A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions
Phase: PHASE3
Conditions: Lymphocytic Leukemia, Chronic
Sponsor: Hoffmann-La Roche

 
Official Title: 
 
A PROSPECTIVE, OPEN-LABEL, MULTICENTER 
RANDOMIZED PHASE III TRIAL TO COMPARE THE 
EFFICACY AND SAFETY OF A COMBINED REGIMEN OF 
OBINUTUZUMAB AND VENETOCLAX (GDC-0199/ABT-199) 
VERSUS OBINUTUZUMAB AND CHLORAMBUCIL IN 
PREVIOUSLY UNTREATED PATIENTS WITH CLL AND 
COEXISTING MEDICAL CONDITIONS 
NCT Number: 
NCT02242942 
Document Date: 
Protocol Version 7: 12 Feb 18 
 
 
 
 

PROTOCOL AMENDMENT APPROVAL 
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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. 
 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
Protocol BO25323, Version 7 
PROTOCOL 
TITLE: 
A PROSPECTIVE, OPEN-LABEL, MULTICENTER 
RANDOMIZED PHASE III TRIAL TO COMPARE THE 
EFFICACY AND SAFETY OF A COMBINED REGIMEN OF 
OBINUTUZUMAB AND VENETOCLAX (GDC-0199/ABT-199) 
VERSUS OBINUTUZUMAB AND CHLORAMBUCIL IN 
PREVIOUSLY UNTREATED PATIENTS WITH CLL AND 
COEXISTING MEDICAL CONDITIONS 
PROTOCOL NUMBER: 
BO25323/CLL14 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2014-001810-24 
IND NUMBER: 
110159 
TEST PRODUCTS: 
Venetoclax (GDC-0199 [ABT-199]; RO5537382), 
Obinutuzumab (GA101; RO5072759), and 
Chlorambucil 
MEDICAL MONITOR: 
MB ChB 
SPONSOR: 
F. Hoffmann-La Roche Ltd in collaboration with the 
German Chronic Lymphocytic Leukaemia Study Group 
CO-SPONSOR (United 
States only): 
AbbVie, Inc. 
DATE FINAL: 
Version 1:  July 23, 2014 
DATES AMENDED: 
Version 2:  October 21, 2014 
Version 3:  November 7, 2014 
Version 4:  May 21, 2015 
Version 5:  November 2, 2015 
Version 6:  March 29, 2017 
Version 7:  See electronic date stamp below 
 
12-Feb-2018 18:28:50
Title
Approver's Name
Company Signatory
Date and Time (UTC)

Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
2/Protocol BO25323, Version 7 
PROTOCOL AMENDMENT, VERSION 7: 
RATIONALE 
Protocol BO25323 has been amended to include the option to add an additional earlier 
interim efficacy analysis to mitigate the potential for an undue delay in the delivery of the 
study read-out; to prolong collection of blood samples to characterize the minimal 
residual disease kinetics in patients who might be responding longer than originally 
expected; and to add complete response as a stand-alone secondary endpoint in order 
to more comprehensively explore the potential depth of response to study treatment.  
Clarifications have been made regarding the time windows for assessments in the study 
and timing of blood sampling for safety monitoring/B-cell recovery.  Additionally, an 
inconsistency in the reporting instructions for unrelated serious adverse events has been 
removed.  
Changes to the protocol, along with a rationale for each change, are summarized below: 
• 
The option to add an earlier interim analysis for efficacy has been added to reflect 
accumulating data, including minimal residual disease (MRD) response rate data 
from the 12 patients in the safety run-in portion of the study (Fischer et al. 2017) 
and early-phase Study GP28331 in front-line chronic lymphocytic leukemia (CLL) 
patients (Flinn et al. 2017) who have all been treated with the obinutuzumab and 
venetoclax regimen.  Data from these patients have indicated levels of response 
that are anticipated to translate into longer progression-free survival (PFS), such 
that events of disease progression are taking longer to accrue than originally 
projected in the study protocol.  As a result of these preliminary findings, it is 
expected that the original interim analysis might be significantly delayed, and the 
statistical analysis for the study has now been modified to introduce a possible 
additional earlier interim efficacy analysis.  The early additional interim analysis may 
be conducted at or after 1 year after the last patient’s last venetoclax dose (i.e., 
Month 37 of the study [August 2018]), provided that at least 85 PFS events (50% of 
the total of 170 PFS events) have occurred.  If 85 PFS events have not been 
observed by 1 year after the last patient’s last venetoclax dose, then the interim 
analysis will be conducted once a minimum of 85 PFS events have occurred.  PFS 
will be tested such that the overall two-sided type I error rate will be maintained at 
the 0.05 level.  The study would only stop for efficacy if a treatment effect HR of 
0.35 or better is observed when the interim analysis is based on 85 events.  This 
approach is designed to mitigate the potential for a protracted waiting period for the 
necessary PFS events to accrue, which would result in an undue delay in the study 
read-out and availability of a potential new treatment option for patients with chronic 
lymphocytic leukemia (CLL) (Section 6.11). 
• 
The wording of the original interim analysis text has been changed to simplify the 
protocol and will be done when a minimum of 110 PFS events have occurred now 
that it is clear that 128 events will not have been observed by 28th February 
2018.  There is no change to the timing of this analysis (Section 6.11).  
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
3/Protocol BO25323, Version 7 
• 
The duration of the collection of blood samples for MRD assessments by ASO-
PCR and NGS has been extended to beyond 18 months after treatment until 5 
years after last patient enrolled  to reflect the MRD response rate data from the 12 
patients in the safety run-in portion of the study in order to enable characterization 
of the MRD kinetics in patients who might be responding longer than originally 
projected (Appendix 3 and Appendix 13).An additional secondary endpoint of 
complete response has been added to more comprehensively explore the potential 
depth of response to study treatment in a clinically meaningful manner and further 
differniate response beyond ORR (Section 3.4.2 and Section 6.4.2). 
• 
The time windows for study assessments have been aligned with Section 4.5.10, 
such that all assessments during the treatment period and follow-up Day 28 visit 
should be performed within 7 days of the scheduled visit, unless otherwise 
specified.  On treatment days, all assessments should be performed prior to dosing, 
unless otherwise specified.  Following the end-of-treatment assessment (3 months 
after treatment completion/early termination), all other follow-up assessments, 
whether tumor assessments or other study assessments, will be done within 
±14 days for 3-monthly and within a 1 month for 6-monthly assessments of the 
scheduled visits (Appendix 1 and Appendix 3). 
• 
Wording for blood sampling for safety monitoring/B-cell recovery has been clarified 
for consistency with Section 4.5.14 throughout the protocol.  Timing of samples 
after treatment completion/early termination has been clarified to be required at 
28 days; 12, 18, and 24 months; and then every 6 months until 5 years from last 
patient enrolled (Appendix 2 and Appendix 3). 
• 
A prior inconsistency in the reporting period for serious adverse events considered 
by the investigator to be unrelated to study medication has been removed.  There 
is now a reference to Appendix 14 for details of the duration and reporting of 
adverse events in Section 5.4.2.2. 
 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.   
Additional minor changes have been made to improve clarity and consistency.   
 
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
5/Protocol BO25323, Version 7 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14 
PROTOCOL SYNOPSIS .................................................................................... 15 
1. 
BACKGROUND .......................................................................................... 27 
1.1 
Background on Chronic Lymphocytic Leukemia .................... 27 
1.2 
Background on Venetoclax (GDC-0199) ............................... 29 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 29 
1.3.1 
Efficacy .................................................................................. 29 
1.3.2 
Safety .................................................................................... 30 
1.3.3 
Rationale for the Combination of Venetoclax with 
Obinutuzumab ....................................................................... 31 
1.3.4 
Benefit-Risk Assessment ....................................................... 32 
2. 
OBJECTIVES .............................................................................................. 32 
2.1 
Efficacy Objectives ................................................................ 32 
2.2 
Safety Objectives ................................................................... 32 
2.3 
Pharmacokinetic Objective .................................................... 33 
2.4 
Patient-Reported Outcome Objectives .................................. 33 
2.5 
Health Economic Objective .................................................... 33 
2.6 
Exploratory Objectives ........................................................... 33 
3. 
STUDY DESIGN ......................................................................................... 34 
3.1 
Description of Study .............................................................. 34 
3.1.1 
Assessment of Efficacy.......................................................... 34 
3.1.2 
Summary of Study Procedures .............................................. 35 
3.1.2.1 
Screening/Baseline Tests ...................................................... 35 
3.1.2.2 
Treatment Period ................................................................... 36 
3.1.2.3 
Monitoring of Disease Progression during 
Treatment Period ................................................................... 37 
3.1.2.4 
Post-Treatment Follow-Up Visits ........................................... 38 
3.2 
End of Study .......................................................................... 38 
3.3 
Rationale For Design ............................................................. 38 
3.3.1 
Rationale for Dose and Schedule .......................................... 38 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
6/Protocol BO25323, Version 7 
3.3.1.1 
Venetoclax ............................................................................. 38 
3.3.1.2 
Obinutuzumab ....................................................................... 39 
3.3.1.3 
Chlorambucil .......................................................................... 39 
3.3.2 
Rationale for the Combination of Venetoclax with 
Obinutuzumab ....................................................................... 40 
3.3.3 
Rationale for Patient Population ............................................ 40 
3.3.4 
Rationale for Control Group ................................................... 41 
3.3.5 
Rationale for Minimal Residual Disease 
Assessments ......................................................................... 42 
3.3.6 
Rationale for Biomarker Assessments ................................... 42 
3.3.7 
Rationale for Chronic Lymphocytic Leukemia 
Diagnostic Laboratory Assessments ..................................... 43 
3.3.8 
Rationale for Pharmacokinetic Assessments ......................... 44 
3.3.9 
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 44 
3.4 
Outcome Measures ............................................................... 45 
3.4.1 
Efficacy Outcome Measures .................................................. 45 
3.4.2 
Secondary Efficacy Outcome Measures ................................ 45 
3.4.3 
Safety Outcome Measures .................................................... 46 
3.4.4 
Pharmacokinetic Outcome Measures .................................... 46 
3.4.5 
Pharmacodynamic Outcome Measures ................................. 46 
3.4.6 
Patient-Reported Outcome Measures ................................... 46 
3.4.7 
Health Economic Outcome Measure ..................................... 47 
3.4.8 
Exploratory Outcome Measures ............................................ 47 
4. 
MATERIALS AND METHODS .................................................................... 47 
4.1 
Patients .................................................................................. 47 
4.1.1 
Inclusion Criteria .................................................................... 47 
4.1.2 
Exclusion Criteria ................................................................... 49 
4.2 
Method of Treatment Assignment and Blinding ..................... 50 
4.3 
Study Treatment .................................................................... 51 
4.3.1 
Formulation, Packaging, and Handling .................................. 51 
4.3.1.1 
Venetoclax ............................................................................. 51 
4.3.1.2 
Chlorambucil .......................................................................... 51 
4.3.1.3 
Obinutuzumab ....................................................................... 51 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
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4.3.2 
Dosage, Administration, and Compliance .............................. 52 
4.3.3 
Investigational Medicinal Products ........................................ 59 
4.3.4 
Non-Investigational Medicinal Products ................................. 59 
4.3.5 
Post-Trial Access to Venetoclax ............................................ 60 
4.4 
Concomitant Therapy ............................................................ 60 
4.4.1 
Permitted Therapy ................................................................. 60 
4.4.2 
Prohibited Therapy ................................................................ 60 
4.4.2.1 
Drug−Drug Interaction ........................................................... 61 
4.4.3 
Other Prohibited Medication .................................................. 64 
4.4.4 
Prohibited Food ..................................................................... 64 
4.5 
Study Assessments ............................................................... 64 
4.5.1 
Informed Consent Forms and Screening Log ........................ 64 
4.5.2 
Procedures for Enrollment of Eligible Subjects ...................... 64 
4.5.3 
Medical History and Demographic Data ................................ 65 
4.5.4 
Physical Examinations ........................................................... 65 
4.5.5 
Performance Status ............................................................... 66 
4.5.6 
Clinical Staging ...................................................................... 66 
4.5.7 
Criteria for Initiation of First-Line Treatment .......................... 66 
4.5.8 
Vital Signs .............................................................................. 67 
4.5.9 
Tumor and Response Evaluations ......................................... 67 
4.5.10 
Tumor Response ................................................................... 68 
4.5.11 
Response Criteria .................................................................. 69 
4.5.12 
MRD Response Criteria ......................................................... 71 
4.5.13 
Other Disease-Specific Assessments .................................... 72 
4.5.13.1 
Complete Blood Count........................................................... 72 
4.5.13.2 
Bone Marrow ......................................................................... 72 
4.5.13.3 
Lymphadenopathy and 
Hepatomegaly/Splenomegaly ................................................ 72 
4.5.13.4 
B-Symptoms .......................................................................... 73 
4.5.14 
Laboratory, Biomarker, and Other Biological 
Assessments (Local and Central) .......................................... 73 
4.5.15 
Electrocardiograms ................................................................ 77 
4.5.16 
Patient-Reported and Clinician-Reported 
Outcomes .............................................................................. 77 

 
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8/Protocol BO25323, Version 7 
4.5.17 
German Chronic Lymphocytic Leukaemia Study 
Group Biobanking Samples ................................................... 79 
4.5.17.1 
Overview of the GCLLSG Biobanking ................................... 79 
4.5.17.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 80 
4.5.17.3 
Sample Collection .................................................................. 80 
4.5.17.4 
Confidentiality ........................................................................ 80 
4.5.17.5 
Consent to Participate in the GCLLSG 
Biobanking ............................................................................. 80 
4.5.17.6 
Withdrawal from the GCLLSG Biobanking............................. 81 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 81 
4.6.1 
Patient Discontinuation .......................................................... 81 
4.6.2 
Study Treatment Discontinuation ........................................... 82 
4.6.3 
Study and Site Discontinuation .............................................. 82 
5. 
ASSESSMENT OF SAFETY ....................................................................... 82 
5.1 
Safety Plan ............................................................................ 82 
5.1.1 
Risks Associated with Venetoclax ......................................... 83 
5.1.1.1 
Tumor Lysis Syndrome .......................................................... 83 
5.1.1.2 
Cytopenia .............................................................................. 84 
5.1.1.3 
Infectious Complications ........................................................ 84 
5.1.1.4 
Effects on Cardiac Function ................................................... 84 
5.1.1.5 
Effects on Fertility .................................................................. 85 
5.1.1.6 
Drug Interactions ................................................................... 85 
5.1.2 
Risks Associated with Obinutuzumab .................................... 85 
5.1.2.1 
Infusion-Related Reactions .................................................... 86 
5.1.2.2 
Tumor Lysis Syndrome .......................................................... 86 
5.1.2.3 
Neutropenia ........................................................................... 86 
5.1.2.4 
Lymphopenia ......................................................................... 86 
5.1.2.5 
Thrombocytopenia ................................................................. 86 
5.1.2.6 
Infection ................................................................................. 87 
5.1.2.7 
Immunization ......................................................................... 90 
5.1.2.8 
Gastrointestinal Perforation ................................................... 90 

 
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5.1.2.9 
Risks Associated with the Combination of 
Venetoclax and Obinutuzumab .............................................. 90 
5.1.3 
Management of Specific Adverse Events .............................. 91 
5.1.3.1 
Prophylaxis and Management of Tumor Lysis 
Syndrome for Patients Being Treated with 
Venetoclax ............................................................................. 94 
5.1.3.2 
Prophylaxis for Infections..................................................... 108 
5.1.3.3 
Prophylaxis for Infusion-Related Reactions ......................... 108 
5.1.3.4 
Life-Threatening Infusion-Related Reactions and 
Anaphylaxis ......................................................................... 109 
5.2 
Safety Parameters and Definitions ...................................... 109 
5.2.1 
Adverse Events ................................................................... 109 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) .................................................................... 110 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................. 110 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .............................................. 111 
5.3.1 
Adverse Event Reporting Period ......................................... 111 
5.3.2 
Eliciting Adverse Event Information ..................................... 111 
5.3.3 
Assessment of Severity of Adverse Events ......................... 112 
5.3.4 
Assessment of Causality of Adverse Events ....................... 112 
5.3.5 
Procedures for Recording Adverse Events .......................... 113 
5.3.5.1 
Infusion-Related Reactions .................................................. 113 
5.3.5.2 
Diagnosis versus Signs and Symptoms............................... 113 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................. 113 
5.3.5.4 
Persistent or Recurrent Adverse Events .............................. 114 
5.3.5.5 
Abnormal Laboratory Values ............................................... 114 
5.3.5.6 
Abnormal Vital Sign Values ................................................. 115 
5.3.5.7 
Abnormal Liver Function Tests ............................................ 116 
5.3.5.8 
Deaths ................................................................................. 116 
5.3.5.9 
Preexisting Medical Conditions ............................................ 116 
5.3.5.10 
Lack of Efficacy or Worsening of Chronic 
Lymphocytic Leukemia ........................................................ 117 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ........................ 117 

 
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5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 117 
5.3.5.13 
Patient-Reported Outcome Data ......................................... 118 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 118 
5.4.1 
Emergency Medical Contacts .............................................. 119 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ................... 119 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................. 119 
5.4.2.2 
Events That Occur after Study Drug Initiation ...................... 119 
5.4.3 
Reporting Requirements for Pregnancies ............................ 120 
5.4.3.1 
Pregnancies in Female Patients .......................................... 120 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ............... 120 
5.4.3.3 
Abortions ............................................................................. 121 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 121 
5.5 
Follow-Up of Patients after Adverse Events ........................ 121 
5.5.1 
Investigator Follow-Up ......................................................... 121 
5.5.2 
Sponsor Follow-Up .............................................................. 122 
5.6 
Post-study Adverse Events .................................................. 122 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 122 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 123 
6.1 
Determination of Sample Size ............................................. 123 
6.2 
Summaries of Conduct of Study .......................................... 124 
6.3 
Summaries of Treatment Group Comparability ................... 124 
6.4 
Efficacy Analyses ................................................................ 124 
6.4.1 
Primary Efficacy Endpoint .................................................... 124 
6.4.2 
Secondary Efficacy Endpoints ............................................. 125 
6.5 
Safety Analyses ................................................................... 126 
6.6 
Pharmacodynamic Analyses ............................................... 127 
6.7 
Pharmacokinetic Analyses ................................................... 127 
6.8 
Patient-Reported Outcome Analyses .................................. 127 
6.9 
Health Economics Analysis ................................................. 128 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
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6.10 
Exploratory Analyses ........................................................... 128 
6.11 
Interim Analyses .................................................................. 129 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 129 
7.1 
Data Quality Assurance ....................................................... 129 
7.2 
Electronic Case Report Forms ............................................. 130 
7.3 
Source Data Documentation ................................................ 130 
7.4 
Use of Computerized Systems ............................................ 131 
7.5 
Retention of Records ........................................................... 131 
8. 
ETHICAL CONSIDERATIONS .................................................................. 131 
8.1 
Compliance with Laws and Regulations .............................. 131 
8.2 
Informed Consent ................................................................ 132 
8.3 
Institutional Review Board or Ethics Committee .................. 133 
8.4 
Confidentiality ...................................................................... 133 
8.5 
Financial Disclosure ............................................................ 134 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 134 
9.1 
Study Documentation .......................................................... 134 
9.2 
Protocol Deviations .............................................................. 134 
9.3 
Site Inspections ................................................................... 134 
9.4 
Administrative Structure....................................................... 134 
9.4.1 
Roles and Responsibilities ................................................... 134 
9.4.2 
Independent Data Monitoring Committee ............................ 134 
9.4.3 
Independent Review Committee .......................................... 135 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 135 
9.6 
Protocol Amendments ......................................................... 136 
10. REFERENCES ......................................................................................... 137 
 
 
LIST OF TABLES 
Table 1 
Treatment Arm A:  Obinutuzumab + Venetoclax Study Visits ..... 36 
Table 2 
Treatment Arm B:  Obinutuzumab + Chlorambucil ...................... 37 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
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Table 3 
Administration of First Infusion of Obinutuzumab, if Split 
Over Two Days, and Subsequent Infusions of Obinutuzumab .... 57 
Table 4 
Excluded and Cautionary Medications for Patients 
Randomized to Arm A (Venetoclax + Obinutuzumab) ................. 63 
Table 5 
Management of Hepatitis B Virus Reactivation ........................... 89 
Table 6 
Guidelines for Management of Specific Adverse Events (for 
Patients Randomized to Arms A or B) ........................................ 91 
Table 7 
National Cancer Institute Grading Scale for Chronic 
Lymphocytic Leukemia ............................................................... 94 
Table 8 
Risk Categories for Developing Tumor Lysis Syndrome ............. 95 
Table 9 
Summary of Tumor Lysis Syndrome Prophylaxis for 
Venetoclax and Monitoring Measures ......................................... 96 
Table 10 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 112 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 34 
Figure 2 
Difference in Plasma S-Warfarin Concentration Following 
Treatment with Warfarin + Venetoclax versus Warfarin Alone .... 62 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments Treatment-Period Visits (RAMP-
UP to 400 mg) ........................................................................... 141 
Appendix 2 
Schedule of Assessments Cycle 3−Cycle 12 and Follow-Up 
Day 28 ...................................................................................... 149 
Appendix 3 
Schedule of Assessments (Follow-Up Period) .......................... 152 
Appendix 4 
Schedule of Pharmacokinetic Assessments ............................. 156 
Appendix 5 
Sample List of Excluded and Cautionary Medications for 
Patients Randomized to Arm A (Venetoclax + Obinutuzumab)
 .................................................................................................. 157 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) .............. 159 
Appendix 7 
Standard Cockcroft and Gault Formula for Calculated 
Creatinine Clearance ................................................................ 175 
Appendix 8 
Body Surface Area Calculation (BSA) Calculation Using the 
Mosteller Formula ..................................................................... 176 
Appendix 9 
National Cancer Institute Common Terminology Criteria .......... 177 
Appendix 10 
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome ............. 178 
Appendix 11 
Adverse Events Commonly Associated with Chronic 
Lymphocytic Leukemia Study Population and/or Progression 
of Chronic Lymphocytic Leukemia ............................................ 180 

 
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Appendix 12 
International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) Guidelines ................................................................... 182 
Appendix 13 
Schedule of Response and Minimal Residual Disease Assessments ... 210 
Appendix 14 Duration and Reporting of Adverse Events ............................... 211 
Appendix 15 EQ-5D-3L Questionnaire .......................................................... 212 
Appendix 16 
Eastern Cooperative Oncology Group Performance Status ...... 214 
Appendix 17 
Matutes Scoring System ........................................................... 215 
Appendix 18 
M.D. Anderson Symptom Inventory (MDASI-CLL) ................... 216 
Appendix 19 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-
C30) .......................................................................................... 218 
Appendix 20 
Guidelines for Defining Tumor Lysis Syndrome ........................ 220 
Appendix 21 
The Lawton Instrumental Activities of Daily Living Scale .......... 222 

Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
14/Protocol BO25323, Version 7 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PROSPECTIVE, OPEN-LABEL, MULTICENTER 
RANDOMIZED PHASE III TRIAL TO COMPARE THE 
EFFICACY AND SAFETY OF A COMBINED 
REGIMEN OF OBINUTUZUMAB AND 
VENETOCLAX (GDC-0199/ABT-199) VERSUS 
OBINUTUZUMAB AND CHLORAMBUCIL IN 
PREVIOUSLY UNTREATED PATIENTS WITH CLL 
AND COEXISTING MEDICAL CONDITIONS 
PROTOCOL NUMBER: BO25323/CLL14 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2014-001810-24 
IND NUMBER: 
110159 
TEST PRODUCTS: 
Venetoclax (GDC-0199 [ABT-199]; RO5537382), 
Obinutuzumab (GA101; RO5072759), and 
Chlorambucil  
MEDICAL MONITOR: 
 MB ChB 
SPONSOR: 
F. Hoffmann-La Roche Ltd in collaboration with the 
German Chronic Lymphocytic Leukaemia Study Group 
CO-SPONSOR 
(United States only): 
AbbVie, Inc. 
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 as instructed by your local study monitor.  
Please retain a copy for your study files. 
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
15/Protocol BO25323, Version 7 
PROTOCOL SYNOPSIS 
TITLE: 
A PROSPECTIVE, OPEN-LABEL, MULTICENTER RANDOMIZED 
PHASE III TRIAL TO COMPARE THE EFFICACY AND SAFETY OF 
A COMBINED REGIMEN OF OBINUTUZUMAB AND 
VENETOCLAX (GDC-0199/ABT-199) VERSUS OBINUTUZUMAB 
AND CHLORAMBUCIL IN PREVIOUSLY UNTREATED PATIENTS 
WITH CLL AND COEXISTING MEDICAL CONDITIONS 
PROTOCOL NUMBER: 
BO25323/CLL14 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2014-001810-24 
IND NUMBER: 
110159 
TEST PRODUCT: 
Venetoclax (GDC-0199 [ABT-199]; RO5537382), Obinutuzumab 
(GA101; RO5072759), and Chlorambucil 
PHASE: 
III 
INDICATION: 
Previously untreated patients with chronic lymphocytic leukemia with 
coexisting medical conditions 
SPONSOR: 
F. Hoffmann-La Roche Ltd in collaboration with the German CLL 
Study Group (GCLLSG) 
CO-SPONSOR 
(United States only) 
AbbVie, Inc. 
Objectives 
Efficacy Objectives 
The primary efficacy objective for Study BO25323/CLL14 is as follows: 
• 
To determine efficacy by investigator-assessed progression-free survival (PFS) of a 
combined regimen of obinutuzumab + venetoclax compared with 
obinutuzumab + chlorambucil (GClb) in previously untreated patients with chronic 
lymphocytic leukemia (CLL) who have coexisting medical conditions 
 
The secondary efficacy objective for this study is as follows: 
• 
To determine efficacy as assessed by additional outcome measures (including PFS 
assessed by Independent Review Committee [IRC], overall response, complete response, 
and MRD response rate as measured by allele-specific oligonucleotide polymerase chain 
reaction [ASO-PCR]) 
 
Note:  IRC-assessed PFS will be considered primary for U.S. regulatory purposes. 
Safety Objective 
The safety objective for this study is as follows: 
• 
To evaluate the safety of the combination of obinutuzumab and venetoclax, compared with 
GClb, in patients with previously untreated CLL and coexisting medical conditions, focusing 
on the nature, frequency, and severity of Grade 3 and 4 adverse events and of serious 
adverse events 

 
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16/Protocol BO25323, Version 7 
 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objective for this study is as follows: 
• 
To characterize the pharmacokinetics of venetoclax and of obinutuzumab (including 
population PK [popPK] techniques).  Standard non-compartmental analysis 
(NCA)/descriptive tables, listings, and graphs (TLGs) and popPK approaches will be 
considered. 
 
