to a stratification factor (i.e., 
there is a discrepancy between the IxRS-recorded stratification factor level and the 
eCRF-recorded stratification factor level), the IxRS data will be used in the primary 
analysis.  Discordances between the IxRS and the eCRF data will be summarized.
Further estimates of the treatment effect will be expressed as HRs from a stratified Cox 
proportional-hazards analysis, including 95% confidence intervals.  The stratification 
factors in the Cox model will include aforementioned stratification factors.
The KaplanMeier plot will be used to provide a visual description of the differences in 
duration of PFS across treatment arms.  Median PFS for both treatment groups (if 
available) and the 95% confidence intervals will be estimated based on the method of 
Brookmeyer and Crowley (1982).
Sensitivity analyses for PFS will also be performed as described in Section 4.6.4.


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4.6.2
Secondary Efficacy Endpoints
Secondary endpoints are as defined in Section 2.2.2.
To adjust for multiple testing of key secondary efficacy endpoints, a fixed sequence 
testing procedure will be used (Westfall and Krishen 2001).  The following endpoints will 
be tested in the order listed below (see also Section 2.2.2 for secondary endpoints not 
included in the fixed sequence testing procedure):

IRC-assessed CR rate

IRC-assessed best ORR 

OS
If the study meets its primary efficacy endpoint of prolonged PFS in the treatment arm 
(venetoclaxR) in all randomized patients, then a formal statistical test of IRC-assessed 
CR rate between the two arms will be performed at the two-sided significance level of 
0.05 by using a stratified CochranMantelHaenszel (CMH) test with stratification factors 
in it.  If the study does not meet its primary endpoint, then this test will not be performed.
The IRC-assessed best ORR will only be tested by the same stratified CMH test once 
the null hypothesis for IRC-assessed CR rate in all randomized patients has been 
rejected at a two-sided significance level of 0.05.
If the null hypothesis for IRC-assessed best ORR has been rejected at a two-sided 
significance level of 0.05, the duration of OS will be analyzed at a nominal alpha spend 
of 0.0001. Approximately 3 years after the last patient is enrolled, OS will be tested at a 
two-sided significance level of 0.0499.
Refer to Figure 3 for a schematic of the hierarchical testing of primary and key 
secondary endpoints. Of note, CR and ORR endpoints will only be tested once either at 
interim or final analysis depending on the outcome of the PFS analysis.


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Figure 3
Diagram of hierarchical testing of primary and key secondary 
endpoints
IA interim analysis, FA final analysis, INV investigator assessment, IRC independent 
review committee assessment, LPI last patient in, PFS progression-free survival, 
CR complete response, ORR overall response rate, CR complete response, OS overall 
survival
*Assumes 140 events at interim and 186 events at final. Exact boundaries for IRC and INV may 
differ based on actual number of events observed respectively at each analysis.


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Investigator-assessed best ORR, as well as CR, CRi, nPR, and PR rate at the end of 
combination treatment response visit as assessed by the investigator or by the IRC will 
be compared between the two arms using the stratified CMH tests.  Stratification factors 
to be used are identical to those used for the primary PFS endpoint analyses.  Various 
response rates and 95% confidence intervals will be reported for each treatment group.
Investigator-assessed and IRC-assessed PFS will be analyzed in the subset of CLL 
patients with 17p deletion identified by central laboratory FISH testing. An unstratified 
log-rank test will be used as the main test for treatment effect comparison.  A stratified 
log-rank test with geographic region will also be performed as a supportive analysis.
Peripheral blood-based MRD response rates from the two treatment arms at the end of 
combination treatment response visit will be compared by using the Chi-square test.  In 
cases where no post-baseline MRD assessment is available at this time point, patients 
will be considered as MRD-positive in this analysis, except for those who have not been 
followed up long enough to have MRD data collected for this timepoint.
Time-to-event endpoints, including OS, EFS, and TTNT, will be analyzed using the same 
log-rank tests as described in the primary analysis of PFS.
Time-to-event analysis of DOR will incorporate data only from the subset of patients in 
both treatment arms that achieved a CR/CRi/nPR/PR.  As there is no expectation for 
treatment arm balance, analyses of DOR will not incorporate stratification factors and will 
not produce a p-value but only summarize the treatment arm estimates and confidence 
intervals.
4.6.3
Exploratory Efficacy Endpoints
Relationship between various baseline biomarkers and clinical outcome parameters in 
patients from both arms of the study may be assessed.
The MRD response rates in peripheral blood samples and bone marrow aspirate 
samples will each be assessed separately.  The MRD response rates at each response 
assessment visit will be summarized over time for both treatment arms.  The MRD 
response rates based on the bone marrow aspirate and based on peripheral blood 
samples in responders (CR, CRi, nPR, and PR) will be summarized.  The best MRD 
response rate in two treatment arms based on the peripheral blood samples collected in 
the study will be analyzed.  In cases where no post-baseline MRD assessment is 
available at a specific time point, patients will be considered as MRD-positive, except for 
those who have not been followed up long enough to have MRD data collected for that 
timepoint.