Patient-Reported Outcome Objectives 
The quality-of-life (patient-reported outcome [PRO]) objectives for this study are as follows: 
• 
To compare disease and treatment-related symptoms following treatment with the 
combination of obinutuzumab + venetoclax compared with GClb in patients with previously 
untreated CLL and coexisting medical conditions as measured by M.D. Anderson Symptom 
Inventory (MDASI-CLL) 
• 
To evaluate changes in role functioning and global health status/quality of life (QoL) 
following treatment with the combination of obinutuzumab + venetoclax compared with GClb 
in patients with previously untreated CLL and coexisting medical conditions between arms 
as measured by European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire Core 30 (EORTC QLQ-C30) 
 
Health Economic Objective 
The health economic objective for this study should be considered as a special PRO and is as 
follows: 
• 
To compare the health utility effects of treatment with combination of obinutuzumab and 
venetoclax compared with GClb in patients with previously untreated CLL and coexisting 
medical conditions measured by the EuroQol 5 Dimension questionnaire (EQ-5D-3L). 
 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To assess MRD using new technologies, including flow cytometry and next-generation 
sequencing, to compare results with MRD measured by ASO-PCR 
• 
To evaluate the relationship between PFS and MRD response rate 
• 
To evaluate the relationship between various baseline prognostic markers and clinical 
outcome parameters  
• 
To evaluate the relationship between biomarkers measured at baseline and disease 
progression to understand mechanisms of response and resistance 
 
Study Design 
Description of Study 
This is an open-label, multicenter, randomized Phase III trial to compare the efficacy and safety 
of a combined regimen of obinutuzumab and venetoclax versus GClb in patients with CLL and 
coexisting medical conditions. 
Initially, there will be a 12-patient safety run-in phase, (including at least 1 patient at high risk of 
developing TLS) wherein patients will receive obinutuzumab + venetoclax in a non-randomized 
fashion.  After the twelfth patient has reached the end of Cycle 3, a formal review will be 
undertaken by Roche and the German CLL Study Group ([GCLLSG]; together, hereafter 
referred to as the Sponsor) and an independent Data Monitoring Committee (iDMC). 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
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The following are stopping criteria for the run-in phase of this study:   
• 
One treatment-related death 
or 
• 
One Grade 4 adverse event related to a clinical tumor lysis syndrome (TLS) despite 
protocol-specified prophylaxis, either following the administration of the first dose of 
venetoclax or during dose escalation 
 
If any of these criteria are met, the main study will not be opened for recruitment, and the 
Sponsor will then re-evaluate the study design and amend the protocol accordingly.  If the 
stopping criteria are not met, randomization into the trial will commence. 
Number of Patients 
A total of 420 patients will be enrolled in the randomized part of the study, and 12 patients will 
be enrolled in the safety run-in phase.   
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Have documented previously untreated CLL according to International Workshop on 
Chronic Lymphocytic Leukemia (IWCLL) criteria 
• 
CLL that requires treatment according to the IWCLL criteria 
• 
Total Cumulative Illness Rating Scale (CIRS) score > 6 or creatinine clearance 
(CrCl) < 70 mL/min 
• 
Adequate marrow function independent of growth factor or transfusion support within 
2 weeks of screening as follows, unless cytopenia is due to marrow involvement of CLL: 
Absolute neutrophil count ≥ 1.0 × 109/L  
Platelet counts ≥ 30 × 109/L; in cases of thrombocytopenia clearly due to marrow 
involvement of CLL (per the discretion of the investigator); platelet count should 
be ≥ 10 × 109/L if there is bone marrow involvement 
Total hemoglobin ≥ 9 g/dL (without transfusion support, unless anemia is due to marrow 
involvement of CLL) 
• 
Adequate liver function as indicated by a total bilirubin, AST, and ALT ≤ 2 times the 
institutional upper limit of normal (ULN) value unless directly attributable to the patient’s 
CLL 
• 
For those patients with a screening lymphocyte count < 5,000 cells/µL, historical data that 
confirms a lymphocyte count ≥ 5,000 cells/µL at the time of diagnosis is required 
• 
18 years of age or older 
• 
Life expectancy > 6 months 
• 
Signed informed consent and, in the investigator’s judgment, able to comply with the study 
protocol  
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use single or combined contraceptive methods that result in a failure rate of < 1% per year 
during the treatment period and for at least 30 days after the last dose of venetoclax or 
18 months after the last dose of obinutuzumab, whichever is longer 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Examples of contraceptive methods with a failure rate of < 1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral 
or injected hormonal contraceptives, and certain intrauterine devices.  Alternatively, two 
methods (e.g., two barrier methods such as a condom and a cervical cap) may be 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
18/Protocol BO25323, Version 7 
combined to achieve a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide. 
• 
For men:  agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of < 1% per year during the treatment period and 
for at least 90 days after the last dose of venetoclax or 18 months after the last dose of 
obinutuzumab, whichever is longer, and agreement to refrain from donating sperm during 
the treatment period and for at least 90 days after the last dose of venetoclax 
Men with a pregnant partner must agree to remain abstinent or use a condom for the 
duration of the pregnancy. 
• 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
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) (Richter’s 
transformation or pro-lymphocytic leukemia) 
• 
Known central nervous system involvement 
• 
Patients with a history of confirmed progressive multifocal leukoencephalopathy 
• 
An individual organ/system impairment score of 4 as assessed by the CIRS definition 
limiting the ability to receive the treatment regimen of this trial with the exception of eyes, 
ears, nose, throat organ system (note that symptoms related to CLL should not be included 
in the patient’s screening CIRS score).  Investigators should consult the General Rules for 
Severity Rating as well as the Organ-Specific Categories when assigning scores for certain 
conditions (i.e., pulmonary embolism) and consider the level of morbidity associated with a 
patient’s condition. 
• 
Patients with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
• 
Inadequate renal function:  CrCl < 30 mL/min 
• 
History of prior malignancy, except for conditions as listed below if patients have recovered 
from the acute side effects incurred as a result of previous therapy: 
Malignancies surgically treated with curative intent and with no known active disease 
present for ≥ 3 years before randomization 
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease 
Adequately treated cervical carcinoma in situ without evidence of disease 
Surgically/adequately treated low grade, early stage, localized prostate cancer without 
evidence of disease 
• 
Patients with active infections requiring IV treatment (Grade 3 or 4) within the last 2 months 
prior to enrollment 
• 
History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies or known sensitivity or allergy to murine products 
• 
Hypersensitivity to chlorambucil, obinutuzumab, or venetoclax or to any of the excipients 
(e.g., trehalose) 
• 
Pregnant women and nursing mothers  
• 
Vaccination with a live vaccine ≤ 28 days prior to randomization 
• 
Prisoners or patients who are institutionalized by regulatory or court order or persons who 
are in dependence to the Sponsor or an investigator 
• 
History of illicit drug or alcohol abuse within 12 months prior to screening, in the 
investigator’s judgment 

 
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• 
Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
hepatitis B surface antigen [HBsAg] serology) 
Patients with occult or prior HBV infection (defined as negative HBsAg and positive total 
hepatitis B core antibody [HBcAb]) may be included if HBV DNA is undetectable, 
provided that they are willing to undergo monthly DNA testing.  Patients who have 
protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but 
cured hepatitis B are eligible. 
• 
Positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing) 
Patients who are positive for HCV antibody are eligible only if PCR is negative for HCV 
RNA. 
• 
Patients with known infection with human immunodeficiency virus (HIV) or Human T-Cell 
Leukemia Virus 1 (HTLV-1) 
In countries where mandatory testing by health authorities is required, HIV testing will 
be performed. 
HTLV testing is required in patients from endemic countries (Japan, countries in the 
Caribbean basin, South America, Central America, sub-Saharan Africa, and Melanesia). 
• 
Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study 
• 
Patients who have received: 
Strong and moderate CYP3A inhibitors within 7 days prior to the first dose of study drug 
administration 
Strong and moderate CYP3A inducers within 7 days prior to the first dose of study drug 
administration 
Consumed grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges), or star fruit within 3 days prior to the first dose of study drug 
and throughout venetoclax administration 
• 
Inability to swallow a large number of tablets 
 
Length of Study 
The approximate length of study will be 6 years and 8 months calculated from an estimated 
20-month recruitment period, and the end of study is defined below. 
End of Study 
The end of this study is defined as 5 years from last patient enrolled (unless all patients have 
died). 
Outcome Measures 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 
• 
PFS, defined as the time from randomization to the first occurrence of progression, relapse, 
or death from any cause as assessed by the investigator.  Disease progression will be 
assessed by the investigators using the IWCLL criteria (2008). 
 
The secondary efficacy outcome measures for this study are as follows: 
• 
PFS based on Independent Review Committee (IRC)-assessments (primary outcome for 
U.S. regulatory purposes), defined as the time from randomization to the first occurrence of 
progression or relapse or death from any cause 
• 
Overall response rate (ORR; defined as rate of a clinical response of complete response 
[CR], complete response with incomplete bone marrow recovery [CRi], or PR) at the 
completion of treatment assessment, as determined by the investigator according to the 
IWCLL guidelines (2008) 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
20/Protocol BO25323, Version 7 
• 
Complete response rate (CRR; defined as rate of a clinical response of CR or CRi) at the 
completion of treatment assessment, as determined by the investigator according to the 
2008 IWCLL guidelines 
• 
MRD response rate (determined as the proportion of patients with MRD-negativity) 
measured in the peripheral blood at the completion of treatment assessment and MRD 
response rate as measured in the bone marrow at the completion of treatment, both 
measured by ASO-PCR 
• 
ORR at completion of combination treatment response assessment (Cycle 7, Day 1 or 
28 days after last intravenous [IV] infusion) 
• 
MRD response rates in the peripheral blood at completion of combination treatment 
assessment (Cycle 9, Day 1 or 3 months after last IV infusion) and also MRD response rate 
in the bone marrow, both as measured by ASO-PCR 
 
Note:  the secondary endpoint analyses will be on the basis of MRD assessment performed 
centrally by ASO-PCR with MRD negativity defined using a cutoff of 10-4 (less than 1 cell in 
10,000 leukocytes).  As well as evaluating MRD response rate, it will further be evaluated using 
results of both measures, where a patient will be considered MRD-positive if either blood or 
bone marrow result is positive or both are missing.  MRD response rates at other timepoints 
during treatment and follow-up where MRD is measured in the peripheral blood will also be 
summarized. 
• 
Overall survival (OS), defined as the time between the date of randomization and the date 
of death due to any cause 
• 
Duration of objective response, defined as the time from the first occurrence of a 
documented objective response to the time of progressive disease (PD) as determined by 
the investigator or death from any cause 
• 
Best response achieved (CR, CRi, partial response [PR], stable disease, or PD) up to and 
including the assessment at completion of treatment assessment (within 3 months of last 
day of treatment) 
• 
Event-free survival, defined as the time between date of randomization and the date of 
disease progression/relapse on the basis of investigator-assessment, death, or start of a 
new anti-leukemic therapy 
• 
Time to next anti-leukemic treatment, defined as time between the date of randomization 
and the date of first intake of new anti-leukemic therapy 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Nature, frequency, and severity of adverse events and serious adverse events  
• 
Changes in vital signs, physical findings, and clinical laboratory results during and following 
study treatment 
• 
Lymphocyte immunophenotyping and incidence of human−anti-human antibodies  
• 
Premature withdrawals 
 
Pharmacodynamic Outcome Measures 
For each visit at which CD19 + CD5 + and CD19 + CD5 − B-cell measurements are taken, 
B-cell data will be listed for individual patients by treatment arm. 
Pharmacokinetic Outcome Measures 
The PK outcome measure for this study is as follows: 
• 
Apparent clearance, apparent volume of distribution, and/or other appropriate 
PK parameters of venetoclax and of obinutuzumab characterized with the use of popPK 
techniques.  Standard NCA/descriptive TLGs and popPK approaches will be considered. 

 
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21/Protocol BO25323, Version 7 
Patient-Reported Outcome Measures 
The PRO measures for this study are as described below.  The first assessment will be done 
during the first obinutuzumab infusion, and PROs will be followed until end of study as defined 
by 5 years after last randomized patient: 
• 
To evaluate changes following treatment in disease and treatment-related symptoms in 
MDASI-CLL scores. 
• 
To evaluate changes in role functioning and global health status/QoL scales following 
treatment with the EORTC QLQ-C30.  
 
Health Economic Outcome Measures 
The health economic outcome measure for this study is as follows: 
• 
The EQ-5D-3L questionnaire 
 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows (provided these data are 
available in a sufficiently timely and complete form to perform these analyses at the time of the 
final primary analysis): 
• 
MRD negativity in peripheral blood measured using new technologies, including flow 
cytometry and next-generation sequencing with MRD negativity defined using a cutoff of  
10-4 (less than 1 cell in 10,000 leukocytes) for comparison with ASO-PCR, and secondly by 
the limit of sensitivity of each of the above technologies. 
• 
Relationship between MRD and PFS on the basis of peripheral blood assessed using 
ASO-PCR 
• 
Relationship between various baseline markers and clinical outcome parameters in patients 
from both arms of the study (including but not limited to CLL fluorescence in-situ 
hybridization [FISH; 17p-, 11q-, 13p-,  + 12q], immunoglobulin heavy chain variable [IGHV] 
mutation status, p53 mutation status, serum parameters, Bcl-2 expression and other CLL 
disease markers) 
 
Investigational Medicinal Products 
All investigational medicinal products (IMPs) required for completion of this study (chlorambucil, 
obinutuzumab, and venetoclax) will be provided by the Sponsor where required by local health 
authority regulations.  The study site will acknowledge receipt of IMPs and confirm the shipment 
condition and content.  Any damaged shipments will be replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate documentation.  
The site's method of IMP destruction must be agreed to by the Sponsor.  The site must obtain 
written authorization from the Sponsor 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. 
Venetoclax 
Venetoclax, a highly selective, orally bioavailable, small-molecule Bcl-2 family inhibitor in the 
biarylacylsulfonamide chemical class, will be administered as an oral tablet.  Patients will 
receive venetoclax as follows: 
• 
20 mg daily during Cycle 1, Days 22−28 
• 
50 mg daily during Cycle 2, Days 1−7 
• 
100 mg daily during Cycle 2, Days 8−14 
• 
200 mg daily during Cycle 2, Days 15−21 
• 
400 mg daily during Cycle 2, Days 22−28 and on Days 1−28 for all subsequent cycles until 
the end of Cycle 12  
 

 
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Obinutuzumab 
Obinutuzumab, a novel, humanized, type II glycoengineered monoclonal antibody (mAb) 
directed against the CD20 antigen, will be administered as an IV infusion.  Patients will receive 
obinutuzumab as follows: 
• 
100 mg or 1000 mg, depending on splitting rules, at Cycle 1, Day 1 (if 100 mg was received 
on Day 1, 900 mg will be administered on Cycle 1, Day 2). 
• 
1000 mg at Cycle 1, Day 8 and Day 15 
• 
1000 mg at Day 1 for all subsequent cycles until the end of Cycle 6 
 
Chrorambucil 
Chlorambucil will be administered orally.  Patients will receive chlorambucil as follows: 
• 
0.5 mg/kg at Day 1 and Day 15 for Cycles 1−12 
 
Non-Investigational Medicinal Products 
Rasburicase 
Rasburicase (Fasturtec™ in Europe; Elitek™ in the United States) enzymatically converts uric 
acid in the blood to allantoin and hydrogen peroxide, thereby preventing the formation of uric 
acid crystals and potential renal blockage.  It reduces uric acid levels within 4 hours both in 
pediatric and adult patients, and several studies confirm its safety, effectiveness, and tolerability 
both in the prevention and treatment of TLS, although the prevention of acute renal failure fails 
in over 25% of patients. 
Note:  Rasburicase may be supplied by the Sponsor in countries where rasburicase is not 
approved or cannot be supplied locally. 
Statistical Methods 
Primary Analysis 
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 [2008]), or death from any cause, whichever occurs first.  Progression-free 
survival on the basis of IRC assessments will be considered primary for U.S. regulatory 
purposes (details will be provided in the Statistical Analysis Plan [SAP]).  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.  All patients, including patients who 
discontinue all components of study therapy prior to disease progression (e.g., for toxicity), will 
continue in the study and will be followed for progressive disease and survival regardless of 
whether or not they subsequently receive new anti-leukemic therapy. 
The primary objective of the study is to test the following hypothesis: 
• 
Progression-free survival of obinutuzumab + venetoclax versus GClb (i.e., 
H0:  obinutuzumab + venetoclax = GClb versus H1:  obinutuzumab + venetoclax ≠ GClb) 
 
Treatment comparisons will be made using a two-sided log-rank test (at 0.05 significance-level, 
adjusted for the interim analyses), stratified by Binet stage.  If the null hypothesis is rejected and 
the observed HR is favorable for the obinutuzumab + venetoclax experimental arm, then it is 
concluded that obinutuzumab + venetoclax significantly lowers the risk of PFS events more than 
GClb.  A two-sided non-stratified log-rank test will be performed to support the primary analysis.  
Median PFS and the 95% confidence limits will be estimated using Kaplan-Meier survival 
methodology, with the Kaplan-Meier survival curve presented to provide a visual description.  
PFS rates for 1, 2, and 3 years after randomization with 95% CIs will be reported.  Estimates of 
the treatment effect will be expressed as HR including 95% confidence limits estimated through 
a Cox proportional-hazards analysis stratified by Binet stage.  Primary analysis for U.S. Food 
and Drug Administration (FDA) submission will be based on assessment of PFS by an IRC. 

 
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Determination of Sample Size   
The sample size for the study is determined given the requirements to perform a hypothesis test 
for clinically relevant statistical superiority in the primary endpoint of PFS. 
Estimates of the number of events required to demonstrate efficacy with regard to PFS are 
based on the following assumptions: 
• 
Log-rank test at the two-sided 0.05 level of significance 
• 
Median PFS for obinutuzumab and chlorambucil control arm (27 months) 
• 
80% power to detect HR = 0.65 for the comparison of obinutuzumab + venetoclax 
experimental arm versus GClb,  with median PFS for obinutuzumab + venetoclax increased 
to 41.5 months  
• 
Exponential distribution of PFS 
• 
Annual drop-out rate of 10% 
• 
One interim analysis for efficacy after 75% of PFS events, utilizing a stopping boundary 
according to the γ family error spending function with parameter γ =  −9.21. 
 
The addition of an optional early analysis requires no adjustment to the sample size, as the 
impact on the statistical power calculation is negligible.   
Based on these assumptions, a total of 170 PFS events are required for the final analysis of 
PFS.   
The minimum detectable difference at the final analysis corresponds approximately to an 
HR = 0.74. 
The sample size calculation was performed using EAST version 6.2. 
Interim Analyses 
In addition to the periodic safety data reviews, the iDMC will evaluate efficacy and safety at up 
to two formal interim analyses of PFS and recommend if the study should be stopped early for 
efficacy.  
Summaries and analyses will be prepared by an independent data coordinating center and 
presented by treatment arm for the iDMC's review.  
An interim efficacy analysis may be conducted at or after 1 year after the last patient’s last 
venetoclax dose (i.e., Month 37 of the study [August 2018]), provided that at least 85 PFS 
events (50% of the total of 170 PFS events) have occurred.  If 85 PFS events have not been 
observed by 1 year after the last patient’s last venetoclax dose, then the interim analysis will 
be conducted once a minimum of 85 PFS events have occurred.  PFS will be tested at the 
significance level determined using the gamma family error spending function with parameter 
γ=−21.12 so that the overall two-sided type I error rate will be maintained at the 0.05 level.  
This gamma family boundary only allows the study to stop for efficacy if a treatment effect 
HR of 0.35 or better is observed when the interim analysis is based on 85 events. 
Because this option is added to mitigate a potential delay in the study read-out, the Sponsor’s 
decision to conduct this interim analysis will be based on a number of factors including, but 
not limited to, the number of events observed by 1 year after the last patient’s last venetoclax 
dose and the subsequent predicted time to reach 110 events.  If the Sponsor does not conduct 
this interim analysis or if this interim analysis is conducted and is negative, then the Sponsor 
will proceed with the later original interim analysis as follows. 
Provided the above early interim analysis is not done or not passed, the original interim 
analysis for efficacy will be performed once a minimum of 110 PFS events have occurred.  PFS 
will be tested at the significance level determined using the gamma family error spending 
function with parameter γ=−9.21 so that the overall two-sided type I error rate will be maintained 
at the 0.05 level.  If the early interim analysis (at a minimum of 85 events) is performed and is 
passed, the later original interim analysis will not be undertaken. 
The final analysis will be performed after 170 events have occurred. The significance level will 
be adjusted to incorporate the α spent at either interim analysis, so that the overall two-sided 
type I error rate will be maintained at the 0.05 level. 

 
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Abbreviation 
Definition 
ALL 
acute lymphoblastic lymphoma 
AML 
acute myeloid leukemia 
ALC 
absolute lymphocyte count 
ANC 
absolute neutrophil count 
ASO-PCR 
allele-specific oligonucleotide polymerase chain reaction 
CIRS 
Cumulative Illness Rating Scale 
CLL 
chronic lymphocytic leukemia 
CR 
complete response 
CrCl 
creatinine clearance 
CRi 
complete response with incomplete bone marrow recovery 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
diffuse large B-cell lymphoma 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
EFS 
event-free survival 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 
EQ-5D-3L 
EuroQol 5-Dimension questionnaire 
FC 
fludarabine+ cyclophosphamide 
FCR 
fludarabine + cyclophosphamide + rituximab 
FDA 
U.S. Food and Drug Administration 
FFPE 
formalin-fixed paraffin embedded 
FISH 
fluorescence in-situ hybridization 
FL 
follicular lymphoma 
GClb 
obinutuzumab + chlorambucil 
GCLLSG 
German Chronic Lymphocytic Leukaemia Study Group 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HR 
hazard ratio 
HSC 
hematopoietic stem cell 

 
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Abbreviation 
Definition 
IADL 
instrumental activities of daily living 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee 
IGHV 
immunoglobulin heavy chain variable 
IHC 
immunohistochemsitry 
INR 
international normalized ratio 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IV 
intravenous 
IxRS 
interactive voice-/web-based system 
JCV 
John Cunningham Virus 
LDT 
lymphocyte doubling time 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MDASI-CLL 
M.D. Anderson Symptom Assessment InventoryChronic 
Lymphocytic Leukemia 
MCL 
mantle cell lymphoma 
MM 
multiple myeloma 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
NCA 
non-compartmental analysis 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NHL 
non-Hodgkin’s lymphoma 
NLT 
new leukemia treatment 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
popPK 
population pharmacokinetic 
PR 
partial response 

 
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Abbreviation 
Definition 
PRO 
patient-reported outcome 
PS 
performance status 
PVC 
polyvinyl chloride 
QoL 
quality of life 
QTcF 
Corrected (Fridericia’s correction) QTc interval 
RClb 
rituximab + chlorambucil 
RCR 
Roche Clinical Repository 
SAP 
Statistical Analysis Plan 
SLL 
small lymphocytic lymphoma 
SmPC 
summary of product characteristics 
SNP 
single nucleotide polymorphism 
TLG 
table, listing, and graph 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON CHRONIC LYMPHOCYTIC LEUKEMIA  
With an age-adjusted incidence of 4.1/100,000 inhabitants in the United States, chronic 
lymphocytic leukemia (CLL) is the most common type of leukemia in western countries.  
More than 15,000 newly diagnosed cases and 4,500 deaths are currently estimated 
annually (Jemal et al. 2007; National Cancer Institute 2010).  The median age at 
diagnosis is between 67 and 72 years (Molica 2006).  More male than female patients 
(1.7:1) are affected (Molica 2006; Morton et al. 2006; Watson et al. 2008).  Because the 
incidence rate increases with age, the prevalence and mortality of CLL are likely to 
increase over the next decades because of the demographic changes associated with 
an aging population.  Moreover, the proportion of younger patients with early-stage CLL 
and minimal symptoms seems to increase because of more frequent blood testing 
(Mauro et al. 1999).  CLL is characterized by clonal proliferation and accumulation of 
mature, typically CD5-positive, B cells within the blood, bone marrow, lymph nodes, and 
spleen (Rozman et al. 1995).  It has recently been reported that in CLL, the capacity to 
generate clonal B cells might be acquired at the hematopoietic stem cell (HSC) stage 
(Kikushige et al. 2011), suggesting that the primary leukemogenic event in CLL might 
involve multipotent, self-renewing HSCs.  The leukemic transformation is initiated by 
specific genetic alterations that cause the deletion of specific micro-RNA genes and 
increase the resistance of B cells toward apoptosis (Calin et al. 2002).  Deletions on the 
long arm of chromosome 13, specifically involving band 13q14 (del(13q14)), represent 
the single most frequently observed cytogenetic aberration in CLL, occurring in 
approximately 55% of all cases.  An isolated del(13q14) is typically characterized by a 
benign course of the disease.  Deletions of the long arm of chromosome 11 (del(11q)) 
can be found in approximately 25% of chemotherapy-naive patients with advanced 
disease stages and in 10% of patients with early-stage disease (Zenz et al. 2010a; 
Quesada et al. 2011).  Some of the poor prognostic features of del(11q) seem to be 
overcome by the use of chemoimmunotherapy (Hallek et al. 2010). 
Deletions of the short arm of chromosome 17 (del(17p)) are found in 5%−8% of 
chemotherapy-naive patients.  These deletions almost always include band 17p13, 
where the prominent tumor suppressor gene TP53 is located.  Patients with CLL who 
carry a del(17p) clone show marked resistance against genotoxic chemotherapies that 
cannot be overcome by the addition of anti-CD20 antibodies in the context of state-of-the 
art chemoimmunotherapy (Hallek et al. 2010).  Mutations of TP53 are found in 4%−37% 
of patients with CLL and have been associated with poor prognosis (ultra-high risk) in a 
number of studies (Zenz et al. 2010b). 
The recently reported whole genome sequencing projects in CLL have revealed a 
number of recurrent somatic gene mutations that occur in parallel to the above 
mentioned structural genomic aberrations.  These include the genes NOTCH1, MYD88, 
TP53, ATM, SF3B1, FBXW7, POT1, CHD2, and others (Puente et al. 2011; 
Quesada et al. 2011).   

 
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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) updated guidelines for diagnosis and 
treatment of CLL (Hallek et al. 2008; see Appendix 12). 
During the past 10 years, the combination of fludarabine + cyclophosphamide + rituximab 
(FCR) has become the standard front-line treatment for most of the physically fit patients 
with CLL.  The German Chronic Lymphocytic Leukaemia Study Group (GCLLSG) 
performed a randomized trial, Study CLL8/ML17102, that compared FCR with 
fludarabine + cyclophosphamide (FC) chemotherapy.  FCR produced an overall 
response rate (ORR) of 95%; the complete response (CR) rate seen with FCR was 
double that seen with FC alone (44% vs. 22%).  A recent update showed that the 
median progression-free survival (PFS) with FCR is 5 years, and this was the first trial to 
show a survival advantage for a front-line regimen in treatment of CLL 
(Hallek et al. 2010). 
However, for a large subgroup of elderly patients with coexisting conditions and elderly 
patients with CLL, FCR is not a suitable treatment.  Therefore, a large, randomized 
Phase III trial CLL11/BO21004 was conducted which investigated first-line 
chemoimmunotherapy in patients with CLL with coexisting medical conditions 
(i.e., patients typically treated in daily practice) (Chiorazzi et al. 2005).  In the final Stage 
2 analysis with efficacy and safety, results of the head-to-head comparison between 
obinutuzumab + chlorambucil (GClb) and rituximab + chlorambucil (RClb) were evaluated. 
In the GClb versus RClb arm, the ORR was 78% versus 65%, and CR was 21% versus 
7%, respectively.  The number of patients with minimal residual disease (MRD)-negative 
blood samples at end of treatment was more than 10-fold higher with GClb compared 
with RClb (63 of 214 patients [29.4%] versus 6 of 243 patients [2.5%]).  Grade 3−4 
infusion-related reaction (IRR) with GClb occurred at first infusion only.  Treatment with 
GClb, as compared with RClb, resulted in prolongation of PFS (hazard ratio [HR] = 0.39; 
95% confidence interval [CI]:  0.31, 0.49; p < 0.001).  Median PFS was 26.7 months with 
GClb and 16.3 months with RClb (Goede et al. 2014). 
It can be concluded that GClb demonstrates statistically significant and clinically 
meaningful prolongation of PFS and a higher CR rate and MRD response rate compared 
with RClb in previously untreated patients with CLL and coexisting medical conditions.  
IRRs, thrombocytopenia, and neutropenia were more common with GClb without an 
increase in infections or deaths due to adverse events.  Furthermore, GClb versus 
chlorambucil alone demonstrated a significant prolongation of overall survival (OS).  
Overall, GClb is superior to RClb and a highly active treatment in this typical CLL−patient 
population.  

 
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1.2 
BACKGROUND ON VENETOCLAX (GDC-0199) 
Venetoclax (also known as GDC-0199 or ABT-199) is a highly selective, orally 
bioavailable, small-molecule Bcl-2 family inhibitor in the biarylacylsulfonamide chemical 
class.  Venetoclax binds with high affinity (Ki < 0.010 nM) to anti-apoptotic protein Bcl-2 
and with lower affinity to other anti-apoptotic Bcl-2 family proteins, including Bcl-XL and 
Bcl-w (> 4000-fold and > 2000-fold to > 20,000-fold lower affinity than to Bcl-2, 
respectively) (Souers et al. 2013). 
Anti-apoptotic Bcl-2 family members are associated with tumor initiation, disease 
progression, and chemotherapy resistance (Fesik 2005), as well as autoimmunity 
(Mérino et al. 2009).  Overexpression of Bcl-2 is a major contributor to the pathogenesis 
of some lymphoid malignancies; antagonism of the action of these proteins may 
enhance response to therapy and overcome resistance, and, thus, these proteins are 
compelling targets for anti-tumor therapy.  In vitro, venetoclax demonstrated cell killing 
activity against patient-derived CLL cells and acute myeloid leukemia (AML) cells and a 
variety of lymphoma and leukemia cell lines, including B-cell follicular lymphoma (FL), 
mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple 
myeloma (MM) (Venetoclax Investigator’s Brochure, 2014).  Venetoclax was especially 
potent against cell lines expressing high levels of Bcl-2.  Venetoclax inhibits 
subcutaneous xenograft growth of human tumor cell lines derived from acute 
lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), and AML and is highly 
efficacious when using various doses and combined with other regimens.  The drug is 
also active in a model of disseminated ALL.  Venetoclax enhanced the activity of a broad 
variety of chemotherapeutic agents in other human hematological models 
(Venetoclax Investigators Brochure, 2014).  Specifically, venetoclax enhances the 
efficacy of obinutuzumab and rituximab in models of MCL and DLBCL (Venetoclax 
/Obinutuzumab Investigators Brochure, 2014).  Furthermore, venetoclax demonstrated 
potential to enhance the efficacy of bortezomib in a transgenic murine lymphoma model 
(Vandenberg and Cory 2013) and shows single agent efficacy in a human model of 
multiple myeloma (Touzeau et al. 2014). 
See the Investigator’s Brochure for additional details on nonclinical and clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Efficacy 
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.  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 because of age or coexisting medical conditions.  As a result, a cure 
for patients with CLL necessitates more effective drugs that also have a safety profile 
suited for patients who are unfit and patients who are elderly.  A chemotherapy-free 
regimen could meet these expectations. 

 
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Preliminary data from ongoing clinical studies with venetoclax demonstrate its high 
activity in patients with CLL.  Preliminary efficacy results were available for patients with 
CLL/small lymphocytic lymphoma (SLL) in Studies M12-175 (Arm A) and M13-365 as of 
09 April 2014 and 17 January 2014, respectively. 
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
In Arm A of the Phase I Study M12-175 (relapsed/refractory CLL/SLL treated with 
venetoclax monotherapy), the ORR, consisting of CR/CR with incomplete bone marrow 
recovery (CRi) plus partial response (PR), was 77% (60 of 78 evaluable patients) with 
CR/CRi in 18 patients (23%) and PR in 42 patients (54%).  The ORR was 75% in the 
24 patients with unmutated immunoglobulin heavy chain variable region (IGHV) status 
with 29% achieving CR/Cri (Venetoclax Investigator’s Brochure, 2014). 
The ORR was 79% in the 19 patients harboring the deletion of the p13 locus on 
chromosome 17 with 26% achieving CR/CRi.  The ORR was 76% in the 41 patients who 
were fludarabine-refractory with 9 of 41 patients (22%) achieving CR/CRi.  In 
Study M13-365 (relapsed CLL treated with venetoclax + rituximab), the ORR was 78% 
(14 of 18 evaluable patients) with 7 of 18 patients (39%) achieving CR/CRi and 7 of 
18 patients (39%) achieving PR. 
1.3.2 
Safety 
Known and potential risks associated with venetoclax administration include tumor lysis 
syndrome (TLS), hematological effects (including lymphopenia, neutropenia/febrile 
neutropenia, thrombocytopenia and anemia/hemoglobin decreased), serious and/or 
opportunistic infections, nausea, and diarrhea.  
Clinical evaluations of the risks identified from previous preclinical studies (single-cell 
necrosis, allergic reactions, liver enzyme elevations, and hair color change) did not 
reveal any clinically significant concerns, and, thus, routine surveillance is recommended 
in ongoing studies.  Clinical evaluation of adverse events that could potentially be 
associated with decreased left ventricular ejection fraction (LVEF) and evaluation of 
available pre- and post-dose LVEF data showed no risk of decreased LVEF following 
venetoclax dosing.  Because study populations in venetoclax oncology studies are likely 
to be elderly and have received multiple prior chemotherapeutic agents, baseline LVEF 
assessments are recommended per the investigator’s discretion. 
Principal risks identified for the combination regimen of obinutuzumab with venetoclax 
include:  TLS, IRRs to obinutuzumab, cytopenia (i.e., neutropenia and thrombocytopenia 
especially during the first cycle of obinutuzumab, or lymphopenia), infections, transient 
transaminitis, and other malignancies. 
However, toxicities expected to be associated with the combined treatment of 
obinutuzumab and venetoclax can largely be managed (e.g., first dose TLS and IRRs), 

 
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or are commonly encountered with the treatment of CLL and can be mitigated with the 
measures outlined in this protocol. 
The protocol includes the following features to address these risks: 
• 
TLS appears to be an adverse event that can be mitigated by starting therapy with 
venetoclax at the low dose of 20 mg, by slow dose ramp-up, and by appropriate 
preventive measures.  Measures to prevent TLS include prophylactic hydration and 
medication prior to initial dosing with careful monitoring during the first 24 hours 
after dosing for metabolic or clinical signs of impending TLS (Section 5.1.1.1). 
• 
Staggered dosing of venetoclax initiated on Day 22 during the first cycle of 
chemoimmunotherapy 
• 
Prophylactic medication (Section 5.1.1.3) will be administered, and careful 
monitoring guidelines will be used to manage IRRs to obinutuzumab. 
• 
Frequent blood testing throughout the treatment period to monitor for cytopenia 
• 
Dose delays or dose reductions are mandated for severe cytopenia.  In addition, all 
supportive measures, including transfusion, antibiotics, and the use of growth 
factors are allowed. 
• 
Neutropenia will be closely monitored and may be treated with growth factors, and 
any signs of infection will be treated with appropriate medication. 
Note:  Anti-infection prophylaxis is not mandated for all patients because of the 
potential risks of adding additional concomitant medications but may be 
prescribed by the investigator in specific cases where patients are at especially 
high risk.  Patients with pre-existing infections and past hepatitis are excluded 
from the study to avoid reactivation.  
• 
Incidences of prolonged neutropenia are of concern and will be monitored carefully. 
• 
Guidelines to use with caution or avoid concomitant medications are provided in 
view of the possible drug−drug interactions (see Appendix 5). 
 
1.3.3 
Rationale for the Combination of Venetoclax with 
Obinutuzumab 
Obinutuzumab (Gazyva™ also known as GA101 and RO5072759) is a novel, 
humanized, type II glycoengineered monoclonal antibody (mAb) directed against the 
CD20 antigen, which is found on most malignant and benign cells of B-cell origin.  
Obinutuzumab was derived by humanization of the parental B Ly1 mouse antibody and 
subsequent glycoengineering, leading to the following characteristics:  high-affinity 
binding to the CD20 antigen, low complement-dependent cytotoxicity activity, high direct 
cell death induction, high antibody-dependent cellular cytotoxicity, and 
antibody-dependent cellular phagocytosis. 
Obinutuzumab was approved on 1 November 2013 by the U.S. Food and Drug 
Administration (FDA) for the treatment of patients with previously untreated CLL on the 
basis of the primary analysis of data from the pivotal study, BO21004/CLL11 

 
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(Goede et al. 2014).  On 22 May 2014, the European Medicines Agency (EMA) adopted 
a positive opinion recommending a marketing authorization for obinutuzumab for the 
treatment, in combination with chlorambucil, of adult patients with previously untreated 
CLL with coexisting medical conditions that made them unsuitable for full-dose 
fludarabine based therapy. 
1.3.4 
Benefit-Risk Assessment 
It is anticipated that because obinutuzumab and venetoclax exhibit different mechanisms 
of action, a combination of both drugs could improve tumor response and delay 
progression of disease or completely avoid the occurrence of resistance.  Safety profiles 
of both drugs seem to be compatible, especially in light of a chemotherapy-free setting.  
The run-in phase of the study will provide initial safety data on the combination of 
obinutuzumab and venetoclax.  The head-to-head design of the study, precautionary 
safety measures, and regular monitoring of safety by an independent Data Monitoring 
Committee (iDMC) and the sponsor enable early identification of safety signals in the 
study and minimize the risk to patients enrolled.  In conclusion, it is considered that the 
benefit-risk ratio for this study is favorable. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary objective of Study BO25323/CLL14 is as follows: 
• 
To determine efficacy by investigator-assessed PFS of a combined regimen of 
obinutuzumab + venetoclax compared with GClb in previously untreated patients 
with CLL who have coexisting medical conditions 
 
The secondary efficacy objective of the study is as follows: 
• 
To determine efficacy as assessed by additional outcome measures (as specified in 
Section 3.4.2, including PFS assessed by Independent Review Committee [IRC], 
overall response, complete response, and MRD response rate as measured by 
allele-specific oligonucleotide polymerase chain reaction [ASO-PCR] (see 
secondary safety objective in Section 2.2) 
 
Note:  IRC-assessed PFS will be considered primary for United States regulatory 
purposes. 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is as follows: 
• 
To evaluate the safety of the combination of obinutuzumab and venetoclax, 
compared with GClb, in patients with previously untreated CLL and coexisting 
medical conditions, focusing on the nature, frequency, and severity of Grade 3 and 
4 adverse events and of serious adverse events 
 

 
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2.3 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective for this study is as follows: 
• 
To characterize the pharmacokinetics of venetoclax and of obinutuzumab (including 
population PK [popPK] techniques).  Standard NCA/descriptive TLGs and popPK 
approaches will be considered. 
 
2.4 
PATIENT-REPORTED OUTCOME OBJECTIVES  
The quality of life (patient-reported outcome [PRO]) objectives for this study are as 
follows: 
• 
To compare disease and treatment-related symptoms following treatment with the 
combination of obinutuzumab + venetoclax compared with GClb in patients with 
previously untreated CLL and coexisting medical conditions as measured by M.D. 
Anderson Symptom Inventory (MDASI-CLL; see Appendix 18) 
• 
To evaluate changes in role functioning and global health status/quality of life (QoL) 
following treatment with the combination of obinutuzumab + venetoclax compared 
with GClb in patients with previously untreated CLL and coexisting medical 
conditions between arms as measured by European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) 
 
2.5 
HEALTH ECONOMIC OBJECTIVE 
The health economic objective for this study should be considered as a special PRO and 
is as follows: 
• 
To compare the health utility effects of treatment with combination of obinutuzumab 
and venetoclax compared with GClb in patients with previously untreated CLL and 
coexisting medical conditions measured by the EuroQol 5 Dimension questionnaire 
(EQ-5D-3L)  
 
2.6 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To assess MRD using new technologies, including flow cytometry and 
next-generation sequencing, to compare results with MRD measured by ASO-PCR 
• 
To evaluate the relationship between PFS and MRD response rate 
• 
To evaluate the relationship between various baseline prognostic markers and 
clinical outcome parameters  
• 
To evaluate the relationship between biomarkers measured at baseline and disease 
progression to understand mechanisms of response and resistance 
 

 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is an open-label, multicenter, randomized Phase III trial to compare the efficacy and 
safety of a combined regimen of obinutuzumab and venetoclax versus GClb in patients 
with CLL and coexisting medical conditions.  Figure 1 illustrates the design of the study.  
Initially, there will be a 12-patient safety run-in phase, (including at least 1 patient at high 
risk of developing TLS) wherein patients will receive obinutuzumab + venetoclax in a 
non-randomized fashion.  After the twelfth patient has reached the end of Cycle 3, a 
formal review will be undertaken by Roche and the German CLL Study Group 
([GCLLSG]; together, hereafter referred to as the Sponsor) and an iDMC. 
The following are stopping criteria for the run-in phase of this study:   
• 
One treatment-related death 
or 
• 
One Grade 4 adverse event related to a clinical TLS despite protocol-specified 
prophylaxis, either following the administration of the first dose of venetoclax or 
during dose escalation 
 
If any of these criteria are met, the main study will not be opened for recruitment, and the 
Sponsor will then re-evaluate the study design and amend the protocol accordingly.  If 
the stopping criteria are not met, randomization into the trial will commence.   
Figure 1 Study Schema 
 
GDC-0199 = venetoclax; PFS = progression-free survival. 
 
3.1.1 
Assessment of Efficacy 
Response will be assessed according to the 2008 International Workshop on Chronic 
Lymphocytic Leukemia (IWCLL) guidelines.  An IRC that is blinded to treatment groups 
will assess all patients for progression on the basis of peripheral blood counts, bone 

 
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marrow biopsy results, and reports of physical examination.  Computed tomography (CT) 
scan reports from pre- and post-treatment will be provided to the IRC to support the 
evaluation. 
3.1.2 
Summary of Study Procedures 
Written informed consent will be obtained before any study specific procedures are 
undertaken. 
3.1.2.1 
Screening/Baseline Tests  
All screening assessments documented in the schedule of assessments will be 
performed a maximum of 28 days prior to either starting obinutuzumab + venetoclax, the 
safety run-in phase, or to randomization into the main study (Appendix 2 and 
Appendix 3).  Those patients who fail screening based on no immediate requirement for 
treatment can be rescreened in the future when their CLL is in need of treatment.  
Similarly, potential patients who fail screening because of recent infection (patients with 
infections requiring IV treatment [Grade 3 or 4] within the last 2 months prior to 
enrollment) may be rescreened once their infections resolve (see Section 4.1.2). 
Randomization will be performed by an interactive voice-/web-based system (IxRS).  
Patients will be assigned to the two treatment arms via a 1:1 randomization procedure.  
Patients will be stratified by Binet stage and by country/region.  Baseline tests will be 
used to assess the Binet Stage.  If a patient’s Binet stage progresses between screening 
and randomization, then the Binet stage at the screening timepoint should be used for 
stratification. 

 
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3.1.2.2 
Treatment Period  
Table 1 
Treatment Arm A:  Obinutuzumab + Venetoclax Study Visits 
Cycle, Day 
Dose 
Obinutuzumaba 
Cycle 1, Day 1 
100 mg or 1000 mg (follow splitting rules) 
Cycle 1, Day 2 b 
900 mg (if 100 mg on Cycle 1 Day 1) 
Cycle 1, Day 8 
1000 mg 
Cycle 1, Day 15 
1000 mg 
Cycles 2−6, Day 1 
1000 mg 
Venetoclax c, d 
Cycle 1, Day 22−28 
20 mg daily 
Cycle 2, Day 1−Day 7 
50 mg daily 
Cycle 2, Day 8−Day 14 
100 mg daily 
Cycle 2, Day 15−Day 21 
200 mg daily 
Cycle 2, Day 22−Day 28 
400 mg daily 
Cycle 3, Day 1−end of Cycle 12 
400 mg daily  
IV = intravenous; TLS = tumor lysis syndrome. 
Note:  Cycles will comprise 28 days.  Treatment for obinutuzumab will be for six cycles, and 
venetoclax will end at Cycle 12. 
a IV infusion.  Overnight hospitalization may be required on Day 1 following the first infusion of 
obinutuzumab (100 mg). 
b Only the first dose (1000 mg) of obinutuzumab drug administration can be split over 2 days.  
Two infusion bags should be prepared for the infusion on Days 1 and 2 (100 mg for Day 1 and 
900 mg for Day 2).  If the first bag is completed without modifications of the infusion rate or 
interruptions, the second bag may be administered on the same day (no dose delay 
necessary, no repetition of premedication), provided that appropriate time, conditions, and 
medical supervision are available throughout the infusion.  If there are any modifications of the 
infusion rate or interruptions during the first 100 mg, the second bag should be administered 
the following day.  If patients require a delay of greater than 24 hours between the 100- and 
900-mg infusions of obinutuzumab, please consult Section 4.3.1.3 and the Obinutuzumab 
Investigator’s Brochure regarding drug stability. 
c The 20 mg and 50 mg doses of venetoclax will be administered in the hospital for patients who 
are at high risk of TLS, or if indicated to hospitalize, and thereafter at home daily for 7 days.  
The dose will increase every 7 days to the target dose of 400 mg, and venetoclax will be 
administered at home unless a patient is indicated to hospitalize. 
d Oral tablets.  
 
Guidance on patient management for TLS prophylaxis prior to and following venetoclax 
dosing is provided in Section 5.1.3.1. 
Because it is possible that de-bulking from obinutuzumab therapy before starting 
venetoclax dosing already significantly reduces the risk of TLS, TLS prophylactic 

 
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measures will be re-assessed at the time of the first safety review conducted by the 
iDMC (Section 9.4.2). 
Table 2 
Treatment Arm B:  Obinutuzumab + Chlorambucil 
Cycle, Day 
Dose 
Obinutuzumab 
Cycle 1, Day 1 a, b 
100 mg or 1000 mg (follow splitting rules) 
Cycle 1, Day 2 
900 mg (if 100 mg on Cycle 1 Day 1) 
Cycle 1, Day 8 
1000 mg 
Cycle 1, Day 15 
1000 mg 
Cycles 2−6, Day 1 
1000 mg 
Chlorambucil c 
Cycle 1−Cycle 12, Day 1 
0.5 mg/kg oral 
Cycle 1−Cycle 12, Day 15 
0.5 mg/kg oral 
Note:  Cycles will comprise 28 days.  Treatment for obinutuzumab will be for six cycles and 
12 cycles for chlorambucil. 
a Intravenous infusion.  Overnight hospitalization may be required on Day 1 following the first 
infusion of obinutuzumab (100 mg).   
b Only the first dose (1000 mg) of obinutuzumab drug administration can be split over 2 days.  
Two infusion bags should be prepared for the infusion on Days 1 and 2 (100 mg for Day 1 and 
900 mg for Day 2).  If the first bag is completed on Day 1 without modifications of the infusion 
rate or interruptions, the second bag may be administered on the same day (no dose delay 
necessary, no repetition of premedication), provided that appropriate time, conditions, and 
medical supervision are available throughout the infusion.  If there are any modifications of the 
infusion rate or interruptions during the first 100 mg, the second bag should be administered 
the following day.  If patients require a delay of greater than 24 hours between the 100- and 
900-mg infusions of obinutuzumab, please consult Section 4.3.1.3 and the Obinutuzumab 
Investigator’s Brochure regarding drug stability. 
c Chlorambucil is given orally on Days 1 and 15 at a dose of 0.5 mg/kg.  
 