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4.6.4
Sensitivity Analyses
To check robustness of the statistical models and underlying assumptions to be 
implemented in the primary endpoint analyses, the following sensitivity analyses for PFS
(both investigator-assessed and IRC-assessed) will be performed:

An unstratified log-rank test for the primary PFS comparison between treatment 
arms will be conducted.

The impact of patients’ initiation of non-protocolspecified anti-CLL therapy without 
meeting the criteria of disease progression on PFS will be assessed by censoring 
these patients at the start date of the non-protocolspecified anti-CLL treatment.  
Stopping only one component of the randomized study treatment will not be 
considered a reason for censoring patients.

To assess the impact of missing assessments on PFS, an analysis on PFS will be 
performed by censoring those patients who progressed or died after missing more 
than one visit consecutively at their last adequate response assessment date before 
the missed visits. 
4.6.5
Subgroup Analyses
Subgroup analyses of investigator-assessed PFS, IRC-assessed PFS, and ORR as 
assessed by the investigator or by IRC will be performed to assess internal consistency.  
The odds ratio of response and their 95% confidence intervals, HR of time-to-event 
endpoint and their 95% confidence intervals, as well as the sample sizes will be reported 
separately for each level of the following subgroups in forest plot:

Baseline characteristics (including, but not limited to age at randomization, sex, race, 
IgVH mutational status, relapsed versus refractory disease to most recent prior 
therapy; response duration [12 months vs greater] to most recent prior therapy, 
17p deletion detected by central laboratory test, 11q deletion detected by central 
laboratory test, P53 mutation status, TP53 mutation and/or 17p deletion detected by 
central laboratory test, number of prior CLL therapy [1, 2, 3 or greater], Fludarabine 
refractory, baseline nodal size, baseline ALC counts, renal impairment, hepatic 
impairment, etc.)

Stratification factors (17p deletion by local test, risk status, and geographic region)
4.7
SAFETY ANALYSES
Safety data of the study will be assessed through adverse events reporting, including 
serious adverse events and non-serious adverse events of special interest, safety 
laboratory assessments, measurement of vital signs, and other protocol-specified tests 
that are deemed critical to the safety evaluation.
The safety analyses will be performed on the treated patients.
4.7.1
Exposure to Study Medication
Information on study drug administration such as the duration of treatment, dose 
intensity (percentage of planned dosage received) and number of dose/cycles will be 


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summarized by treatment arm and by study medication by using the following statistics:  
sample size, mean, standard deviation, median, minimum, and maximum.
Withdrawals of patients from study treatment will be reported as listings and summary 
tables by treatment arms as well.
4.7.2
Adverse Events
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
After initiation of study drug, all adverse events will be reported in accordance with the 
protocol.  Verbatim descriptions of adverse events will be mapped to the most recent 
version of the Medical Dictionary for Regulatory Activities thesaurus terms.
Treatment-emergent adverse events and serious adverse events will be summarized by 
treatment arm, by body system and by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 grading system.  For 
all adverse events, the most extreme intensity will be used for reporting.  Individual 
listings and summary tables will be presented by body system and severity.  In tables 
showing the overall incidence of adverse events, patients who experienced the same 
event on more than one occasion will be counted only once in the calculation of the 
event frequency.
Adverse events of special interest (including elevated ALT or AST in combination with 
either elevated bilirubin or clinical jaundice, suspected transmission of an infectious 
agent by the study drug, Grade3 TLS, and Grade3 IRR) will be summarized by 
treatment arm and listings will be provided.
Adverse events leading to dose interruptions, treatment discontinuation, and study 
withdrawal will be summarized by treatment arm.
Summary tables of adverse events by age (65 or65 years), gender, and race will 
also be provided.
Deaths reported during the study treatment period and those reported after treatment 
completion/discontinuation will be summarized by treatment arm and by adverse event 
versus non-adverse event.
4.7.3
Laboratory Data
All applicable laboratory measurements and mean of changes from baseline will be 
summarized over time by treatment arm, where baseline measurement is defined as the 
last valid measurement before first dose of any study medication.  For example, 
TLS-related lab measurements (including uric acid, potassium, inorganic phosphorus, 
and calcium) and changes from baseline will be summarized by treatment arm over time.  
In addition, laboratory measurements from individual patients who developed an adverse 