From Cycle 2 (treatment arm B only) onward, the patients have the option to have the 
Day 15 hematology and biochemistry tests performed at a local laboratory.  The results 
will be communicated to the investigator, and, if satisfactory, the investigator will instruct 
the patient either to take the Day 15 chlorambucil dose at home or to return to the clinic 
for a formal visit. 
3.1.2.3 
Monitoring of Disease Progression during Treatment Period 
All patients should be continually monitored for disease progression (PD) during the 
treatment period and this should be clearly documented in the electronic Case Report 
Form (eCRF).  Interim staging assessments will be performed at Cycle 4, Day 1; Cycle 7, 
Day 1; and Cycle 9, Day 1.  In addition to an assessment of hematological status, this 
will also include a full physical examination to assess any lymphadenopathy and 
hepatomegaly/splenomegaly. 

 
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Unless disease progression is confirmed, the patient is withdrawn due to toxicity, or the 
patient has died, patients should receive up to six cycles of study treatment of 
obinutuzumab and 12 cycles of either venetoclax or chlorambucil.  
3.1.2.4 
Post-Treatment Follow-Up Visits  
All patients will be followed until 5 years after last patient randomization.  Response will 
be followed at all visits by clinical/laboratory signs and symptoms until progression is 
identified.  A CT scan should be performed 3 months after end of treatment in order to 
confirm CR and PR if lymphadenopathy was present at baseline.  In those patients who 
have achieved a CR or CRi, a bone marrow aspirate and biopsy will be obtained.  If PD 
is detected by physical examination in the absence of any objective hematological 
progression, a CT scan of the involved nodes will be performed.  After PD, patients will 
be followed until the next anti-leukemic treatment is given and then for survival for a 
maximum of 5 years from the last patient enrolled unless all patients have died.  To 
capture PROs post progression among those receiving subsequent therapies, PRO 
assessment will be made at the time of the subsequent treatment visit, but before any 
procedures or drug infusions are performed.  A schedule of assessments is provided in 
Appendix 2 and Appendix 3. 
3.2 
END OF STUDY 
The approximate length of study will be 6 years and 8 months calculated from an 
estimated 20-month recruitment period, and the end of study is defined below. 
The end of this study is defined as 5 years from last patient enrolled (unless all patients 
have died). 
3.3 
RATIONALE FOR DESIGN 
3.3.1 
Rationale for Dose and Schedule 
3.3.1.1 
Venetoclax 
Venetoclax dosing for this study was based on the experience from the Phase I 
dose-escalation Study M12-175, which examined single-agent venetoclax in relapsed 
and refractory patients with CLL and NHL, and the safety analysis of 58 patients enrolled 
in the study after enhanced TLS prophylaxis measures were introduced and who 
completed the dosing ramp-up period.  
This experience has determined that starting venetoclax at 20 mg for 1 week followed by 
a gradual ramp-up of venetoclax over the period of 5 weeks is an adequate measure in 
order to safely administer venetoclax.  The dosing regimen proved to reduce the risk for 
TLS by more gradually reducing the leukemia cell burden prior to administration of the 
full target dose with no loss of effect. 
The starting dose of venetoclax in Study M12-175 was 20 mg followed by weekly 
increases in dose levels to a maximum dose of 600 mg.  However, the dose to be used 
in combination with anti-CD20 monoclonal antibodies and other agents may be below 

 
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the maximum dose established as a single agent.  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. 
In Arm A of Study M12-175 (relapsed/refractory CLL/SLL treated with venetoclax 
monotherapy), the ORR, consisting of CR/CRi plus PR was 77% (60 of 78 evaluable 
patients) with CR/CRi in 18 patients (23%) and PR in 42 patients (54%).  The ORR was 
75% in the 24 patients with unmutated IGHV status with 29% achieving CR/CRi. 
The ORR was 79% in the 19 patients harboring the deletion of the p13 locus on 
chromosome 17 with 26% achieving CR/CRi.  The ORR was 76% in the 41 patients who 
were fludarabine-refractory with 9 of 41 patients (22%) achieving CR/CRi.  In 
Study M13-365 (relapsed CLL treated with venetoclax + rituximab), the ORR was 78% 
(14 of 18 evaluable patients) with 7 of 18 patients (39%) achieving CR/CRi and 7 of 
18 patients (39%) achieving PR (see Section 1.3.1). 
The number of cycles of dosing (combination therapy × six 28-day cycles followed by 
monotherapy for six 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. 
In the single-agent, Phase I, dose-escalation Study M12-175, responses to single-agent 
venetoclax have been seen to improve over time at the 36−50-week timepoint as 
treatment continues; therefore, the treatment duration has been determined to be 1 year.   
To date, no evidence of unexpected late toxicities has emerged from continued 
treatment with venetoclax beyond 6 months. 
3.3.1.2 
Obinutuzumab 
The approved dose of obinutuzumab for front-line treatment will be used in this study. 
• 
Cycle 1:  1000 mg Days 1 (or split dose Day 1 and Day 2), 8, and 15 (see 
Section 4.3.2 for details) 
• 
Cycles 2−6:  1000 mg on Day 1 
 
Treatment will be on a 28-day cycle, for a total of six cycles. 
Evaluation of potential PK interactions between venetoclax and obinutuzumab is 
incorporated into the PK assessment plan in an ongoing Phase Ib study (Study 
GP28331). 
3.3.1.3 
Chlorambucil 
The rationale for the chlorambucil dose and schedule are based on the findings from the 
GCLLSG CLL5 trial.  This trial demonstrated that chlorambucil is equally effective as 

 
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fludarabine monotherapy in elderly (and in the subgroup of medically unfit) patients with 
CLL.  In the GCLLSG-CLL5 trial protocol, chlorambucil was scheduled with 0.4-mg/kg 
body weight initially with a subsequent increase of the dose to a maximum of 0.8-mg/kg 
body weight.  However, there was no such dose escalation in the majority of patients, 
mostly due to adverse events, and median PFS was relatively long (17 months).  In 
clinical practice, chlorambucil may be given at higher doses than 0.5 mg/kg body weight.  
Higher doses can be achieved with a fixed starting dose or with dose escalations.  
Starting with a fixed high dose of chlorambucil (e.g., 0.8-mg/kg body weight) could be of 
risk in elderly and medically unfit patients because it will increase toxicity without 
necessarily ensuring better efficacy.  If the outcome in the different trials is compared, 
there are no convincing data that higher doses of chlorambucil are more effective than 
low-dose schedules.  Although there is no definitive conclusion that efficacy of 
chlorambucil significantly increases with duration of treatment, the majority of trials used 
up to 12 cycles of treatment.  To ensure clinical equipoise in the duration of therapy 
received in both treatment arms in the planned trial, a total of 12 cycles of chlorambucil 
therapy will be used in the control arm as well. 
3.3.2 
Rationale for the Combination of Venetoclax with 
Obinutuzumab 
Obinutuzumab is a novel, humanized, type II glycoengineered monoclonal antibody 
(mAb) directed against the CD20 antigen, which is found on most malignant and benign 
cells of B-cell origin.  Obinutuzumab was derived by humanization of the parental B Ly1 
mouse antibody and subsequent glycoengineering, leading to the following 
characteristics:  high-affinity binding to the CD20 antigen, low complement-dependent 
cytotoxicity activity, high direct cell death induction, high antibody-dependent cellular 
cytotoxicity, and antibody-dependent cellular phagocytosis. 
Because obinutuzumab and venetoclax exhibit different mechanisms of action, a 
combination of both drugs could delay or completely avoid the occurrence of resistance.  
The safety profiles of both drugs seem to be compatible, especially in light of a 
chemotherapy-free setting. 
3.3.3 
Rationale for Patient Population 
The target population for the study is patients with previously untreated CLL and 
coexisting medical conditions.  Such patients are compromised by these conditions or an 
age-related decline in organ function. 
Various scores for systematic evaluation of the coexisting medical conditions of geriatric 
oncology patients have been developed and evaluated over the last decades.  In the 
Cumulative Illness Rating Scale (CIRS) score, the number and severity of the coexisting 
medical conditions are qualitatively documented and quantified (Linn et al. 1968).  
Several studies have documented a high reliability and validity of the CIRS score 
(Miller et al. 1992; Waldman et al. 1992; Parmelee et al. 1995).  For a geriatric 
non-oncology patient population, CIRS threshold scores have been defined, which 

 
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permit differentiation of different patient groups with different risks of hospitalization and 
mortality (Keller and Potter 1994).  In geriatric patients, the CIRS score correlates with 
mortality, rate, and duration of hospitalization; need for medication; functional 
impairment; and psychological status (Miller et al. 1992; Keller and Potter 1994) as well 
as with post-mortem findings (Conwell et al. 1993).  In some more recent studies, the 
extent of coexisting conditions as determined by the CIRS score has proved to be 
prognostically relevant for the overall survival of tumor patients (Firat et al. 2002; 
Hall et al. 2002).  Two further studies also describe the distribution of CIRS scores in a 
sample of older cancer patients with different cancers (Extermann et al. 1998; 
Chen et al. 2003).  In approximately half of the patients studied, a total CIRS score of 
0−6 (i.e., no to mild coexisting medical conditions) was determined, while in the other 
half, the total CIRS score was 7−18 (i.e., moderate to high coexisting medical conditions) 
(Extermann et al. 1998).  A CIRS score of 6 or higher is reached in the presence of 
multiple coexisting medical conditions.  Patients with CLL who present with such a 
coexisting medical condition burden have been reported to have inferior outcome 
compared with patients with CLL who are not suffering from multiple conditions 
(Goede et al. 2005; Cramer et al. 2006).  A CIRS threshold of six, thus, may be a 
suitable risk discriminator in patients with CLL.  With the help of the CIRS score, the 
extent of coexisting medical conditions for a potential study patient can be assessed 
qualitatively and quantitatively with relatively little effort before the patient is admitted to 
the study.  Appendix 6 outlines CIRS criteria. 
A possible surrogate for a decline in functional organ reserve is the glomerular filtration 
rate.  This can be estimated by calculating the creatinine clearance (CrCl) using the 
Cockcroft-Gault formula (Appendix 7). 
Currently, there is limited clinical experience for venetoclax in patients with CrCl 
30−50mL/min.  Therefore, these patients should receive additional consideration by the 
investigator with regard to their management, including the decision on whether to 
administer IV hydration and to hospitalize the patient at the initial dosing as well as at 
each first dose during the ramp-up period. 
3.3.4 
Rationale for Control Group 
Obinutuzumab was approved on 1 November 2013 by the U. S. Food and Drug 
Administration (FDA) and on 22 May 2014, the European Medicines Agency (EMA) 
granted a positive opinion for the registration of obinutuzumab for the treatment in 
combination with chlorambucil, of adult patients with previously untreated CLL with 
coexisting medical conditions that make them unsuitable for full-dose fludarabine-based 
therapy, on the basis of the primary analysis of data from the pivotal study, 
BO21004/CLL11. 
The combination of chlorambucil with obinutuzumab is considered to be the 
standard-of-care in the elderly unfit patient population with coexisting medical conditions 
(Section 1.1 and NCCN Guidelines, NHL 2014 v.2). 

 
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3.3.5 
Rationale for Minimal Residual Disease Assessments 
The eradication of MRD is becoming the desirable endpoint in the treatment of CLL 
(Böttcher et al. 2012).  Evidence suggests that patients who achieve a MRD-negative 
remission have significantly lower relapse rates, longer PFS, and better OS.  MRD has 
been demonstrated to have a high correlation with PFS in multiple studies.  MRD data in 
the pivotal CLL8 study (ML17102) showed that significantly more patients in the 
rituximab + FC group achieved MRD-negative status compared with the FC-only group 
(MRD response rate 68% versus 31%; p < 0.0001; [Böttcher et al. 2012]).  Patients 
reaching MRD-negative status had a better PFS outcome irrespective of the treatment 
they received (HR = 4.46; p < 0.0001).  As a result, understanding the relationship of the 
peripheral blood MRD status and PFS is important to the use of MRD response rate as a 
primary endpoint in future CLL trials. 
MRD can be measured in peripheral blood or bone marrow, and both will be collected in 
this study.  Previous studies have shown that some patients who were MRD-negative in 
peripheral blood at the final response assessment were MRD-positive in bone marrow 
(Böttcher et al. 2012; Goede et al. 2014).  Reasons for this difference may be the 
eradication of CLL in the blood and the limited ability of current therapies to efficiently 
eradicate the disease in bone marrow.  Therefore, MRD negativity will be measured in 
bone marrow in responding patients on this study at the end-of-treatment response 
assessment after completion of combination therapy and again at the completion of 
treatment.  Refer to Appendix 13 for more detail on the methodology for the MRD 
assessments in this study. 
3.3.6 
Rationale for Biomarker Assessments 
Venetoclax inhibits the ability of cancer cells to evade cell death (apoptosis) by blocking 
the activity of the anti-apoptotic protein Bcl-2.  Nonclinical studies have demonstrated a 
pattern of response to venetoclax on the basis of 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.  In addition, high levels of at least one pro-apoptotic “sensor,” such as Noxa 
or Bim, are required.  Measurement of relevant RNAs and proteins (including those in 
the Bcl-2 family) in CLL cells will be examined pre-treatment and at the time of 
progression for correlation with outcome. 
Additionally, several prognostic markers have been described that can be used as 
stratification factors for CLL therapies.  These include del(17p), del(11q), del(13q14), 
trisomy 12, IGHV, and TP53 mutations as well as serum parameters (thymidine kinase, 
β2 microglobulin).  There is increasing evidence from prospective clinical trials that 
detection of certain chromosomal deletions has prognostic significance in CLL.  For 
example, patients with leukemia cells that have del(17p) and/or p53 mutations have an 
inferior prognosis and appear resistant to standard chemotherapy regimens.  Therefore, 
detection of these and other cytogenetic abnormalities could have prognostic value and 
may guide therapeutic decisions (Fink et al. 2013; Goede et al. 2014; Zenz et al. 2009). 

 
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Various studies have demonstrated that other molecular characteristics can influence 
the prognosis of patients with CLL with respect to time to progression and survival.  
Therefore, additional exploratory prognostic markers, such as rare cytogenetic 
abnormalities as detected by metaphase cytogenetics and telomere length will also be 
evaluated.  Telomere length is a potential prognostic marker that predicts sensitivity to 
DNA damaging agents, such as Clb (Mansouri et al. 2013). 
CLL remains an incurable disease because of residual CLL cells in the 
microenvironment, especially in lymph nodes.  Interaction of CD40:CD40L induces 
several pro-survival pathways and, thereby, up-regulates mitochondrial, anti-apoptotic 
molecules, including BCL2, MCL1, or BCL-XL, which can affect sensitivity to venetoclax.  
Analyses will be performed to determine in vitro venetoclax drug sensitivity in CLL cells 
after stimulation with CD40L-expressing feeder cells as well as western blot analysis for 
Bcl-2, Bcl-xL, and Mcl-1.  This experiment will explore the hypothesis that CD40:CD40L 
interaction in the lymph nodes will induce the pro-survival pathway and effect drug 
sensitivity to venetoclax. 
Recurrent somatic mutations, (i.e., in genes such as NOTCH1, SF3B1, TP53), which 
have recently been identified in CLL in small subsets of patients (approximately 2%−10% 
of patients), might evolve over time (clonal evolution) and associate with clinical 
long-term prognosis (Dreger et al. 2013; Schnaiter et al. 2013; Stilgenbauer et al. 2014).  
A blood sample will be used to sequence commonly mutated genes mentioned above, 
as well as genomic variation in genes associated with the cellular DNA damage 
response, cellular key pathways in CLL, (e.g., B-cell receptor signaling), and genes 
encoding for new treatment targets, including BCL2. 
In addition, resistance mechanisms will also be evaluated by genome-wide analyses 
(e.g., whole exome sequencing, whole genome sequencing, RNA sequencing) on paired 
samples taken pre-treatment and at the time of relapse in patients who consent to the 
GCLLSG biobanking program. 
Biomarkers that are described here may have both predictive and prognostic value; both 
arms of the study will be evaluated, and their potential association with disease 
progression will also be explored.  These studies may help identify responsive patient 
populations and develop better therapies for patients with CLL.  The analyses described 
in this section are exploratory and will be done retrospectively. 
3.3.7 
Rationale for Chronic Lymphocytic Leukemia Diagnostic 
Laboratory Assessments 
Lymphocyte Count 
The clinical diagnosis of CLL requires an absolute lymphocytosis with a lower threshold 
of at least 5000 mature-appearing lymphocytes/µL in the peripheral blood.  Lymphocyte 
counts may fluctuate from time of diagnosis to the point at which treatment is required. 

 
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Lymphocyte Immunophenotyping 
Patients must have documented CD20-positive CLL according to the IWCLL criteria (see 
Appendix 12 ) and the Matutes Scoring system (Matutes et al. 1994; see Appendix 17).  
CLL cells co-express the T-cell antigen CD5 and B-cell antigen (CD19, CD20, and 
CD23).  CD20 and CD16 median fluorescence intensity should be used to facilitate 
prediction of IRR risk after obinutuzumab infusion.  The levels of surface immune-
globulins, CD20 and CD79b, are characteristically low compared with those found on 
normal B cells.  Each B cell is monoclonal with regard to expression of either κ or λ.  
Variations of the intensity of expression of these markers may exist and do not exclude 
entry in the study. 
3.3.8 
Rationale for Pharmacokinetic Assessments 
PK is defined in this protocol as a dual timepoint drug level testing (18 mL blood at 
Cycle 4, Day 1 in all patients receiving venetoclax [Arm A]; see Appendix 4). 
Venetoclax is a small molecule administered orally and is primarily metabolized by 
CYP3A4, and obinutuzumab is a mAb administered by intravenous (IV) infusion.  mAbs 
do not interact directly with cytochrome P450 (CYP) isoforms and other metabolizing 
enzymes.  Therefore, the risk for obinutuzumab to significantly alter the 
pharmacokinetics of venetoclax is expected to be low. 
Tumor burden affects the clearance of obinutuzumab, especially at the beginning of 
treatment.  With decreasing tumor burden, the clearance was shown to reach an 
asymptote.  This finding is most likely the result of proteolytic metabolic clearance.  
Consequently, some patients with a high tumor burden may appear to clear the drug 
from the blood faster than patients with a low tumor burden because obinutuzumab 
binds to the CD20 + tumor cells and is effectively removed from the blood.  As a result, 
the clearance of the drug is expected to vary with time because repeated doses of 
obinutuzumab should reduce the number of CD20 + tumor cells.  Venetoclax has the 
potential to alter tumor burden and, therefore, affect the clearance of obinutuzumab.  
The drug interaction potential between venetoclax and obinutuzumab is being 
investigated in the Phase Ib Study GP28331.  Sparse PK samples for venetoclax and 
obinutuzumab will also be collected in all patients in Arm A (obinutuzumab + venetoclax) 
of this study to assess any interaction and explore potential exposure−response (efficacy 
or safety) relationships. 
3.3.9 
Rationale for Patient-Reported Outcome Assessments 
Unfit patients with CLL experience a 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, 
health-related quality of life.  There is strong reason to believe that if the anticipated 
clinical benefit is observed between the combination of venetoclax + obinutuzumab in the 
trial, patients might report an accompanying improvement in distinct key symptoms of 
the disease (i.e., reduction in fatigue, reduction in nodular pain, and decrease in night 

 
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sweats).  PROs will be used to comprehensively capture a patient’s report of disease 
symptom changes as well as evaluate the impact of treatment-related side effects.  
Specifically, with PFS being a primary clinical endpoint, understanding the time to 
disease progression through PROs and how patients perceive disease symptoms during 
this time can be used to support PFS.  Additionally, quantifying the importance of MRD 
from the patient perspective on change in symptom burden could better support this 
novel endpoint. 
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 
• 
PFS, defined as the time from randomization to the first occurrence of progression, 
relapse, or death from any cause as assessed by the investigator.  Disease 
progression will be assessed by the investigators using the IWCLL criteria (2008). 
 
3.4.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
PFS based on IRC-assessments (primary outcome for U.S. regulatory purposes), 
defined as the time from randomization to the first occurrence of progression or 
relapse or death from any cause 
• 
ORR (defined as rate of a clinical response of CR, CRi, or PR) at the completion of 
treatment assessment, as determined by the investigator according to the IWCLL 
guidelines (2008) 
• 
Complete response rate (CRR; defined as rate of a clinical response of CR or CRi) 
at the completion of treatment assessment, as determined by the investigator 
according to the IWCLL guidelines (2008) 
• 
MRD response rate (determined as the proportion of patients with MRD-negativity) 
measured in the peripheral blood at the completion of treatment assessment and 
MRD response rate as measured in the bone marrow at the completion of treatment, 
both measured by ASO-PCR 
• 
ORR at completion of combination treatment response assessment (Cycle 7, Day 1 
or 28 days after last IV infusion) 
• 
MRD response rates in the peripheral blood at completion of combination treatment 
assessment (Cycle 9, Day 1 or 3 months after last IV infusion) and also MRD 
response rate in the bone marrow, both as measured by ASO-PCR 
 
Note:  the secondary endpoint analyses will be on the basis of MRD assessment 
performed centrally by ASO-PCR with MRD negativity defined using a cutoff of 10-4 (less 
than 1 cell in 10,000 leukocytes).  As well as evaluating MRD response rate, it will 
further be evaluated using results of both measures, where a patient will be considered 
MRD-positive if either blood or bone marrow result is positive or both are missing.  MRD 

 
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response rates at other timepoints during treatment and follow-up where MRD is 
measured in the peripheral blood will also be summarized. 
• 
OS, defined as the time between the date of randomization and the date of death 
due to any cause 
• 
Duration of objective response, defined as the time from the first occurrence of a 
documented objective response to the time of PD as determined by the investigator 
or death from any cause 
• 
Best response achieved (CR, CRi, PR, stable disease, or PD) up to and including 
the assessment at completion of treatment assessment (within 3 months of last day 
of treatment) 
• 
Event-free survival (EFS), defined as the time between date of randomization and 
the date of disease progression/relapse on the basis of investigator-assessment, 
death, or start of a new anti-leukemic therapy 
• 
Time to next anti-leukemic treatment, defined as time between the date of 
randomization and the date of first intake of new anti-leukemic therapy 
 
3.4.3 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Nature, frequency, and severity of adverse events and serious adverse events  
• 
Changes in vital signs, physical findings, and clinical laboratory results during and 
following study treatment 
• 
Lymphocyte immunophenotyping and incidence of human−anti-human antibodies  
• 
Premature withdrawals 
 
3.4.4 
Pharmacokinetic Outcome Measures 
The PK outcome measure for this study is follows: 
• 
Apparent clearance, apparent volume of distribution, and/or other appropriate 
PK parameters of venetoclax and of obinutuzumab characterized with the use of 
popPK techniques.  Standard NCA/descriptive TLGs and popPK approaches will be 
considered. 
3.4.5 
Pharmacodynamic Outcome Measures 
For each visit at which CD19 +, CD5 +, and CD19 + CD5− B-cell measurements are taken, 
B-cell data will be listed for individual patients by treatment arm. 
3.4.6 
Patient-Reported Outcome Measures 
The PRO measures for this study are as described below.  The first assessment will be 
done during the first obinutuzumab infusion, and PROs will be followed until end of study 
as defined by 5 years after the last randomized patient: 
• 
To evaluate changes following treatment in disease and treatment-related 
symptoms in MDASI-CLL scores 

 
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• 
To evaluate changes in role functioning and global health status/QoL scales 
following treatment with the EORTC QLQ-C30 
 
3.4.7 
Health Economic Outcome Measure 
The health economic outcome measure for this study is as follows: 
• 
The EQ-5D-3L questionnaire 
 
3.4.8 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows (provided these data are 
available in a sufficiently timely and complete form to perform these analyses at the time 
of the final primary analysis): 
• 
MRD negativity in peripheral blood, measured using new technologies, including 
flow cytometry and next-generation sequencing with MRD negativity defined using a 
cutoff of 10-4 (less than 1 cell in 10,000 leukocytes) for comparison with ASO-PCR, 
and secondly by the limit of sensitivity of each of the above technologies 
• 
Relationship between MRD and PFS on the basis of peripheral blood assessed 
using ASO-PCR 
• 
Relationship between various baseline markers and clinical outcome parameters in 
patients from both arms of the study (including but not limited to CLL FISH [17p-, 
11q-, 13p-, + 12q], IGHV mutation status, p53 mutation status, serum parameters, 
Bcl-2 expression, and other CLL disease markers) 
 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
Inclusion Criteria 
A total of 420 patients will be enrolled in the randomized part of the study, and 
12 patients will be enrolled in the safety run-in phase.  Patients must meet the following 
criteria for study entry: 
• 
Have documented previously untreated CLL according to IWCLL criteria 
(Appendix 12) 
• 
CLL that requires treatment according to the IWCLL criteria 
• 
Total CIRS score > 6 or CrCl < 70 mL/min 
• 
Adequate marrow function independent of growth factor or transfusion support 
within 2 weeks of screening as follows, unless cytopenia is due to marrow 
involvement of CLL: 
Absolute neutrophil count ≥ 1.0 × 109/L  
Platelet counts ≥ 30 × 109/L; in cases of thrombocytopenia clearly due to marrow 
involvement of CLL (per the discretion of the investigator); platelet count should 
be ≥ 10 × 109/L if there is bone marrow involvement 
Total hemoglobin ≥ 9 g/dL (without transfusion support, unless anemia is due to 
marrow involvement of CLL) 

 
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• 
Adequate liver function as indicated by a total bilirubin, AST, and ALT ≤ 2 times the 
institutional upper limit of normal (ULN) value unless directly attributable to the 
patient’s CLL 
• 
For those patients with a screening lymphocyte count < 5,000 cells/µL, historical 
data that confirms a lymphocyte count ≥ 5,000 cells/µL at the time of diagnosis is 
required 
• 
18 years of age or older 
• 
Life expectancy > 6 months 
• 
Signed informed consent and, in the investigator’s judgment, able to comply with the 
study protocol  
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 30 days 
after the last dose of venetoclax or 18 months after the last dose of obinutuzumab, 
whichever is longer 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Examples of contraceptive methods with a failure rate of < 1% per year include 
tubal ligation, male sterilization, hormonal implants, established, proper use of 
combined oral or injected hormonal contraceptives, and certain intrauterine 
devices.  Alternatively, two methods (e.g., two barrier methods such as a 
condom and a cervical cap) may be combined to achieve a failure rate of < 1% 
per year.  Barrier methods must always be supplemented with the use of a 
spermicide. 
• 
For men:  agreement to remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of < 1% per year during the 
treatment period and for at least 90 days after the last dose of venetoclax or 
18 months after the last dose of obinutuzumab, whichever is longer, and agreement 
to refrain from donating sperm during the treatment period and for at least 90 days 
after the last dose of venetoclax 
Men with a pregnant partner must agree to remain abstinent or use a condom 
for the duration of the pregnancy. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 

 
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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 (Richter’s transformation or 
pro-lymphocytic leukemia). 
• 
Known central nervous system involvement. 
• 
Patients with a history of confirmed progressive multifocal leukoencephalopathy 
(PML). 
• 
An individual organ/system impairment score of 4 as assessed by the CIRS 
definition limiting the ability to receive the treatment regimen of this trial with the 
exception of eyes, ears, nose, throat organ system (note that symptoms related to 
CLL should not be included in the patient’s screening CIRS score).  Investigators 
should consult the General Rules for Severity Rating as well as the Organ-Specific 
Categories in Appendix 6 when assigning scores for certain conditions 
(i.e., pulmonary embolism) and consider the level of morbidity associated with a 
patient’s condition. 
• 
Patients with uncontrolled autoimmune hemolytic anemia or immune 
thrombocytopenia. 
• 
Inadequate renal function:  CrCl < 30 mL/min. 
• 
History of prior malignancy, except for conditions as listed below if patients have 
recovered from the acute side effects incurred as a result of previous therapy: 
Malignancies surgically treated with curative intent and with no known active 
disease present for ≥ 3 years before randomization. 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
Adequately treated cervical carcinoma in situ without evidence of disease. 
Surgically/adequately treated low grade, early stage, localized prostate cancer 
without evidence of disease. 
• 
Patients with infections requiring IV treatment (Grade 3 or 4) within the last 
2 months prior to enrollment. 
• 
History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies or known sensitivity or allergy to murine products. 
• 
Hypersensitivity to chlorambucil, obinutuzumab, or venetoclax or to any of the 
excipients (e.g., trehalose). 
• 
Pregnant women and nursing mothers. 
• 
Vaccination with a live vaccine ≤ 28 days prior to randomization. 
• 
Prisoners or patients who are institutionalized by regulatory or court order or 
persons who are in dependence to the Sponsor or an investigator. 
• 
History of illicit drug or alcohol abuse within 12 months prior to screening, in the 
investigator’s judgment. 

 
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• 
Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
HBsAg serology). 
Patients with occult or prior HBV infection (defined as negative hepatitis B 
surface antigen [HBsAg] and positive total hepatitis B core antibody [HBcAb]) 
may be included if HBV DNA is undetectable, provided that they are willing to 
undergo monthly DNA testing.  Patients who have protective titers of hepatitis B 
surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are 
eligible. 
• 
Positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing). 
Patients who are positive for HCV antibody are eligible only if PCR is negative 
for HCV RNA. 
• 
Patients with known infection with human immunodeficiency virus (HIV) or Human 
T-Cell Leukemia Virus 1 (HTLV-1). 
In countries where mandatory testing by health authorities is required, HIV 
testing will be performed. 
HTLV testing is required in patients from endemic countries (Japan, countries in 
the Caribbean basin, South America, Central America, sub-Saharan Africa, and 
Melanesia). 
• 
Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion 
of the study. 
• 
Patients who have received the following agents: 
Strong and moderate CYP3A inhibitors (see Appendix 5 for examples) within 
7 days prior to the first dose of study drug administration.  
Strong and moderate CYP3A inducers (see Appendix 5 for examples) within 
7 days prior to the first dose of study drug administration. 
Consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges), or star fruit within 3 days prior to the 
first dose of study drug and throughout venetoclax administration. 
• 
Inability to swallow a large number of tablets. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is an open-label study.  Initially, there will be a 12-patient safety run-in phase, 
(including at least 1 patient at high risk of developing TLS) wherein patients will receive 
obinutuzumab + venetoclax in a non-randomized fashion.  After the 12th patient has 
reached the end of Cycle 3, a formal review will be undertaken by the Sponsor and an 
iDMC.  After the completion of this run-in phase, including full review by the Sponsor and 
the iDMC, full randomization into the trial will begin. 
Randomization will be performed by an IxRS.  Patients will be assigned in 1:1 ratio to 
one of the two treatment arms through a block stratified randomization procedure. 

 
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The randomization scheme will ensure approximately equal sample sizes in the two 
treatment groups in regard to the following stratification factors: 
• 
Binet stage (3 levels):  A, B, or C 
• 
Geographic region (US/Canada/Central America; Australia/New Zealand; Western 
Europe; Central and Eastern Europe; or Latin America). 
 
A unique patient number will be assigned to all patients.  This patient number will be 
used to identify the patient in the electronic data capture (EDC) system and all other 
data sources. 
The iDMC will review unblinded safety data by treatment arm for the purpose of interim 
safety reviews and the planned interim analyses of efficacy.  The Sponsor and study 
team will not have access to the unblinded information reviewed by the iDMC.  
Assessments by the IRC will be blinded to treatment arm. 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Venetoclax 
Venetoclax will be supplied by the Sponsor.  For information on the formulation, 
packaging, and handling of venetoclax, see the pharmacy manual and the Investigator’s 
Brochure. Section 4.3.1.3  
4.3.1.2 
Chlorambucil 
For information on the formulation, packaging, and handling of chlorambucil, see the 
local prescribing information for chlorambucil.  
4.3.1.3 
Obinutuzumab 
Obinutuzumab will be supplied centrally for all countries participating in the study as a 
single-dose, sterile liquid formulation in a 50-mL pharmaceutical grade glass vial 
containing a nominal 1000 mg obinutuzumab.  The vial contains 40 mL of solution with 
2.5% overfill.  For information on the formulation, packaging, and handling of 
obinutuzumab, see the local prescribing information. 
For a single dose, use a 250-mL infusion bag containing 0.9% sodium chloride and 
withdraw and discard 40 mL of the sodium chloride.  Withdraw 40 mL of obinutuzumab 
from a single glass vial and inject into the infusion bag.  Discard any unused portion of 
obinutuzumab left in the vial.  Gently invert the infusion bag to mix the solution; do not 
shake.  
Compatibility of the obinutuzumab with 0.9% sodium chloride has been tested in a 
concentration range from 0.2 mg/mL to 20 mg/mL.  Dilutions of obinutuzumab in 0.9% 
sodium chloride have been found to be stable for 24 hours at 2°C−8°C and an additional 
24 hours at ambient temperature and ambient room lighting.  Storage conditions prior to 

 
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use are the responsibility of the user and would normally not be longer than 24 hours at 
2°C−8°C.  
Administration sets with polyvinyl chloride, polyurethane, or polyethylene as product 
contact surfaces and IV bags with polyolefin, polypropylene, polyvinyl chloride or 
polyurethane as product contact surfaces are compatible and may be used.  
For further details, see the Obinutuzumab Investigator’s Brochure. 
4.3.2 
Dosage, Administration, and Compliance 
Venetoclax 
Study patients will self-administer venetoclax tablets by mouth daily.  Each dose of 
venetoclax will be taken with approximately 240 mL of water within 30 minutes after the 
patient’s first meal of the day (e.g., breakfast).   
On days that pre-dose PK sampling is required, the patient’s first meal of the day (e.g., 
breakfast) will be provided in the morning at the clinic, and venetoclax dosing will occur 
in the clinic after completion of the meal to facilitate PK sampling.  
On days when both venetoclax and obinutuzumab are given, the order of study 
treatment administration will be venetoclax followed by obinutuzumab (there is no 
minimum time required between the administration of venetoclax and the start of the 
obinutuzumab infusion).  If vomiting occurs within 15 minutes of taking venetoclax and 
all expelled tablets are still intact, another dose may be given and the second dose 
noted in the drug log.  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 within 8 hours of the missed dose with food.  
Otherwise, the dose should not be taken.  On days when patients are scheduled to have 
blood samples collected for PK assessments, the time of each dose of venetoclax will be 
recorded to the nearest minute.  Venetoclax must be stored according to labeled storage 
conditions.  There is to be no break between cycles. 
All patients, including the open-label run-in phase and the randomized phase of the 
study, regardless of the assigned study arm, must receive prophylaxis for TLS prior to 
the initiation of study treatment (see Appendix 10) and after pre-infusion laboratory 
values are checked. 
Obinutuzumab- First Infusion 
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 1000 mg.  
Obinutuzumab may be administered in a single day; however (as per local prescribing 
information), for the first administration, patients can receive their first dose of 
obinutuzumab over 2 consecutive days (split dose) in Cycle 1:  100 mg on Day 1 and 
900 mg on Day 2.  Two infusion bags should be prepared for the infusion on Days 1 and 
2 (100 mg for Day 1 and 900 mg for Day 2).  If the first bag is completed without 

 
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modifications of the infusion rate or interruptions, the second bag may be administered 
on the same day (no dose delay necessary, no repetition of premedication), provided 
that appropriate time, conditions, and medical supervision are available throughout the 
infusion.  If there are any modifications of the infusion rate or interruptions during the first 
100 mg, the second bag should be administered the following day.  If patients require a 
delay of greater than 24 hours between the 100- and 900-mg infusions of obinutuzumab, 
see Section 4.3.1.3 and the Obinutuzumab Investigator’s Brochure regarding drug 
stability. 
From a microbiological perspective, the prepared infusion solution should be used 
immediately.  If it is not used immediately, in-use storage times and conditions prior to 
use are the responsibility of the user and would normally not be longer than 24 hours at 
2°C−8°C, unless dilution has taken place in controlled and validated aseptic conditions. 
Obinutuzumab should be prepared by a healthcare professional using aseptic technique.  
Do not shake the vial. 
Withdraw 40 mL of concentrate from the vial and dilute in polyvinyl chloride (PVC) or 
non-PVC polyolefin infusion bags containing sodium chloride 9 mg/mL (0.9%) solution 
for injection.  
To ensure differentiation of the two infusion bags for the initial 1,000-mg dose, it is 
recommended to utilize bags of different sizes to distinguish between the 100-mg dose 
for Cycle 1, Day 1 and the 900-mg dose for Cycle 1, Day 1 (continued) or Cycle 1, Day 2.  
To prepare the two infusion bags, withdraw 40 mL of concentrate from the vial and dilute 
4 mL into a 100-mL PVC or non-PVC polyolefin infusion bag and the remaining 36 mL in 
a 250-mL PVC or non-PVC polyolefin infusion bag containing sodium chloride 9 mg/mL 
(0.9%) solution for injection.  Clearly label each infusion bag.  For storage conditions of 
the infusion bags see Section 4.3.1.3. 
Obinutuzumab must be administered in a clinical setting (inpatient or outpatient).  Full 
emergency resuscitation facilities should be immediately available, and patients should 
be under close supervision of the investigator at all times.  Obinutuzumab should be 
given as a slow IV infusion through a dedicated line.  IV infusion pumps (such as Braun 
Infusomat Space) should be used to control the infusion rate of obinutuzumab.  Do not 
administer as an IV push or bolus.  After the end of the first infusion, the IV line should 
remain in place for at least 2 hours in order to be able to administer IV drugs if 
necessary.  If no adverse events occur after 2 hours, the IV line may be removed.  For 
subsequent infusions, the IV line should remain in place for at least 1 hour from the end 
of infusion, and if no adverse events occur after 1 hour, the IV line may be removed. 
Hypotension may be expected with infusions; therefore, withholding of antihypertensive 
treatment should be considered for 12 hours prior to the obinutuzumab infusions, 

 
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throughout the obinutuzumab infusions, and for the first hour after obinutuzumab 
infusions.  
The first infusion of obinutuzumab should be started only after administration of 
prophylactic medications to mitigate the risks of IRRs and TLS (see Appendix 11) and 
after pre-infusion laboratory values are checked. 
The first obinutuzumab infusion will be administered at an initial rate of 25 mg over 
4 hours.  In the absence of IRRs/hypersensitivity, the rate of the infusion will be 
escalated in increments of 50 mg/hour every 30 minutes to a maximum rate of 
400 mg/hour.  If the start of infusion is delayed or adverse events occur that require 
delaying or stopping the infusion such that infusion in a single day is not feasible, the 
infusion may be split and completed on the next day. 
During the initial infusion of obinutuzumab, vital signs will be obtained pre-infusion, then 
every 15 minutes for 90 minutes, then every 30 minutes until the end of infusion, and 
then every 60 minutes until the infusion line is removed.  If obinutuzumab is 
well-tolerated without significant infusion-related symptoms, vital signs for subsequent 
infusions can be obtained every 30 minutes until the infusion line is removed. 
Patients with pre-existing cardiac and/or pulmonary conditions or who have had a prior 
clinically significant cardiopulmonary adverse event with obinutuzumab should be 
monitored very carefully throughout the infusion and post-infusion period.  Patients with 
prior clinically significant cardiac disease are excluded per eligibility criteria.  
Prophylaxis for Infusion-Related Reactions  
All obinutuzumab infusions should be administered 30−60 minutes after premedication 
with oral acetaminophen (e.g., 650−1000 mg) and an antihistamine such as 
diphenhydramine (50−100 mg). 
For the first dose of obinutuzumab, premedication with corticosteroids (100 mg IV 
prednisolone or equivalent) is mandatory for all patients and must be administered at 
least 1 hour prior to the 100 mg dose on Cycle 1, Day 1 and the 900 mg dose on Cycle 1, 
Day 2.  An equivalent dose of dexamethasone (20 mg) or methylprednisolone (80 mg) is 
permitted, but hydrocortisone should not be used.  The required corticosteroid 
premedication may be modified by the investigator, in consultation with the sponsor, on 
the basis of observed safety from this study and review of data from other ongoing 
studies with obinutuzumab. 
For subsequent infusions, corticosteroid premedication should be given to patients who 
experienced a Grade 3 IRR with the previous infusion, to patients with lymphocyte 
counts > 25 × 109/L, and at the investigator’s discretion.  

 
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For patients who do not experience Grade ≥ 3 infusion-related symptoms with their 
previous infusion (i.e., do not receive medication to treat the reaction symptoms and do 
not experience infusion interruption), premedication for subsequent infusions may be 
omitted at the investigator’s discretion.  
For patients with a high lymphocyte count or bulky lymphadenopathy, the infusion may 
be given extremely slowly over a longer period of time or the dose may be split and 
given over more than 1 day.  
If a hypersensitivity or IRR develops, the infusion should be temporarily interrupted or 
slowed down and concomitant medication may be administered if deemed appropriate 
by the investigator.  Investigators should consider administering the following 
medications/interventions in response to an IRR:  
• 
Patients may be treated with acetaminophen/paracetamol and an antihistamine if 
the patient had not received them in the 4 hours prior to the start of the IRR. 
• 
Patients may receive additional IV hydration. 
• 
In the event of bronchospasm, urticaria, or dyspnea, patients may require 
antihistamines, oxygen, additional corticosteroids (e.g., 100 mg of IV prednisolone 
or equivalent; please note hydrocortisone should not be used to manage an IRR), 
and/or bronchodilators. 
• 
In the event of hypotension, patients may require vasopressors. 
 
Upon resolution of symptoms, the infusion will resume at half of the previous rate (the 
rate being used at the time that the hypersensitivity or IRR occurred), and infusion rate 
escalation may resume at the increments and intervals described above. 
Obinutuzumab TLS Prophylaxis 
• 
Prophylaxis of hyperuricemia and dehydration as well as laboratory monitoring are 
similar as described below for venetoclax dosing.  
• 
Patients with a high tumor burden (absolute lymphocyte count [ALC] ≥ 25 × 109/L or 
bulky lymphadenopathy) must receive prophylaxis for TLS prior to the initiation of 
treatment.  These patients must be well-hydrated.  It is desirable to maintain a fluid 
intake of approximately 3 L/day, 1−2 days before the first dose of obinutuzumab.  All 
such patients with a high tumor burden must be treated with allopurinol or a suitable 
alternative treatment starting 12-24 hours prior to the first infusion.  Patients should 
continue to receive prophylaxis with allopurinol and adequate hydration prior to each 
subsequent infusion, if deemed appropriate by the investigator. 
• 
If any laboratory abnormalities that are consistent with TLS are observed, patients 
should undergo further management and monitoring as per the Recommendations 
for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis 
Syndrome (see Appendix 10).  

 
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• 
Hematology and chemistry samples will be obtained prior to obinutuzumab dosing, 
24 hours after the initiation of the obinutuzumab infusion (Cycle 1 Day 3 if split dose 
is given; see Appendix 1 for details).  Discharge of patient is dependent upon review 
of the 24-hour laboratory values by the investigator or designee.  
 
Subsequent Infusions of Obinutuzumab 
If the patient’s previous infusion of obinutuzumab was well tolerated (defined by an 
absence of Grade 2 IRRs during a final infusion rate of ≥ 100 mg/hour), subsequent 
infusions will be administered at an initial rate of 100 mg/hour and increased by 
100 mg/hour increments at 30-minute intervals, as tolerated, to a maximum rate of 
400 mg/hour.  If a hypersensitivity or IRR develops, the infusion should be temporarily 
interrupted or slowed down, and concomitant medication may be administered if deemed 
appropriate by the investigator.  Investigators should consider administering the 
following medications/interventions in response to an IRR:  
• 
Patients may be treated with acetaminophen/paracetamol and an antihistamine if 
the patient had not received them in the 4 hours prior to the start of the IRR. 
• 
Patients may receive additional IV hydration. 
• 
In the event of bronchospasm, urticaria, or dyspnea, patients may require 
antihistamines, oxygen, additional corticosteroids (e.g., 100 mg of IV prednisolone 
or equivalent; please note hydrocortisone should not be used to manage an IRR), 
and/or bronchodilators. 
• 
In the event of hypotension, patients may require vasopressors. 
 
Upon resolution of symptoms, the infusion will resume at half the previous rate (the rate 
being used at the time that the hypersensitivity or IRR occurred), and infusion rate 
escalation may resume at the increments and intervals described above.  If the previous 
infusion rate was not well tolerated as defined above, instructions for the first infusion 
rate will be used. 
On days when both venetoclax and obinutuzumab are given, the order of study 
treatment administration will be venetoclax followed by obinutuzumab (there is no 
minimum time required between the administration of venetoclax and the start of the 
obinutuzumab infusion). 

 
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Table 3 
Administration of First Infusion of Obinutuzumab, if Split Over Two Days, and Subsequent Infusions of 
Obinutuzumab 
First Infusion 
Subsequent Infusions 
• 
On Day 1:  All patients will receive an infusion at a fixed dose of 100 mg 
obinutuzumab administered at a fixed rate of 25 mg/hr with no increase in 
infusion rate (total duration of the first infusion:  4 hours).  
• 
If the patient experiences an IRR, follow the protocol (Section 4.3.2) 
regarding treatment but at the resolution of symptoms, restart at half the 
initial rate (12.5 mg/hr).  Increase to 25 mg/hr after an hour but do not 
increase further. 
• 
If the patient tolerates 100mg without dose modification and local label 
permits, the Investigator may continue to administer the remaining 900mg 
on the same day at the infusion rate described below. 
• 
On Day 2:  All patients will receive 900 mg starting at the rate of 50 mg/hr, 
and the rate of the infusion will be escalated in increments of 50 mg/hr 
every 30-minutes to a maximum rate of 400 mg/hr. 
• 
If a hypersensitivity or IRR develops, the infusion should be temporarily 
interrupted or slowed down and concomitant medication may be 
administered if deemed appropriate by the investigator. 
Investigators should consider administering the following 
medications/interventions in response to an IRR:  
Patients may be treated with acetaminophen/paracetamol and an 
antihistamine if the patient had not received them in the 4 hours 
prior to the start of the IRR. 
Patients may receive additional IV hydration. 
In the event of bronchospasm, urticaria, or dyspnea, patients may 
require antihistamines, oxygen, additional corticosteroids (e.g., 100 
• 
If the first infusion of obinutuzumab was well tolerated (defined by an 
absence of IRRs during a final infusion rate of ≥100 mg/hr), subsequent 
infusions will be administered at an initial rate of 100 mg/hr and increased 
by 100 mg/hr increments at 30-minute intervals, as tolerated, to a 
maximum rate of 400 mg/hr. 
• 
If a hypersensitivity or IRR develops, the infusion should be temporarily 
interrupted or slowed down, and concomitant medication may be 
administered if deemed appropriate by the investigator. 
Investigators should consider administering the following 
medications/interventions in response to an IRR:  
Patients may be treated with acetaminophen/paracetamol and an 
antihistamine if the patient had not received them in the 4 hours 
prior to the start of the IRR. 
Patients may receive additional IV hydration. 
In the event of bronchospasm, urticaria, or dyspnea, patients may 
require antihistamines, oxygen, additional corticosteroids (e.g., 
100 mg of IV prednisolone or equivalent; please note 
hydrocortisone should not be used to manage an IRR), and/or 
bronchodilators. 
In the event of hypotension, patients may require vasopressors. 
• 
Upon resolution of symptoms, the infusion will resume at half of the 
previous rate (the rate being used at the time that the hypersensitivity or 
IRR occurred), and infusion rate escalation may resume at the increments 
and intervals described above.  If the previous infusion rate was not well 

 
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First Infusion 
Subsequent Infusions 
mg of IV prednisolone or equivalent; please note hydrocortisone 
should not be used to manage an IRR), and/or bronchodilators. 
In the event of hypotension, patients may require vasopressors. 
• 
Upon resolution of symptoms, the infusion will resume at half of the 
previous rate (the rate being used at the time that the hypersensitivity or 
IRR occurred), and infusion rate escalation may resume at the increments 
and intervals described above. 
tolerated, as defined above, instructions for the first infusion rate will be 
used. 
 
IRR = infusion-related reaction; IV = intravenous. 
 

 
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Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 4.6. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse Events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 
Chlorambucil 
Chlorambucil will be administered to patients who are randomized to receive 
chlorambucil.  Patients will receive 0.5mg/kg orally (tablets) on Days 1 and 15 for 
12 cycles according to the Chlorambucil Summary of Product Characteristics (SmPC). 
On days when both chlorambucil and obinutuzumab are given, the order of study 
treatment administration will be chlorambucil followed by obinutuzumab (there is no 
minimum time required between the administration of chlorambucil and the start of the 
obinutuzumab infusion). 
If weight changes are observed by 10%, chlorambucil dosing must be adjusted 
accordingly. 
4.3.3 
Investigational Medicinal Products 
All investigational medicinal products (IMPs) required for completion of this study 
(chlorambucil, obinutuzumab, and venetoclax) will be provided by the Sponsor where 
required by local health authority regulations.  The study site will acknowledge receipt of 
IMPs and confirm the shipment condition and content.  Any damaged shipments will be 
replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor 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 
Non-Investigational Medicinal Products 
Rasburicase 
Rasburicase (Fasturtec™ in Europe; Elitek™ in the United States) enzymatically 
converts uric acid in the blood to allantoin and hydrogen peroxide, thereby preventing 
the formation of uric acid crystals and potential renal blockage.  It reduces uric acid 
levels within 4 hours both in pediatric and adult patients, and several studies confirm its 
safety, effectiveness, and tolerability both in the prevention and treatment of TLS, 
although the prevention of acute renal failure fails in over 25% of patients. 