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event of TLS during the study will be presented by listings.  Important hematology 
parameters, such as absolute lymphocyte count, absolute neutrophil count, hemoglobin, 
hematocrit, and WBC will be categorized according to NCI CTCAE grading version 4.0.  
Shift tables will be generated to cross-tabulate the number of patients grouped into each 
grade at baseline versus post-baseline observations.
4.7.4
Vital Signs
Vital signs will be summarized over time for absolute values and changes from baseline 
without imputation for missing data.  Descriptive statistics will be provided by treatment 
arm.
ECG data at the screening visit will be summarized by treatment arm.
4.8
MISSING DATA
For PFS, patients who do not have documented disease progression or death will have 
observations censored on the date of the last adequate response assessment or, if no 
response assessments were performed after the baseline visit, at the time of 
randomization.
For OS, patients for whom death has not been documented will have observations 
censored on the last date at which they were known to be alive.
For response endpoints, patients with no response assessments (for any reason) will be 
considered non-responders.
For DOR, patients with no documented progression after CR, CRi, nPR, or PR will be 
censored at the last date of adequate response assessment.  Patients who have never 
responded will not be included in this analysis.
4.9
PHARMACODYNAMIC ANALYSES
The pharmacodynamic endpoint in this study is serial assessment of B-cell, T-cell, and 
NK-cell lymphocyte subsets by flow cytometry.  Proportions of each lymphocyte subset 
and change from baseline in the proportions will be summarized by treatment arm over 
time as warranted by the data.
4.10
PHARMACOKINETIC ANALYSES
Individual plasma concentrations of venetoclax will be tabulated after appropriate 
grouping, summarized (e.g., mean, standard deviation, coefficient of variation, median, 
minimum, and maximum), and plotted.
Population PK methods will be used to characterize the pharmacokinetics of venetoclax 
in this study in conjunction with appropriate historical data.  Apparent clearance, 
apparent volume of distribution, and other appropriate PK parameters of venetoclax may 
be calculated and summarized as data allow.  Potential correlations of exposure with 


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dose, demographics, pharmacodynamic variables, safety, and efficacy outcomes may 
be explored as warranted by the data.  The results from the population PK analysis may 
be reported separately from the Clinical Study Report.
4.11
PATIENT-REPORTED OUTCOMES ANALYSES
Unless otherwise specified, patient reported outcome endpoint analyses will include all 
randomized patients who have a non-missing baseline and at least one post-baseline 
patient report outcome assessment.  Patients in this subset will be analyzed according to 
their randomized treatment assignment, irrespective of the treatment received.
Compliance, summary statistics of HRQOL and CLL symptom scores and change from 
baseline as measured by MDASI, QLQ-C30, and QLQ-CLL16 questionnaires will be 
provided.  Mean of changes in scores from baseline, as well as time to disease-related 
symptom progression in both treatment arms will be assessed as data allow.  As 
deemed necessary, additional analyses may be performed.
4.12
INTERIM ANALYSES
One IA is planned during the conduct of the study to assess the efficacy of 
venetoclaxR combination treatment compared with BR treatment, and to allow for 
release of the results earlier than the planned final analysis in case of significant 
differences.
The IA will be performed when approximately 140 investigator-assessed PFS events 
have occurred in both treatment arms combined (75% of the 186 events required for the 
final primary efficacy analysis is available).  The stopping boundary follows a unified 
family with parameter P2 (Kittelson and Emerson 1999).  Based on 140 events, the 
duration of PFS will be tested at the IA, which corresponds to approximately a 2-sided 
p-value of 2 0.0013 0.0026.  Table 1 summarizes the probability of crossing 
boundary at the planned IA given assumed true HRs.
Table 1
Probability of Passing Boundary at the Interim Analysis for a 
Given True Hazard Ratio 
True Hazard Ratio
0.66
0.42
0.35
Approximate 
median PFS in 
venetoclax + R arm 
(months) a
23.0
36.2
43.4
Probability of 
passing boundary 
at interim analysis
29%
98%
99%
PFS progression-free survival; venetoclax + Rvenetoclax rituximab.
a Assumes a median duration of PFS of 15.2 months for the BR arm and 
exponential distributions for PFS in both treatment arms. 


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Both investigator-assessed PFS analysis and a corresponding analysis on the basis of 
IRC-assessed PFS events will be conducted in this IA.  In case the observed number of 
events is not exactly 140, the boundaries will be updated to reflect the number of events 
based on investigator assessment and IRC assessment, respectively.  The same 
stratification factors as specified in the primary efficacy endpoint analysis will be used.  If 
the p-value of the stratified two-sided log-rank test is less than or equal to the respective 
boundary for both investigator-assessed PFS analysis and IRC-assessed PFS analysis 
and the observed HR is favorable for the venetoclaxR combination treatment, the trial 
will have met its primary efficacy endpoint.
An iDMC will evaluate IA results and provide a recommendation as to whether to release 
the trial results early.  All summaries and analyses according to treatment arm will be 
prepared by an iDCC for the iDMC review.  
 
The final primary efficacy analysis will be performed when approximately 
186 investigator-assessed PFS events have been observed.  The statistical test level will 
be adjusted to incorporate the alpha spent at the IA (if it was conducted) so that the 
overall type I error rate will be maintained at the two-sided 0.05 level.
5.
REFERENCES
Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. 
Biometrics 1982;38:29-41.
Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients 
with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter Phase 
II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 
2011;29:355966.
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 
1996 guidelines. Blood 2008;111:544656.
Kittelson J, Emerson S. A Unifying Family of Group Sequential Test Designs. Biometrics 
1999;55:874-82
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple 
testing procedures. J Stat Plan Inference 2001;99:25–40.