 
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Note:  Rasburicase may be supplied by the Sponsor in countries where rasburicase is 
not approved or cannot be supplied locally. 
4.3.5 
Post-Trial Access to Venetoclax 
Treatment switching from one arm to the other is not allowed, even after disease 
progression. 
The Sponsor will offer post-trial access to venetoclax free of charge to eligible patients in 
accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product. 
A patient will be eligible to receive study drug after the end of the study in case of 
withdrawal if all of the following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being. 
• 
There are no appropriate alternative treatments available to the patient. 
• 
The patient and his/her physician comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 
A patient will not be eligible to receive study drug after the end of the study in the case of 
withdrawal if any of the following conditions are met: 
• 
The study drug 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 would not 
otherwise create a financial hardship for the patient). 
• 
Provision of study drug 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 http://www.roche.com/responsibility/business_ethics/ethical_standards.htm. 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy  
Concomitant medication includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from 30 days prior to the screening period.  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. 
4.4.2 
Prohibited Therapy 
Patients who require the use of any of the excluded therapies listed below will be 
discontinued from study treatment.  Patients who are discontinued from study treatment 
will be followed for safety outcomes for 30 days following the patient’s last dose of 

 
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venetoclax or 90 days following the patient’s last dose of obinutuzumab, whichever is 
later.  All patients who discontinue study treatment for any reason should be followed 
until progression. 
Use of the following therapies is prohibited during the study: 
• 
Radiotherapy 
• 
Immunotherapy 
• 
Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate) 
• 
Any therapies intended for the treatment of lymphoma/leukemia whether approved 
or experimental (outside of this study) 
 
4.4.2.1 
Drug−Drug Interaction 
4.4.2.1.1 
Patients Randomized to Arm A 
(Venetoclax + Obinutuzumab) 
The following concomitant medications are not allowed within 7 days prior to the 
administration of the first dose of study drug and during the venetoclax dose ramp-up.  
These medications are cautionary once patients are receiving 400 mg per day of 
venetoclax: 
• 
Strong and moderate CYP3A inhibitors (see Appendix 5 for examples) 
Furthermore, patients who require these medications while they are receiving 
400 mg per day of venetoclax should reduce the venetoclax dose by 2-fold for 
moderate inhibitors and 4-fold for strong inhibitors during co-administration.  See 
Table 4 for additional details. 
• 
Strong and moderate CYP3A inducers (see Appendix 5 for examples) 
 
If clinically indicated, anti-herpes and anti-pneumocystis prophylaxis should be 
considered.  Although there is a potential for drug-drug interactions, there are likely to be 
limited potential clinical effects; therefore trimethoprim-sulfamethoxazole can be 
considered for pneumocystis prophylaxis, with close clinical monitoring. 
Study M15-065 demonstrated that following co-administration of single doses of 400-mg 
venetoclax with 5-mg warfarin, maximum plasma concentration observed, and area 
under the concentration–time curve from Time 0 to infinity of R- and S-warfarin 
increased by approximately 18%−28%.  Based on these data, warfarin has been moved 
from the excluded medication list to the cautionary medication list.  Warfarin may be 
co-administered with venetoclax with caution and with the guidance of the Medical 
Monitor (additional international normalized ratio [INR] monitoring may also be required).  
Figure 2 describes the plasma concentrations of S-warfarin in patients treated with 
venetoclax and warfarin versus those treated with warfarin alone.  Based on these data, 
warfarin has been moved to the cautionary list of concomitant medication. 

 
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Figure 2 Difference in Plasma S-Warfarin Concentration Following 
Treatment with Warfarin + Venetoclax versus Warfarin Alone 
 
Results expressed as mean + standard deviation of S-warfarin plasma concentration over time 
following administration of warfarin + venetoclax and warfarin alone using a log-linear scale. 
 
Table 4 lists categories of excluded and cautionary medications for patients randomized 
to Arm A (venetoclax + obinutuzumab).  See Appendix 5 for a sample list of excluded and 
cautionary medications for patients randomized to Arm A (venetoclax + obinutuzumab).   

 
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Table 4 
Excluded and Cautionary Medications for Patients Randomized 
to Arm A (Venetoclax + Obinutuzumab) 
Excluded 
Anticancer therapies, including chemotherapy, radiotherapy, or other investigational therapy 
(which includes targeted small molecule agents): 
 Excluded 5 half-lives prior to first dose and throughout venetoclax administration. 
Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent: 
Excluded 8 weeks prior to first dose of study drug. 
Grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville 
oranges) or starfruit: 
Excluded 3 days prior to first dose and throughout venetoclax administration. 
Excluded during the venetoclax ramp-up period and cautionary thereafter:  
Strong and moderate CYP3A inhibitors: 
Excluded during the venetoclax ramp-up period; consider alternative medications.   
If a patient requires use of these medications while they are receiving 400 mg per day of 
venetoclax, 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 target dose. 
Strong and moderate CYP3A inducers: 
Excluded during the venetoclax ramp-up period; consider alternative medications. 
If a patient requires use of these medications while they are receiving 400 mg per day of 
venetoclax, use with caution and contact the Medical Monitor for guidance. 
Cautionary 
Warfarin  
Weak CYP3A inducers 
Weak CYP3A inhibitors 
P-gp substrates 
BCRP substrates 
OATP1B1/1B3 substrates 
P-gp inhibitors 
BCRP inhibitors 
OATP1B1/B3 inhibitors 
Note:  See Appendix 5 for examples of these medications. 
 
A sample list of cautionary and excluded medications that fall into the categories within 
this section can be found in Appendix 5 .  It is not possible to produce a 100% 
exhaustive list of medications that fall into these categories; therefore, if in question, 
refer to the appropriate product label. 

 
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4.4.3 
Other Prohibited Medication 
Steroid therapy for anti-neoplastic intent with the exception of inhaled steroids for 
asthma, topical steroids, or replacement/stress corticosteroids are not permitted during 
the study at any time. 
4.4.4 
Prohibited Food 
Use of the following foods by patients randomized to Arm A is prohibited for at least 
3 days prior to initiation of venetoclax treatment and throughout venetoclax 
administration.   
Constituents of these foods have been shown to inhibit CYP3A4, the major enzyme 
responsible for the metabolism of venetoclax.  Consumption of these foods could lead to 
increased venetoclax exposure: 
• 
Grapefruit 
• 
Grapefruit products 
• 
Seville oranges (including marmalade containing Seville oranges) 
• 
Star fruit 
 
4.5 
STUDY ASSESSMENTS  
Appendix 2 and Appendix 3 outline the schedule of assessments performed during the 
study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  ICFs, including biobanking 
ICFs, for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
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. 
4.5.2 
Procedures for Enrollment of Eligible Subjects 
A medical review of selected screening data will be performed by the GCLLSG to 
confirm eligibility prior to randomization. 
A blood sample will be sent for central immunophenotyping for patients entered at 
investigational sites that can ship the samples to reach the laboratory in 
 
Germany.  The results must be available and reviewed by the GCLLSG physician prior 
to randomization.  Exceptionally, confirmation of CLL and CD20 expression by 
immunophenotyping will be performed locally at the investigational site, but the results 
must be reviewed by the GCLLSG physician prior to randomization.  A copy of the 

 
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original diagnostic report (e.g., FACS plots) will be sent to the sponsor and stored for 
possible future validation by an independent reviewer if required. 
All patients in the randomized part of the study must commence treatment within 7 days 
of randomization.  
For patients who experience a Grade 3 or 4 adverse event between randomization and 
the start of study drug, the start of the treatment may be delayed for up to 28 days.  If the 
Grade 3 or 4 event does not improve within 28 days, the patient will be withdrawn from 
the study. 
The investigator or designee will use the eCRF and assign a new patient number and 
enter the corresponding number for allocation to the treatment groups in the appropriate 
place on each patient’s eCRF.  Patient numbers will be chronologically assigned within 
each center as patients are enrolled into the study.  Each patient number within the 
study will be unique. 
A Subject Enrollment and Identification Code List must be maintained by the investigator.  
4.5.3 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by the patient within 28 days prior to the screening visit.  At this time the patient’s CIRS 
score should be assessed to determine eligibility for entry into the study (note that 
symptoms related to CLL should not be included in the patient’s screening CIRS score).  
The Instrumental Activities of Daily Life (IADL) should also be assessed by the physician 
(see Appendix 21).  Demographic data will include age, sex and self-reported 
race/ethnicity. 
4.5.4 
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, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 

 
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4.5.5 
Performance Status 
Performance status (PS) will be measured using the Eastern Cooperative Oncology 
Group (ECOG) Performance Status Scale (see Appendix 16).  It is recommended, 
where possible, that a patient’s PS be assessed by the same person throughout the 
study. 
4.5.6 
Clinical Staging 
At baseline, patients should be assessed according to Binet Staging criteria.  Staging is 
based on the number of involved areas, as defined by the presence of enlarged lymph 
nodes of > 1 cm in diameter (by physical examination only) or organomegaly, and on 
whether anemia or thrombocytopenia are present. 
Areas of involvement to be assessed for staging: 
• 
Head and neck, including the Waldeyer’s ring (this counts as one area, even if more 
than one group of nodes is enlarged) 
• 
Axillae (involvement of both axillae is counted as one area) 
• 
Groins, including superficial femorals (involvement of both groins is counted as 
one area) 
• 
Palpable spleen 
• 
Palpable liver (clinically enlarged) 
 
Binet Stage A: 
Hemoglobin ≥ 100 g/L (10 g/dL) and platelets ≥ 100 × 109/L and up to 2 areas involved 
Binet Stage B: 
Hemoglobin ≥ 100 g/L (10 g/dL) and platelets ≥ 100 × 109/L and 3−5 areas involved 
Binet Stage C: 
Hemoglobin < 100 g/L (10 g/dL) and/or platelets < 100 × 109/L and irrespective of nodal or 
organ enlargement 
4.5.7 
Criteria for Initiation of First-Line Treatment 
At the time of screening, the patient must satisfy the National Cancer Institute (NCI) 
criteria for active disease that requires treatment: 
• 
Evidence of progressive marrow failure as manifested by the development 
or worsening of anemia and/or thrombocytopenia 
• 
Massive (i.e., ≥ 6 cm below the left costal margin) or progressive or symptomatic 
splenomegaly 
• 
Massive nodes (i.e., ≥ 10 cm in the longest diameter) or progressive or symptomatic 
lymphadenopathy 

 
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• 
Progressive lymphocytosis with an increase of more than 50% over a 2-month 
period or lymphocyte doubling time (LDT) of less than 6 months.  LDT can be 
obtained at intervals of 2 weeks over an observation period of 2−3 months.  In 
patients with initial blood lymphocyte counts of < 30 × 109/L, LDT should not be used 
as a single parameter to define a treatment indication.  In addition, factors 
contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) 
should be excluded. 
• 
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
corticosteroids or other standard therapy 
• 
Constitutional symptoms, defined as any one of more of the following 
disease-related symptoms or signs: 
Unintentional weight loss of ≥ 10% within the previous 6 months 
Significant fatigue (ECOG PS 2 or worse; inability to work or perform 
usual activities) 
Fevers > 100.5°F or 38.0°C for ≥ 2 weeks without other evidence of infection 
Night sweats for > 1 month without evidence of infection 
 
4.5.8 
Vital Signs 
Vital signs will include measurements of pulse rate, temperature, and systolic and 
diastolic blood pressures while the patient is in a seated position. 
4.5.9 
Tumor and Response Evaluations  
Response will be assessed according to the IWCLL guidelines (see Appendix 12).  
The investigator assessment of response and progression, on the basis of peripheral 
blood counts, physical examination, bone marrow aspirate and biopsy results, and CT 
scans (when indicated), is the basis for individual patient treatment decisions and is 
considered primary for all endpoints in the study.  For purposes of regulatory decision-
making in the United States, PFS by IRC will be considered primary. 
The primary objective of the early response assessment at Cycle 4, Day1 and Cycle 7, 
Day 1 is to identify disease progression.  At these visits, response to treatment (CR/PR) 
should be determined according to the assessments planned for that visit:  physical 
examination and laboratory tests.  With the availability of imaging and bone marrow 
examination data at the + 3 month follow up visit, the end of treatment response 
assessment can then be fully assessed according to the IWCLL Guidelines (2008; see 
Appendix 12). 
CT imaging will not be used to determine PD because its value is questionable in a 
leukemia setting.  Only when PD is detected by physical examination in the absence of 
any objective hematological progression will a CT scan of the involved nodes be 
performed. 

 
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4.5.10 
Tumor Response 
An independent review committee will review efficacy data for disease progression (see 
Section 9.4.3 for more details). 
Baseline tumor assessments must be assessed a maximum of 4 weeks before 
randomization.  Given that response is a secondary endpoint of the trial and that PD will 
be followed by physical examination, CT scans performed prior to screening as part of 
the regular clinical work-up of the patient will be allowed up to 8 weeks before 
randomization.  This is to prevent the re-irradiation of patients who have recently 
undergone a CT scan.  However, a CT scan must be performed within the 4-week period 
prior to randomization for those patients with signs of rapidly progressing disease at 
screening. 
All patients should be continuously monitored for PD during the treatment period.  At any 
time, if progression is confirmed, it should be clearly documented in the eCRF.  Interim 
staging assessments will be performed at Cycle 4, Day 1, Cycle 7 Day 1, and Cycle 9 
Day 1.  In addition to an assessment of hematological status, this will also include a full 
physical examination to assess any lymphadenopathy and hepato/splenomegaly. 
Unless disease progression is confirmed, the patient is withdrawn due to toxicity, or the 
patient has died, patients should receive a maximum of 6 cycles of obinutuzumab and 
12 cycles of venetoclax/chlorambucil (28 daily venetoclax doses and 2 chlorambucil 
doses at Days 1 and 15).  If there is suspicion of PD given clinical or laboratory findings 
before the next scheduled assessment, an unscheduled assessment should be 
performed. 
The end of treatment response assessment must be performed 3 months after the last 
study treatment (no earlier than 2 months after the end of study treatment).  For those 
patients with a CR and PR confirmed by laboratory and physical examination and CT 
scan, a bone marrow aspirate and biopsy must also be performed.  The bone marrow 
aspirate sample will also be tested for MRD status by ASO-PCR. 
All other follow-up tumor assessments will be done within ± 14 days for 3-monthly and 
within a month for 6-monthly assessments of the scheduled visits described in 
Appendix 2 and Appendix 3. 
If a patient inadvertently misses a prescribed tumor evaluation or a technical error 
prevents the evaluation, the patient may continue treatment until the next scheduled 
assessment unless signs of clinical progression are present. 

 
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4.5.11 
Response Criteria 
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 (4,000/µL) 
• 
Absence of significant lymphadenopathy (nodes ≤ 15 mm in longest diameter or any 
extra nodal disease) by physical examination and CT scan 
• 
No hepatomegaly as determined by measurement below costal margin.  
Hepatomegaly considered to be due to CLL disease is defined as > 3 cm below 
costal margin. 
• 
No splenomegaly by physical examination as determined by measurement below 
the costal margin.  A palpable spleen of any size is considered to be related to 
CLL disease. 
• 
Absence of disease or constitutional symptoms (B symptoms) 
• 
Blood counts above the following values: 
Neutrophils > 1.5 × 109/L [1500/µL] (without growth factors) 
Platelets > 100 × 109/L [100,000/µL] (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, < 30% of nucleated cells being 
lymphocytes.  Lymphoid nodules should be absent. 
Bone marrow aspirate and biopsy should be performed 3 months after the 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.  However, this time interval should not exceed 
6 months.  A marrow biopsy result should be compared to a pre-treatment 
marrow result if available.  Patients who are otherwise in a complete remission 
but have bone marrow nodules that can be identified histologically should be 
considered to have a PR.  Immunohistochemistry should be performed to 
define whether these nodules are composed of primarily T cells, lymphocytes 
other than CLL cells, or CLL cells. 
 
Complete Response and Incomplete Bone Marrow Recovery 
For patients who fulfil the criteria for CR (including bone marrow) but who have 
persistent cytopenia, anemia, thrombocytopenia, or neutropenia, the marrow evaluation 
described above should be performed with scrutiny and should not show any clonal 
infiltrate. 

 
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Partial Response 
To be considered to have a PR, patients must exhibit the following features for at least 
2 months from the end of treatment: 
• 
≥ 50% decrease in peripheral blood lymphocyte count from the pre-treatment value 
AND either 
• 
≥ 50% reduction in lymphadenopathy (sum of longest diameter of up to six largest 
lymph nodes by physical exam and 50% reduction in the sum of product of the 
diameter of up to six of the largest lymph nodes measured by CT scan).  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. 
OR 
• 
≥ 50% reduction of liver enlargement, if enlarged at baseline, as assessed by 
physical examination 
OR 
• 
≥ 50% reduction of spleen enlargement, if enlarged at baseline, as assessed by 
physical examination 
AND at least one of the following 
• 
Neutrophils > 1.5 × 109/L (1500/µL) (without growth factors) or ≥ 50% increase of 
pretreatment value 
• 
Platelets > 100 × 109/L (100,000/µL) (without platelet transfusion or growth factors) or 
≥ 50% increase of pretreatment value 
• 
Hemoglobin > 110g/L (11 g/dL) (without blood transfusions or erythropoietin) or 
≥ 50% increase of pretreatment value 
 
Progressive Disease 
Progressive disease during or after therapy will be characterized by at least one of 
the following:  
• 
Increase of ≥ 50% in the absolute number of circulating lymphocytes, to at least 
5 × 109/L.  During combination treatment and up to Cycle 9, Day 1 (or 3 months after 
last IV infusion), the increase should be assessed against baseline using a Day 1 
(pre-cycle) nadir lymphocyte count and not interim cycle lymphocyte counts, which 
may not be stable.  During monotherapy treatment and during follow up, increases 
should be assessed against the assessment at Cycle 9, Day 1 (or 3 months after 
last IV infusion). 
• 
Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new 
extra nodal lesion (regardless of size) 

 
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• 
Increase of ≥ 50% in the longest diameter of any previous site of clinically significant 
lymphadenopathy (i.e., any lesion > 10 mm at baseline).  During combination 
treatment and up to Cycle 9, Day 1 (or 3 months after last IV infusion), the increase 
should be assessed against baseline.  During monotherapy treatment and during 
follow up, increases should be assessed against the assessment at Cycle 9, Day 1 
(or 3 months after last IV infusion). 
• 
Increase of ≥ 50% 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.  During 
combination treatment and up to Cycle 9, Day 1 (or 3 months after last IV infusion), 
the increase should be assessed against baseline.  During monotherapy treatment 
and during follow up, increases should be assessed against the assessment at 
Cycle 9, Day 1 (or 3 months after last IV infusion). 
• 
Transformation to a more aggressive histology (e.g., Richter’s syndrome or 
pro-lymphocytic leukemia with > 55% prolymphocytes).  Whenever possible, this 
diagnosis should 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 < 100 g/L 
(10 g/dL), by a decrease of platelet counts by > 50% or to < 100 × 109/L 
(100,000/µL), or by a decrease of neutrophil counts by > 50% or to < 1 × 109/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.  Patients without CT evaluation who would 
otherwise meet the criteria for CR or PR will also be considered to have stable 
disease. 
4.5.12 
MRD Response Criteria 
For the evaluation of MRD as part of the secondary endpoints of this study, MRD 
response rate will be determined as the proportion of patients with MRD-negativity 
measured in the peripheral blood at the completion of treatment assessment.  
Assessment of MRD in bone marrow is also required in patients with CR or PR and will 
be used to determine MRD response rate in bone marrow at the completion of treatment. 
MRD response rates in the peripheral blood at completion of combination treatment 
assessment (Cycle 9, Day 1 or 3 months after last IV infusion) will also be determined. 
As well as evaluating MRD response rate in peripheral blood and bone marrow, it will 
further be evaluated using results of both measures, where a patient will be considered 
MRD positive if either the blood or bone marrow result is positive or both are missing.  
MRD response rates at other timepoints during treatment and follow-up where MRD is 
measured in the peripheral blood (see time and events schedule) will also be 

 
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summarized for ASO-PCR.  Additional details on MRD methodology by ASO-PCR will 
be specified separately in an MRD Charter document. 
Additional Exploratory Assessments of MRD Response 
MRD response rate will be evaluated at each timepoint using flow cytometry and by 
Next-Generation Sequencing using the cutoff of < 10-4 and also at the limit of sensitivity 
of these methodologies. 
4.5.13 
Other Disease-Specific Assessments  
4.5.13.1 
Complete Blood Count 
Details on the required hematology panel necessary to assess response are provided in 
Section 3.3.7. 
4.5.13.2 
Bone Marrow 
A bone marrow aspirate and biopsy are generally not requested at study entry.  
Nevertheless, CLL is a disease of the bone marrow, and it may be appropriate to 
evaluate a major site of involvement.  In such cases, the aspirate smear must 
show ≥ 30% of all nucleated cells to be lymphoid.  The percentage of atypical cells 
(e.g., pro-lymphocytes) should be ≤ 55%. 
Bone marrow aspirate and biopsy should be performed at least 3 months after the last 
treatment when clinical and laboratory results listed above demonstrate that a CR/CRi 
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.  However, this 
time interval should not exceed 6 months.  A marrow biopsy should be compared to a 
pre-treatment marrow if available.  Patients who are otherwise in a complete remission 
but bone marrow nodules can be identified histologically should be considered to have 
PR.  Immunohistochemistry should be performed to define whether these nodules are 
composed of primarily T cells, lymphocytes other than CLL cells, or CLL cells. 
4.5.13.3 
Lymphadenopathy and Hepatomegaly/Splenomegaly 
A full physical examination should be performed to assess the extent of disease 
involvement.  Up to a maximum of the six largest palpable lymph nodes, hepatomegaly, 
and splenomegaly should be recorded in the eCRF. 
A CT scan (thorax, neck, abdomen, pelvis) will be performed at screening.  Up to a 
maximum of the six largest bi-dimensional lesions should be reported in the eCRF.  Note 
that these may be different from those lesions assessed by physical examination.  A 
repeat CT scan of involved sites at baseline will be performed in patients who satisfy the 
clinical criteria for PR or CR after the end of treatment.  When PD is detected by physical 
examination in the absence of any objective hematological progression, a CT scan of the 
involved nodes will be performed.  In addition, CT scans may be performed at any time 
at the investigator’s discretion or if clinically indicated.  In patients with severe renal 
insufficiency at screening, CT contrast should be used according to local practice.  If 

 
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necessary, magnetic resonance imaging (MRI) scans can be performed.  CT without 
contrast is not recommended except for patients that develop renal insufficiency during 
treatment and have previously been assessed by CT scan.  It is obligatory to use the 
same imaging technique for all tumor evaluations. 
4.5.13.4 
B-Symptoms 
B-symptoms are considered to be constitutional symptoms defined as any one or more 
of the following disease-related symptoms or signs: 
• 
Unintentional weight loss of 10% or more within the previous 6 months 
• 
Significant fatigue (i.e., ECOG PS 2 or worse; inability to work or perform usual 
activities) 
• 
Fevers > 100.5°F or 38.0°C for ≥ 2 weeks without other evidence of infection 
• 
Night sweats for > 1 month without evidence of infection 
 
B-symptoms should not be reported as adverse events.  Worsening is generally 
considered a symptom (but not an objective criterion) of progression. 
4.5.14 
Laboratory, Biomarker, and Other Biological Assessments 
(Local and Central) 
The following laboratory tests will be performed at the study site's local laboratory for 
analysis. 
During Screening Only (Days −28 to −1) 
• 
Lymphocyte count and immunophenotyping (this is to be done centrally, but in 
exceptional circumstances [e.g., sample could not be shipped in time to the central 
laboratory], it can be done locally) 
• 
Assessment of major site involvement using bone marrow aspirate or biopsy at 
baseline 
• 
Hematology (hemoglobin, WBC with differentials, platelets) 
• 
Coagulation (aPTT, PT, INR) 
• 
Biochemistry (biochemistry and electrolytes [including lactate dehydrogenase, 
sodium, potassium, calcium, phosphorus, chloride, bicarbonate, blood urea 
nitrogen, uric acid, aspartate aminotransferase, alanine aminotransferase, total 
bilirubin, serum creatinine, alkaline phosphatase, total protein, albumin]) 
• 
Coombs Test (Indirect and direct Coombs test should be repeated if positive) 
• 
CrCl (should be estimated using the standard Cockcroft-Gault formula for calculated 
CrCl.  A 24-hour urine collection may be undertaken to determine CrCl in patients 
with a borderline value for eligibility). 
• 
Serum pregnancy test (in women of childbearing potential only); if serum pregnancy 
test has not been performed 14 days prior to dosing, a urine pregnancy test must be 
performed 7 days prior to dosing.  If the test result is positive, patient dosing will be 
postponed until the patient’s status is confirmed by a serum pregnancy test. 

 
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• 
Immunoglobulins (Total IgA, IgG, IgM) 
• 
A dipstick urinalysis for proteinuria will be performed at screening and follow-up for 
all patients. 
• 
Hepatitis B (HBsAg) status in serum and HBcAb status in serum (using the same 
sample) for patients who were HBsAg-negative 
• 
In HBcAb-positive patients, hepatitis B viral DNA (HBV DNA) and HCV RNA will be 
assessed. 
 
Further Assessments 
• 
Patients who are HBsAg-negative/HBcAb-positive with undetectable serum HBV 
DNA should be monitored closely (every month) for HBV DNA by a real-time PCR 
quantification assay (lower limit of detection:  approx. 10 IU/mL) until at least 
12 months after the last treatment cycle.  If the HBV DNA assay becomes positive, 
patients should pre-emptively be treated with a nucleoside analog (i.e., lamivudine) 
for at least 12 months after the last cycle of therapy or be referred to a specialist, 
such as a gastroenterologist for management.  This may not be relevant in all 
participating countries. 
• 
Bone Marrow (optional at screening):  If a bone marrow aspirate and/or biopsy is 
performed as part of the routine clinical work-up for the patient, this information 
should be collected in the eCRF.  A bone marrow aspirate or biopsy is 
recommended in patients with an absolute neutrophil count (ANC) < 1.5 × 109/L or 
platelets < 75 × 109/L to demonstrate bone marrow infiltration by CLL as the cause of 
cytopenia or may be taken during the study to elucidate the cause of cytopenia. 
 
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis as per instructions in the laboratory manual: 
MRD by ASO-PCR 
• 
10-mL ethylenediaminetetraacetic acid (EDTA) blood sample in all patients during 
screening (prior to randomization) and at repeated timepoints during treatment and 
follow-up (see Appendix 2 and Appendix 3).  A patient will not be randomized until a 
viable sample has been collected and received at the testing laboratory.  If a sample 
is found not to be viable, a further sample will be requested. 
• 
A 4-mL EDTA bone marrow aspirate at completion of combination therapy (Cycle 9, 
Day 1 or 3 months after last IV infusion) and at the completion of treatment 
assessment (a minimum of 3 months after last treatment) for patients with CR/CRi 
and PR and will be assessed by ASO-PCR 
 
MRD by Next Generation Sequencing 
• 
6-mL EDTA blood sample during screening/baseline and 10 mL at repeated 
timepoints (as per the schedule of assessments (see Appendix 2 and Appendix 3) 
 

 
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MRD by flow cytometry: 
• 
5-mL sodium heparin blood sample during screening/baseline and 10 mL at 
repeated timepoints (as per the Schedule of Assessments [see Appendix 2 and 
Appendix 3]) 
 
Lymphocyte immunophenotyping includes confirmation of diagnosis, IRR prediction, 
assessment of ZAP70 and CD38, and safety monitoring. 
• 
4-mL EDTA blood for confirmation of diagnosis by flow cytometry will be taken 
during screening.  Analysis will include but is not limited to the following markers:  
CD5, CD16, CD19, CD20, CD23, light chain κ/λ restriction, ZAP-70, and CD38 
expression. 
• 
CD20 mean fluorescence intensity (MFI) on CD19+ B cells and CD16 MFI on NK 
cells and monocytes (FcgR3A) and neutrophils (FcgR3B) will be captured to further 
assess potential predictors for IRR. 
• 
If the central laboratory is not able to obtain a result, local immunophenotyping can 
be undertaken. 
 
Safety monitoring/B-cell recovery:  
• 
Safety Monitoring will be performed during screening and at subsequent visits 
during follow up.  At screening, the sample for lymphocyte immunophenotyping will 
be used.  
• 
4-mL EDTA peripheral blood samples for CD19 + /CD5 +  and C19 + /CD5 −  B, as well 
as CD14 +  monocyte detection, will be collected from all patients at screening 
(lymphocyte immunophenotyping sample) and subsequent visits during treatment 
and follow up (see Appendix 2 and Appendix 3) 
• 
Additional immunophenotyping samples may be collected if required for safety 
reasons at the discretion of the physician 
 
Metaphase cytogenetics: 
• 
A 10-mL sodium heparin peripheral blood sample will be taken at baseline to 
characterize chromosomal translocations. 
 
Serum parameters (thymidine kinase, β2 microglobulin) 
• 
A 10-mL whole blood sample (5-mL serum) will be taken at baseline for the testing 
of serum parameters (including but not limited to thymidine kinase and β2 
microglobulin 
 
CD40L stimulation, telomere length and targeted Next-Generation Sequencing 
• 
A 10-mL EDTA peripheral blood sample will be taken for additional research at 
baseline and at time of relapse/PD. Analyses will include the assessment of cellular 
key pathways in CLL (e.g., pathway analyses after CD40L stimulation, assessment 
of telomere length, mutation analysis of genes associated with B-cell receptor 
signaling, and genes encoding for new treatment targets including BCL2 

 
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Genetic testing, TP53, and IGHV analysis: 
• 
Two 10-mL sodium heparin peripheral blood samples will be taken at screening and 
at time of relapse/PD for the analysis of cytogenetic aberrations by FISH 
(-13q, -11q, -17p, trisomy [12]), TP53 mutations, and somatic hypermutation by 
analysis of IGHV mutational status.  Targeted analysis of tumor-specific 
(non-inherited) genetic aberrations by next-generation sequencing of genes, 
including commonly mutated genes in CLL (including but not limited to ATM, TP53, 
NOTCH1, SF3B1, BIRC3).  Any remaining samples will be stored in the GCLLSG 
Biobank if additional consent is given (see Section 4.5.17.1). 
 
CLL cell count for MRD and Bcl-2 Family Analysis (IHC and Flow Cytometry): 
• 
A 4-mL sodium heparin blood sample will be taken from all patients at screening 
(prior to randomization) for the quantification of CLL cells (required for MRD analysis 
by ASO-PCR) and for the assessment of Bcl-2 family by flow cytometry.  A patient 
will not be randomized until a viable sample has been collected and received at the 
testing laboratory; if a sample is found not to be viable, a further sample will be 
requested. 
• 
A 4-mL sodium heparin blood sample will be taken from all patients at time of 
relapse/PD for the assessment of Bcl-2 family by flow cytometry. 
• 
A 6-mL sodium citrate blood sample will be taken from all patients at baseline and at 
time of relapse/PD for DNA and RNA isolation for evaluation of gene expression and 
mutation status of somatic genetic aberrations in Bcl-2 family genes (i.e., genes 
regulating apoptosis as well as other CLL disease related markers). 
• 
A formalin-fixed paraffin embedded tissue (FFPE) block or 15 unstained, freshly cut 
FFPE tissue slides from lymph node biopsies that were collected as part of patient 
diagnosis, where available, shall be submitted for analysis of markers, including but 
not limited to BCL2, BCL-XL, and MCL1 by immunohistochemistry. 
 
PK Measurements (in all patients of Treatment A; also see Appendix 4) 
• 
A 3-mL blood sample will be collected into an EDTA tube at each PK sampling point 
(Appendix 4) for venetoclax. 
• 
A 6-mL blood sample will be collected into a plain tube at each PK sampling point 
(Appendix 4) for obinutuzumab. 
 
Pregnancy Test:  All women who are not postmenopausal (≥ 12 months of non-therapy-
induced amenorrhea) or surgically sterile will have a serum pregnancy test performed 
monthly while receiving study drug and at the Treatment Completion/Early Termination 
visit. 
Note:  sample shipment for central laboratory assessments must be made to designated 
laboratories as per instructions in the laboratory manual. 
Total blood loss during screening is approximately 40 mL (3 tablespoons).  Total blood 
loss at baseline is approximately 100 mL (7 tablespoons).  Total blood loss during the 

 
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study is approximately 1.2 L (80 tablespoons) but varies slightly, depending upon TLS 
risk assessment.  All samples will be destroyed at the end of analysis or at the end of the 
study, unless otherwise specified (see Section 3.1.2.4). 
Upon optional consent, residual samples will be taken for storage in the GCLLSG 
Biobanking Repository (Section 4.5.17). 
4.5.15 
Electrocardiograms 
Single ECG recordings will be obtained as outlined in the Schedule of Assessments 
(Appendix 2 and Appendix 3) and may be obtained at unscheduled timepoints as 
indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation), should be avoided 
during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator 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.  Digital recordings will be stored at site.  The following should be 
recorded in the appropriate eCRF:  heart rate, RR interval, QRS interval, PR duration, 
uncorrected QT interval, and corrected (Fridericia’s correction) QTc interval (QTcF) on 
the basis of the machine readings of the individual ECG tracings.  Any morphologic 
waveform changes or other ECG abnormalities must be documented on the eCRF.  If 
considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory. 
If, at a particular post-dose timepoint, the mean QTcF is > 500 ms and/or > 60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator.  A decision on study drug 
discontinuation should be made (Section 4.6).  The investigator should also evaluate the 
patient for potential concurrent risk factors (e.g., electrolyte abnormalities, 
co-medications known to prolong the QT interval, severe bradycardia). 
4.5.16 
Patient-Reported and Clinician-Reported Outcomes 
PRO data will be elicited from the patients in this study to more fully characterize the 
clinical profile of the combination of obinutuzumab and venetoclax compared with 

 
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obinutuzumab and chlorambucil in patients with previously untreated CLL and coexisting 
medical conditions.  The PRO instruments, translated as required into 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 should be 
self-administered at the investigational site prior to the completion of other study 
assessments and the administration of study treatment. 
The MDASI-CLL (see Appendix 18) is a cancer-related multi-symptom, valid, and 
reliable self-report questionnaire for clinical and research use.  It consists of 25 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, 
sadness, vomiting, and numbness or tingling) from the original MDASI-CLL 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-CLL 
contains a tumor-specific module 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-CLL items are rated 0−10 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-CLL takes approximately 
5 minutes to complete.  The MDASI-CLL assessment will be conducted during Day 1 of 
each treatment cycle.  The MDASI-CLL will be administered at all follow-up visits until 
new leukemia treatment (NLT). 
The EORTC QLQ-C30 (see Appendix 19) is a validated and reliable self-report measure 
(Fayers et al. 1999) consisting of thirty 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-C30 
assessment will be conducted during Day 1 of each treatment cycle.  The EORTC QLQ-
C30 will be administered at all follow-up visits until NLT. 
The EQ-5D-3L (see Appendix 15) questionnaire is a generic, preference-based health 
utility measure with questions about mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression that are used to build a composite of the patient’s health status.  
The EQ-5D-3L will be utilized in this study to estimate quality adjusted life years (QALY) 
for economic modeling.  The EQ-5D-3L also contains a visual analog scale (VAS) to 

 
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assess the patient’s overall health.  The EQ-5D-3L questionnaire takes 5 minutes or less 
to complete, and assessments are made on Day 1 of each treatment cycle at the same 
time as the MDASI-CLL and QLQ-C30. 
4.5.17 
German Chronic Lymphocytic Leukaemia Study Group 
Biobanking Samples 
4.5.17.1 
Overview of the GCLLSG Biobanking 
Patients will be asked to donate the remaining part of any blood samples taken for 
central lab assessment at the GCLLSG laboratories for later scientific research.  An 
additional blood sample will also be requested from all patients to evaluate resistance 
mechanisms and clonal evaluation by genome-wide analyses (e.g., targeted sequencing, 
whole exome sequencing, whole genome sequencing, RNA sequencing) on samples 
taken pre-treatment and at time of relapse.  Patients may participate in the main study 
without donating their left-over or additional samples for research. 
Left-over and samples for additional research will be frozen in GCLLSG biobanks 
located at the 
 and 
 and kept for up to 15 years after the 
last patient recruited.  Because scientific knowledge is continuously advancing and 
analytical techniques are continuously improving, it is currently not clear exactly what 
analyses will be done and which techniques will be used.  However, it is certain that the 
research will be aimed only at improving the understanding and treatment of CLL. 
Decisions on the research to be conducted on stored samples will be made by the 
GCLLSG Strategy Commission, a group of representative clinicians from the GCLLSG, 
including the GCLLSG chairman and laboratory scientists linked to their centers.  The 
research will include genetic testing and will be similar to and a logical extension of the 
central diagnostic tests (e.g., ZAP-70, CD38, IGHV mutation, chromosomal analysis) 
already included in the protocol. 
The results of the currently unspecified research and single nucleotide polymorphism 
(SNP) testing will be published separately and after publication of the main study.  The 
results will be published in aggregate; individual patients will not be identified.  No 
individual results will be communicated to the investigator or the patient because the 
research is exploratory and hypothesis-generating and will likely require further 
confirmatory studies.  In the unlikely event that SNP testing or the currently unspecified 
research reveals robust and definitive information which might be of importance to 
individual patients or their relatives, Ethics Committee (EC) approval will be sought 
before any communication of individual results is made to the investigator, the patient, or 
the patient’s relatives. 
Samples for genetic testing, i.e. mutation analyses, will be separated into the leukemic 
and non-leukemic fractions.  Separation of the leukemic and non-leukemic compartment 
will enable definition of disease related mutations.  

 
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Such genetic samples collected for analysis of heritable DNA variations 
(the non-leukemic fraction) will be double coded:  a new independent code will be added 
to the first code to increase confidentiality and data protection (see Section 8.4). 
All information, including any genetic information obtained from research on the left-over 
blood samples, will remain confidential.  Research samples will be stored securely but in 
a way that allows samples to be retrieved from the laboratories and destroyed, if needed 
(for example, if a patient wishes to withdraw his/her blood samples). 
4.5.17.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the GCLLSG Biobanking is 
contingent upon the review and approval of the exploratory research and the GCLLSG 
portion of the Informed Consent Form by each site's Institutional Review Board (IRB) or 
EC and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for GCLLSG Biobanking sampling, this section (Section 4.5.17) of the protocol 
will not be applicable at that site. 
4.5.17.3 
Sample Collection 
The following residual samples will be collected for research purposes: 
• 
Residual serum and blood samples extracted under the study protocol for central 
lab assessment at the GCLLSG labs 
, 
) may be transferred into GCLLSG biobanking depending on 
residual sample amount and sample numbers 
 
Any remaining blood from the genetic testing, TP53, and IGVH analyses will be used for 
research purposes: 
• 
Analyses will include but are not limited to whole exome sequencing analyses, 
whole genome sequencing, and RNA sequencing 
 
Samples will be stored at the GCLLSG Central Laboratories at the 
 
and 
 
For all samples, dates of consent should be recorded on the associated GCLLSG 
Biobanking page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual. 
4.5.17.4 
Confidentiality 
Given the sensitive nature of genetic data, GCLLSG (hereafter referred to as the 
Sponsor) has implemented additional processes to ensure patient confidentiality for 
GCLLSG Biobanking specimens and associated data. 
4.5.17.5 
Consent to Participate in the GCLLSG Biobanking 
The Informed Consent Form will contain a separate section that addresses participation 
in the GCLLSG Biobanking of leftover samples.  The investigator or authorized designee 

 
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will explain to each patient the objectives, methods, and potential hazards of 
participation in the GCLLSG Biobanking.  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 GCLLSG Biobanking 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 Informed Consent eCRF. 
In the event of a GCLLSG Biobanking participant's death or loss of competence, the 
participant's specimens and data will continue to be used as part of the GCLLSG 
Biobanking research. 
4.5.17.6 
Withdrawal from the GCLLSG Biobanking 
Patients who give consent to provide GCLLSG Biobanking specimens have the right to 
withdraw their specimens from the GCLLSG Biobanking 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 through 
use of the GCLLSG Biobanking Patient Withdrawal Form and, if the trial is ongoing, 
must enter the date of withdrawal on the GCLLSG Biobanking 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 BO25323 does not, by itself, constitute withdrawal of specimens from the 
GCLLSG Biobanking.  Likewise, a patient’s withdrawal from the GCLLSG Biobanking 
does not constitute withdrawal from Study BO25323. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for 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 Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
 
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.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 

 
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4.6.2 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
• 
Pregnancy 
• 
Patient non-compliance 
• 
Disease progression 
• 
Adverse events:  grade 4 IRR, grade 4 TLS 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has 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 
• 
Unsatisfactory patient enrollment 
• 
Insufficient management of TLS 
 
The Sponsor will notify the investigator of a decision to discontinue the study.  The 
Sponsor has 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 Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Venetoclax was granted accelerated approval by the FDA in 2016 as monotherapy for 
the treatment of patients with CLL who have 17p deletion and who have received at 
least one prior therapy (see Venetoclax US Prescribing Information 2016).  
It also received conditional market approval by the EMA in 2016 as monotherapy for the 
treatment of CLL in the presence of 17p deletion or TP53 mutation in patients who are 

 
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unsuitable for or have failed a B-cell receptor pathway inhibitor also as monotherapy for 
the treatment of CLL in the absence of 17p deletion or TP53 mutation in patients who 
have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor (see 
Venetoclax European Medicines Agency Summary of Product Characteristics 2016).    
Clinical experience with venetoclax in CLL is based on several ongoing Phase I, II, and 
III studies evaluating monotherapy or combination regimens in relapsed/refractory or 
previously untreated patients (see Venetoclax [ABT-199] Investigator’s Brochure).  Thus, 
the entire safety profile is not known at this time.  The safety plan for this study is 
designed to ensure patient safety and will include specific eligibility criteria and 
monitoring assessments. 
5.1.1 
Risks Associated with Venetoclax 
Clinical experience gained thus far with venetoclax has demonstrated that it is generally 
well tolerated, and toxicities appear to be mostly manageable and/or reversible; see the 
Venetoclax Investigator’s Brochure and the joint Obinutuzumab/Venetoclax Investigator 
Brochure for more information. 
On the basis of clinical data to date, the following known and potential risks with 
venetoclax are described below.  Guidelines around the management of these risks 
through dose and schedule modifications are described in Appendix 2 and Appendix 3. 
5.1.1.1 
Tumor Lysis Syndrome 
To date, the most clinically important adverse reaction associated with venetoclax in the 
ongoing clinical program has been TLS, primarily related to the initial ramp-up phase.  
TLS, including cases leading to clinical sequelae (of which two have had a fatal 
outcome), has been observed in patients with CLL treated with venetoclax at doses of 
50 mg and higher.  TLS prophylaxis and monitoring measures implemented in all 
protocols involving patients with CLL/SLL since May 2013, including initiation of therapy 
at the 20-mg dose and more gradual, five-step−dose ramp-up, have effectively reduced 
the severity and risk of TLS in patients with CLL/SLL.   
Although there is a general consensus for a broad definition of TLS as a set of metabolic 
complications that can arise from treatment of rapidly proliferating neoplasm, there have 
been very few attempts to apply a specific definition to the syndrome 
(Hande and Garrow 1993; Razis et al. 1994; Kedar et al. 1995).  Cairo and Bishop (2004) 
further built on the Hande and Garrow definition by modifying the definition to account for 
baseline laboratory abnormalities as well as changes occurring within 7 days following 
treatment.  This definition was further refined in 2011 (Howard et al. 2011; see 
Appendix 20). 
In light of potential synergy between venetoclax and obinutuzumab, rigorous TLS 
monitoring and prophylaxis will be instituted in this study (Section 5.1.3.1).  If it is 

 
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clinically justified and by laboratory assessment, patients can be re-categorized in a 
lower TLS-risk group during the venetoclax ramp-up period. 
5.1.1.2 
Cytopenia 
Effects on lymphocyte numbers are expected on the basis of the mechanism of action, 
and modest reductions in neutrophils have been observed with venetoclax therapy in 
oncology patients.  The majority of serious events of neutropenia and febrile neutropenia 
were confounded with poor bone marrow reserves, multiple prior therapies, disease 
infiltrating the bone marrow, and the use of growth factor prior to entering the studies. 
Thrombocytopenia and anemia have been reported with venetoclax in the ongoing 
single-agent Phase I dose−escalation Study M12-175 that is being conducted in heavily 
pretreated patients with CLL and NHL.  In most cases, the condition was preexisting. 
Treatment-emergent adverse events of neutropenia, anemia, and thrombocytopenia 
showed a higher incidence in a combination study with rituximab (Study M13-365).  
Cytopenias, including neutropenia, anemia, and thrombocytopenia, are known adverse 
reactions of anti-CD20 monoclonal antibodies.  There is still insufficient evidence to 
suggest a higher risk when these agents are used in combination with venetoclax. 
In this study, blood counts will be monitored closely throughout treatment (see the 
Schedule of Assessments in Appendix 2 and Appendix 3.  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 on the basis of 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.  The types of infectious events have been 
consistent with those anticipated in the elderly population of heavily pretreated patients 
with CLL.  CLL can be associated with impaired immune function and increased 
infections, and it is unclear whether or how much the incidence could be further 
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 
No patterns of adverse events indicating changes in cardiac function have been reported 
in clinical studies to date.  However, since study populations in venetoclax oncology 
studies are likely to be elderly and have received multiple prior chemotherapeutic agents, 
patients enrolled in this study are required to have ECGs and assessments of LVEF at 
screening per investigator’s discretion and as clinically indicated afterward. 

 
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5.1.1.5 
Effects on Fertility 
Given non-clinical data, there is a potential for decreased spermatogenesis.  Male 
patients considering preservation of fertility should bank their sperm before treatment 
with venetoclax.  Long-term effects of venetoclax on either male or female reproductive 
potential are unknown. 
5.1.1.6 
Drug Interactions 
Drug-drug interactions may occur with venetoclax.  Venetoclax is eliminated almost 
entirely through the hepatic route via metabolism by CYP3A4.  Specific 
recommendations are provided for co-administration of venetoclax with inhibitors and 
inducers of CYP3A (see Section 4.4.2.1.1, Table 4, and Appendix 5).  Venetoclax does 
not appear to be a clinically significant inhibitor of CYP2C9 or CYP2C8.  Venetoclax is 
not an inducer of CYP1A2, CYP2B6, or CYP3A4; therefore, it is not expected to have 
any potential for drug-drug interaction via CYP induction.  Venetoclax is a substrate 
of the transporters P-gp and BCRP and an inhibitor of P-gp, BCRP and OATP1B1. 
On a case by case basis, equivalent drugs, which do not interact with venetoclax, will be 
selected.  If there is no substitute available for a vital drug, withdrawal of the patient from 
the study is necessary. 
5.1.2 
Risks Associated with Obinutuzumab 
Important risks associated or potentially associated with obinutuzumab are TLS, 
thrombocytopenia (including acute thrombocytopenia), neutropenia, prolonged B‑cell 
depletion, infections (including PML and HBV reactivation), worsening of pre-existing 
cardiac conditions, impaired immunization response, immunogenicity, gastrointestinal 
perforation, and second malignancies.  Physicians should exercise caution when treating 
patients with a history of recurring or chronic infections or with underlying conditions that 
may predispose patients to infections.  Signs and/or symptoms of infection should result 
in prompt evaluation and collection of appropriate samples for bacteriological 
investigation prior to starting antibiotic or other treatment.  Patients may receive 
concomitant prophylactic anti-infective therapy at the physician’s discretion.  

 
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5.1.2.1 
Infusion-Related Reactions 
IRRs are seen with the first infusion in virtually all patients with CLL treated with 
obinutuzumab.  The IRRs are most commonly characterized by symptoms of 
hypotension, fever, chills, flushing, nausea, vomiting, hypertension, dyspnea, and fatigue.  
IRRs occur predominantly during the first infusion, and their incidence and intensity 
decrease with subsequent infusions.  They generally appear early during the infusion or 
shortly after, or in some cases, up to 24 hours after the completion of infusion of 
obinutuzumab.  Some patients have developed severe IRRs resulting in permanent 
discontinuation of obinutuzumab.  In some instances, concurrent signs of TLS are 
observed.  To mitigate the risk for IRRs, the following measures are included in the study 
protocol: 
• 
Patients who have preexisting cardiac or pulmonary conditions or who have had a 
prior clinically-significant cardiopulmonary adverse event with obinutuzumab should 
be monitored carefully throughout the infusion and the post-infusion period. 
• 
Dosing should be split for the first infusion only (100 mg on Cycle 1, Day 1 and 
900 mg on Cycle 1, Day 2). 
 
Management of IRRs and anaphylaxis is described in Section 5.3.5.1. 
5.1.2.2 
Tumor Lysis Syndrome  
Both venetoclax and obinutuzumab cause rapid cell breakdown after initial dosing of 
patients with CLL, and administration of both agents individually has been associated 
with events of laboratory and/or clinical TLS, which can be fatal.  Management of TLS is 
described in Appendix 10. 
5.1.2.3 
Neutropenia  
Some patients who were treated with obinutuzumab developed NCI Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 3−4 neutropenia, including 
febrile neutropenia. 
Increased infections may occur due to neutropenia.  Growth factors may be given during 
treatment with the combination, and patients will be monitored and treated promptly in 
case of infections.  
5.1.2.4 
Lymphopenia  
There is a potential for clinically significant lymphopenia.  Given the mechanism of action 
of B-cell depletion with obinutuzumab and inhibition of Bcl-2 with venetoclax, it is 
possible that there could be a delay in B-cell recovery. 
5.1.2.5 
Thrombocytopenia 
Cases of Grade 3−4 thrombocytopenia have been reported with obinutuzumab. 
A higher incidence of thrombocytopenia and hemorrhagic events was observed during 
the first cycle in patients with CLL with coexisting medical conditions treated with GClb 

 
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as compared with patients treated with RClb or chlorambucil alone in the Phase III 
pivotal Study BO21004/CLL11. 
The incidence of all grade and fatal hemorrhagic events was similar across the study 
arms.  However, all four fatal hemorrhagic events in GClb patients occurred in Cycle 1, 
compared with none in RClb-treated patients and one in chlorambucil-treated patients. 
Due to the small number of patients with fatal hemorrhagic events, lack of laboratory 
data (platelet count), specifically on the day of the hemorrhagic event, and the presence 
of confounding factors in all cases (pre-existing thrombocytopenia due to CLL, 
concomitant medical conditions, and concomitant treatments such as platelet inhibitors, 
and anticoagulants), no clear relationship could be established between 
thrombocytopenia and fatal hemorrhagic events. 
5.1.2.6 
Infection 
Consistent with its intended mode of action resulting in profound B-cell depletion, 
obinutuzumab has been shown to be associated with an increased risk of infections. 
Either new infection or reactivation of viral infections may occur.  Serious viral infections 
may include herpes virus infections (including cytomegalovirus, John Cunningham virus 
infection (JCV), PML, and hepatitis C virus [HCV] infection).  The eligibility of patients 
who are thought to have passive transfer of HCV or HBV core surface antibodies from 
IV immunoglobulin administration must be discussed with the Medical Monitor. 
Patients with HCV or HBV antibody following administration of IV immunoglobulin may 
be eligible only if PCR is negative for HCV or HBV, respectively.  Patients with positive 
HBV antibodies must be willing to undergo monthly HBV DNA testing.  Patients with 
serological evidence of HBV or HCV will not be eligible for treatment in this study. 
Hepatitis B Virus Reactivation 
For the subset of patients who are HBsAg negative and HBcAb positive and have 
undetectable HBV DNA levels at screening, HBV DNA levels must be followed 
approximately every 3−4 weeks during the treatment phase and then approximately 
every 4 weeks during the follow-up phase of the study.  Treatment with GClb/ 
obinutuzumab + venetoclax will be held for patients with a serum HBV DNA level 
of ≥ 29 IU/mL.  Patients should begin treatment with anti-viral medication immediately 
after the first report that shows HBV DNA ≥ 29 IU/mL.  Retest the HBV DNA level as 
soon as possible to rule out a false-positive report and to confirm HBV reactivation 
(≥ 29 IU/mL) (best prior to treatment; [e.g., when prescribing the anti-viral treatment]).  If 
HBV reactivation is confirmed in a second test, continue to treat for at least 1 year after 
the last dose of rituximab or obinutuzumab and immediately refer the patient to a 
gastroenterologist or hepatologist for additional management.  If a second test does not 
confirm HBV reactivation and was taken prior to the start of anti-viral therapy, then 
anti-viral therapy may be stopped again, and GClb/ obinutuzumab + venetoclax may be 

 
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resumed.  If a second test does not confirm HBV reactivation but was potentially 
confounded because it was taken only after the start of anti-viral therapy, then continue 
to treat for at least 1 year after the last dose of obinutuzumab and refer the patient to a 
gastroenterologist or hepatologist for additional management.  Patients may resume 
GClb/ obinutuzumab + venetoclax after HBV DNA levels decrease to undetectable levels 
(< 10 IU/mL) or if retest does not confirm HBV reactivation.  If the HBV DNA level 
exceeds 100 IU/mL and is increasing while a patient is receiving anti-viral medication, 
treatment with GClb / obinutuzumab + venetoclax will be discontinued. 
If HBV DNA level is detectable but < 29 IU/mL, then continue with 
GClb/obinutuzumab + venetoclax, but retest at close intervals (e.g., every 3−4 weeks).  If 
HBV DNA is still detectable but < 29 IU/mL on retest, then continue to administer 
treatment and retest at close intervals (e.g., every 3−4 weeks).  If HBV DNA is ≥ 29 
IU/mL on retest, then follow the instructions for HBV DNA levels ≥ 29 IU/mL (see above). 

 
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Table 5 
Management of Hepatitis B Virus Reactivation 
HBV DNA level of ≥ 29 IU/mL 
• 
Hold GClb/ obinutuzumab + venetoclax. 
• 
Begin anti-viral medication immediately after the first 
report showing HBV DNA ≥ 29 IU/mL 
• 
Retest HBV DNA level as soon as possible to rule out a 
false-positive report and to confirm HBV-reactivation 
(≥ 29 IU/mL) (best prior to treatment; e.g., when 
prescribing the anti-viral treatment). 
• 
If HBV reactivation is confirmed in second test, continue 
to treat for at least 1 year after the last dose of 
obinutuzumab and refer the patient to a 
gastroenterologist or hepatologist for additional 
management. 
• 
If a second test does not confirm HBV reactivation and 
was taken prior to start of anti-viral therapy, then 
anti-viral therapy may be stopped again, and GClb/ 
obinutuzumab + venetoclax may be resumed.  Retest 
the patient at close intervals (every 3−4 weeks). 
• 
If a second test does not confirm HBV reactivation but 
was potentially confounded because it was taken only 
after the start of ant-viral therapy, then continue to treat 
for at least 1 year after the last dose of obinutuzumab 
and refer the patient to a gastroenterologist or 
hepatologist for additional management. 
• 
Resume GClb/ obinutuzumab + venetoclax once HBV 
DNA levels decrease to undetectable levels (< 10 IU/mL) 
or if retest does not confirm hepatitis B reactivation. 
HBV DNA level of > 100 IU/mL 
and increasing while on 
appropriate anti-viral medication 
Discontinue GClb/ obinutuzumab + venetoclax. 
HBV DNA level detectable 
but < 29 IU/mL 
• 
Continue with GClb/ obinutuzumab + venetoclax, but 
retest at close intervals (e.g., every 3−4 weeks). 
If HBV DNA still detectable, but < 29 IU/mL on retest 
• 
Continue to administer treatment and retest at close 
intervals (e.g., every 3−4 weeks). 
If HBV DNA ≥ 29 IU/mL on retest 
• 
Follow instructions for HBV DNA level of ≥ 29 IU/mL 
(see above). 
GClb = obinutuzumab + chlorambucil; HBV = hepatitis B virus. 
 
PML has been reported in patients who have received obinutuzumab.  Particular 
attention should be given to patients who have had significant prior immunosuppressive 
treatment, such as high-dose chemotherapy or a stem cell transplant, and physicians 
should be aware of symptoms that are suggestive of PML and consider the diagnosis of 
PML in any patient presenting with new-onset neurologic manifestations. 

 
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The symptoms of PML are very unspecific and can vary depending on the affected 
region of the brain.  Motor involvement with corticospinal tract findings, sensory 
involvement, cerebellar deficits, and visual field defects are common.  Some syndromes 
regarded as “cortical” (e.g., aphasia or visual-spatial disorientation) can occur.  
Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain 
MRI, and lumbar puncture to quantify DNA of JCV in the cerebrospinal fluid. 
Therapy with obinutuzumab should be withheld during the investigation of potential PML 
and permanently discontinued in case of PML.  Discontinuation or reduction of any 
concomitant chemotherapy or immunosuppressive therapy should also be considered.  
The patient should be referred to a neurologist for the treatment of PML.  
Physicians should exercise caution when treating patients with a history of recurring or 
chronic infections or with underlying conditions that may predispose patients to 
infections.  Signs and/or symptoms of infection should result in prompt evaluation and 
appropriate samples for bacteriological investigation prior to starting antibiotic or other 
treatment.  Patients may receive concomitant prophylactic anti-infective therapy at the 
physician’s discretion.  
5.1.2.7 
Immunization 
The safety of immunization with live viral vaccines following obinutuzumab therapy has 
not been studied.  Patients who participate in this study may not receive vaccination with 
a live vaccine for a minimum of 28 days prior to randomization. 
Investigators should review the vaccination status of potential study patients being 
considered for this study and follow the U.S. Centers for Disease Control and Prevention 
guidelines for adult vaccination with non-live vaccines intended to prevent infectious 
diseases prior to study therapy. 
5.1.2.8 
Gastrointestinal Perforation 
Gastrointestinal perforations, including fatal events, have been reported in patients 
treated with obinutuzumab.  Patients with gastrointestinal involvement should be 
monitored for signs of gastrointestinal perforation. 
5.1.2.9 
Risks Associated with the Combination of Venetoclax and 
Obinutuzumab  
Given their mechanisms of action and review of available single-agent safety data, 
additive or overlapping acute toxicities for the combination of venetoclax and 
obinutuzumab could potentially include neutropenia and TLS.  In terms of chronic toxicity, 
it is possible that inhibition of Bcl-2 could delay B-cell recovery following completion of 
obinutuzumab treatment and/or lead to combined B- and T-cell depletion.  These effects, 
if they occur, would likely manifest as an increased incidence of infections only after 
several months of exposure to the combination.  Given the degree of immunodeficiency 
associated with the underlying disease, all patients will be monitored closely for infection 

 
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and treated aggressively according to institutional guidelines.  Additionally, all patients 
will have lymphocyte subset measurements by flow cytometry throughout the study 
treatment and follow-up period (also see the joint Venetoclax/Obinutuzumab 
Investigator’s Brochure).  
5.1.3 
Management of Specific Adverse Events 
Guidelines for management of specific adverse events are outlined in Table 6.  
Additional guidelines are provided in the subsections below. 
Table 6 
Guidelines for Management of Specific Adverse Events (for 
Patients Randomized to Arms A or B) 
Event 
Dose delay or dose modification 
Grade 3 or 4 (NCI grading 
scale) neutropenia with or 
without fever and infection 
• 
Withhold venetoclax (and obinutuzumab if neutropenia occurs 
during Cycles 1−6) for at least 7 days. 
• 
For chlorambucil:  withhold chlorambucil until adverse event 
resolves to Grade 2. 
• 
Administer G-CSF or growth factors for neutropenia as 
indicated. 
• 
When counts recover to ANC ≥ 1 × 109/L and/or platelets are 
≥ 75 × 109/L, resume venetoclax at one dose level reduction. 
• 
Reinitiate obinutuzumab. 
Severe thrombocytopenia, 
(platelets < 25 000/µL) 
and/or symptomatic 
bleeding 
• 
Withhold venetoclax or chlorambucil (and obinutuzumab if event 
occurs during Cycles 1−6) for severe thrombocytopenia 
(platelets < 25,000/µL) or presence of symptomatic bleeding until 
resolution of bleeding. 
Platelets may be transfused at the discretion of the 
investigator. 
When platelet level rises to > 50,000/µL without 
transfusional support for 5 consecutive days, restart 
venetoclax at previous doses and obinutuzumab. 
• 
For a second episode of severe thrombocytopenia and/or 
symptomatic bleeding, withhold venetoclax or chlorambucil (and 
obinutuzumab if event occurs during Cycles 1−6). 
When platelet level rises to > 50, 000/µL without 
transfusional support for 5 consecutive days, restart 
venetoclax at one dose level reduction and obinutuzumab. 
• 
For subsequent episodes of severe thrombocytopenia, withhold 
venetoclax or chlorambucil (and obinutuzumab if event occurs 
during Cycles 1−6). 
When platelet level rises to > 50,000 µL without 
transfusional support for 5 consecutive days, restart 
venetoclax at one dose level reduction and obinutuzumab. 
• 
For recurrent severe thrombocytopenia in spite of dose 
reduction and/or symptomatic bleeding, consult the Medical 
Monitor regarding continuation on the protocol. 

 
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Table 6 
Guidelines for Management of Specific Adverse Events (for 
Patients Randomized to Arms A or B) (cont.) 
 
Non-hematologic toxicity 
 
Event 
Dose delay or dose modification 
Grade 4 IRR 
• 
Discontinue obinutuzumab permanently.  Patients may continue 
venetoclax or chlorambucil. 
Grade 3 IRR on first dose; 
the same grade 3 IRR on 
two subsequent occasions 
• 
First episode:  To be managed at investigator’s discretion. 
• 
After 2 subsequent episodes of the same grade 3 event:  
Discontinue obinutuzumab permanently.  Patients may continue 
venetoclax or chlorambucil. 
Grade 1−2 IRR, first and 
subsequent episodes 
• 
To be managed at investigator’s discretion 
Grade 3 or 4 TLS, first 
episode and subsequent 
episodes 
• 
See Appendix 10.  
Grade 3 or 4 
non-hematologic events 
not specifically described 
above 
• 
Delay venetoclax (and obinutuzumab 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 obinutuzumab. 
For subsequent episodes:  If improvement to Grade ≤ 1 or 
baseline, restart venetoclax at one dose level reduction. 
• 
Delay chlorambucil (and obinutuzumab 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 chlorambucil and 
obinutuzumab. 
For subsequent episodes:  If improvement to Grade ≤ 1 or 
baseline, dose reduce chlorambucil per local guidelines. 
• 
Certain treatment emergent non-hematologic adverse events 
(e.g., venous thromboembolic events) may be managed and 
become clinically stable following medical intervention but may 
not improve to Grade ≤ 1 according to the NCI CTCAE 
definitions.  In such cases, if a patient is clinically stable, 
resumption of study drug may be possible after consultation with 
the Medical Monitor. 
Grade 2 non-hematologic 
toxicity 
• 
Delay treatment with venetoclax or chlorambucil (and 
obinutuzumab 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 or chlorambucil 
and obinutuzumab. 
Grade 1 non-hematologic 
toxicity 
• 
No dose reduction or delay. 
ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events; 
G-CSF = granulocyte stimulating factor; HBV = hepatitis B virus; NCI = National Cancer Institute; 
WHO = World Health Organization. 
 

 
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Gradual dose increase of venetoclax or chlorambucil 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. 
Dose reduction of obinutuzumab is not permitted. 
Patients who discontinue venetoclax or chlorambucil for toxicity should also discontinue 
obinutuzumab, although they are to continue evaluation per protocol. 
Patients who interrupt all study treatments secondary to treatment-related adverse 
events for longer than 28 days should discontinue all study drugs although they are to 
continue being followed for disease progression as described in Appendix 1, Appendix 2, 
and Appendix 3. 
The evaluation of potential treatment-induced toxicity in patients with advanced CLL may 
be quite difficult requiring 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 hematological toxicity in patients with CLL must consider the 
increased frequency of hematological 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 II to IV hematological 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 NCI grading scale for 
hematological toxicity in CLL studies (see Table 7).  For patients with a normal 
neutrophil count, platelet count, and/or hemoglobin value at baseline, the NCI CTCAE 
Version 4.03 will be used.  

 
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Table 7 
National Cancer Institute Grading Scale for Chronic Lymphocytic 
Leukemia 
Decrease in Platelets or 
Hemoglobin from Pre-Treatment 
(%) 
Grade 
ANC/µL 
No change to 10 
0 
≥ 2000 
11−24 
1 
≥ 1500 and < 2000 
25−49 
2 
≥ 1000 and < 1500 
50−74 
3 
≥ 500 and < 1000 
≥ 75 
4 
< 500 
ANC = absolute neutrophil count. 
 
5.1.3.1 
Prophylaxis and Management of Tumor Lysis Syndrome for 
Patients Being Treated with Venetoclax 
TLS is a risk for patients with CLL who are treated with high cell-killing agents or 
obinutuzumab.  Clinical data from patients with CLL 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 
CrCl of ≤ 80 mL/min at screening was a secondary risk factor for TLS.  A detailed 
description of risk factors for developing TLS following treatment with venetoclax is 
available in the Venetoclax Investigator’s Brochure.   
Based on the data review performed by the Sponsors, the following three risk categories 
for developing TLS after treatment with venetoclax were defined (see Table 8).  These 
risk groups were developed using assessments of nodal disease burden obtained from 
imaging tests performed at screening in several other studies of venetoclax in CLL.  
Therefore, assigning a patient’s TLS risk MUST be made based on an imaging test 
performed at screening (see Section 4.5.13.3).  Assessments of TLS risk categorization 
and monitoring/prophylaxis guidance is being continuously assessed throughout the 
venetoclax program, and future updates to these guidelines are possible. 

 
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Table 8 
Risk Categories for Developing Tumor Lysis Syndrome 
TLS Risk Category 
Definition 
Low 
All measurable lymph nodes with the largest diameter < 5 cm 
and < 25 × 109/L ALC.  Lymph node size will be determined by radiologic 
assessment. 
Medium 
Any measurable lymph node with the largest diameter ≥ 5 cm but < 10 cm 
OR ≥ 25 × 109/L ALC.  Lymph node size will be determined by radiologic 
assessment. 
High 
Any measurable lymph node with the largest diameter ≥ 10 cm or the 
presence of both ≥ 25 × 109/L ALC AND any measurable lymph node with 
the largest diameter ≥ 5 cm but < 10 cm.  Lymph node size will be 
determined by radiologic assessment. 
ALC = absolute lymphocyte count; CT = computed tomography; MRI = magnetic resonance 
imaging; TLS = tumor lysis syndrome. 
TLS Risk Assessment MUST be made based on measurements of nodal disease burden based 
on radiologic assessments (CT scan or MRI, see Section 4.5.13.3) performed during the 
screening period. 
 
All patients enrolling in the study will be assessed at screening and categorized in a risk 
category as described above.  Investigators may reassess patient’s TLS risk after they 
start treatment and may assign them to a lower risk group.  For example, patients 
classified as TLS high-risk at screening because of an ALC of ≥ 25 × 109 AND a 
measurable lymph node with the largest diameter ≥ 5 cm but < 10 cm by radiologic 
assessment may have a re-evaluation of their TLS risk category based on their most 
recent ALC after initiating study treatment.  If the patient’s ALC decreases to < 25 × 109/L, 
the patient may be categorized as TLS medium-risk and may follow the management 
guidelines for the TLS medium-risk category at subsequent visits and during the 
venetoclax ramp-up period.  Re-assessment of the patient’s TLS risk category can occur 
continuously during Cycle 1 and the venetoclax dose ramp-up period.  If a patient is 
re-assigned to a lower risk group, the investigator may follow the prophylaxis guidance 
for the lower risk group to which they are assigned. 
However, patients who are classified as high-risk because they have a lymph node with 
largest diameter ≥ 10 cm MAY NOT have their TLS risk re-assessed and should follow 
the prophylaxis plan for high-risk patients throughout the venetoclax ramp-up period. 
Patients who develop signs or symptoms of TLS regardless of the risk group to which 
they were assigned may have additional monitoring at subsequent visits at the 
investigator’s discretion.  
This section describes the management of patients throughout dosing (as described in 
Section 4.3.2) given their risk factors for developing TLS identified upon study entry. 

 
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Table 9 
Summary of Tumor Lysis Syndrome Prophylaxis for Venetoclax 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 end of the 
ramp-up period with venetoclax is 
completed (C3D1). 
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. 
Hematology and chemistry samples will be taken 
predose and 8 and 24 hours after dosing. 
Predose is defined as up to 4 hours before venetoclax 
administration, and results must be reviewed prior to 
dosing; if it is not possible to review results from a 
sample taken up to 4 hours predose, then it is 
acceptable to take a predose hematology and chemistry 
sample within 24 hours prior to dosing.  The results of 
these samples must be reviewed prior to dosing.  If 
laboratory values from this sample have demonstrated 
no clinically significant abnormalities, the hematology 
and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be 
reviewed prior to dose administration.  However, these 
predose (0−4 hours prior to dosing) laboratory samples 
should still be drawn, and these will serve as baseline 
for later laboratory values when assessing for laboratory 
evidence of TLS at the 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. 

 
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Table 9 
Summary of Tumor Lysis Syndrome Prophylaxis for Venetoclax and Monitoring Measures (cont.) 
 
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 end of the ramp 
up period with venetoclax is 
completed (C3D1). 
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. 
Hematology and chemistry samples will be taken 
predose and 8, and 24 hours after dosing timepoints. 
Predose is defined as up to 4 hours before venetoclax 
administration, and results must be reviewed prior to 
dosing; if it is not possible to review results from a 
sample taken up to 4 hours predose, then it is 
acceptable to take a predose hematology and chemistry 
sample within 24 hours prior to dosing.  The results of 
these samples must be reviewed prior to dosing.  If 
laboratory values from this sample have demonstrated 
no clinically significant abnormalities, the hematology 
and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be 
reviewed prior to dose administration.  However, these 
predose (0−4 hours prior to dosing) laboratory samples 
should still be drawn, and these will serve as baseline 
for later laboratory values when assessing for laboratory 
evidence of TLS at the 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. 
 

 
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Table 9 
Summary of Tumor Lysis Syndrome Prophylaxis for Venetoclax and Monitoring Measures (cont.) 
 
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 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 the Howard et al. 
[2011] threshold of 8 mg/dL 
(475.8 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 3.1.2.2  
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. 
Upon hospital admission, 
IV hydration should be 
started with a target of 
approximately 2−3 L per 
day or as clinically 
appropriate. 
Hematology and chemistry samples will be taken 
predose and 8, 12, and 24 hours after dosing. 
Predose is defined as up to 4 hours before 
venetoclax administration, and results must be 
reviewed prior to dosing; if it is not possible to 
review results from a sample taken up to 4 hours 
predose, then it is acceptable to take a predose 
hematology and chemistry sample within 24 hours 
prior to dosing.  The results of these samples must 
be reviewed prior to dosing.  If laboratory values 
from this sample have demonstrated no clinically 
significant abnormalities, the hematology and 
chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to 
be reviewed prior to dose administration.  
However, these predose (0−4 hours prior to 
dosing) laboratory samples should still be drawn, 
and these will serve as baseline for later laboratory 
values when assessing for laboratory evidence of 
TLS. 
The investigator or subinvestigator must review the 
24-hour laboratory results prior to dosing on the 
next day. 

 
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Table 9 
Summary of Tumor Lysis Syndrome Prophylaxis for Venetoclax and Monitoring Measures (cont.) 
 
TLS Risk 
Category 
Day 1 of 
Dose 
Level 
Prophylaxis Medication 
Hospitalization 
Hydration a 
Laboratory Assessments b, e 
TLS 
high-risk 
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. 
Patients who are not hospitalized at these 
timepoints will have hematology and chemistry 
samples taken predose and 8 and 24 hours after 
dosing. 
Predose is defined as up to 4 hours before 
venetoclax administration, and results must be 
reviewed prior to dosing; if it is not possible to 
review results from a sample taken up to 4 hours 
predose, then it is acceptable to take a predose 
hematology and chemistry sample within 24 hours 
prior to dosing.  The results of these samples must 
be reviewed prior to dosing.  If laboratory values 
from this sample have demonstrated no clinically 
significant abnormalities, the hematology and 
chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be 
reviewed prior to dose administration.  However, 
these predose (0−4 hours prior to dosing) 
laboratory samples should still be drawn, and 
these will serve as baseline for later laboratory 
values when assessing for laboratory evidence of 
TLS. 
 

 
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Table 9 
Summary of Tumor Lysis Syndrome Prophylaxis for Venetoclax and Monitoring Measures (cont.) 
 
TLS Risk 
Category 
Day 1 of 
Dose 
Level 
Prophylaxis Medication 
Hospitalization 
Hydration a 
Laboratory Assessments b, e 
 
 
 
 
 
The investigator or subinvestigator must review the 
24-hour laboratory results prior to dosing on the 
next day. 
Patients who are hospitalized at these timepoints 
will have chemistry and hematology samples 
obtained predose, 8, 12, and 24 hours postdose.  
These results must be reviewed promptly by the 
investigator or subinvestigator.  The 24 hour 
postdose laboratory results must be reviewed by 
the investigator or subinvestigator before the 
patient leaves the hospital or receives any 
additional study drug. 
C = cycle; CrCl = creatinine clearance; D = day; IV = intravenous; 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 For laboratory samples drawn on days of study treatment, “predose” 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.  If it is not possible to review a sample 
taken up to 4 hours predose, then it is acceptable to take a predose hematology and chemistry sample within 24 hours prior to dosing.  The results of these 
samples must be reviewed prior to dosing.  If laboratory values from this sample have demonstrated no clinically significant abnormalities, the hematology and 
chemistry samples drawn on the day of venetoclax administration prior to dosing are not required to be reviewed prior to dose administration.  However, these 
predose (0−4 hours prior to dosing) laboratory samples should still be drawn, and these will serve a baseline for later laboratory values when assessing for 
laboratory evidence of TLS. 

 
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Table 9 
Summary of Tumor Lysis Syndrome Prophylaxis for Venetoclax and Monitoring Measures (cont.) 
 
c Patients with CrCl < 80 mL/min and/or who have a higher tumor burden (defined per the discretion of the investigator) may be handled as TLS high-risk patients.  
Currently, limited clinical experience has been gained with venetoclax in patients with CrCl 30−50mL/min.  Therefore, these patients should receive additional 
consideration by the investigator with regard to their management, including the decision on whether to administer IV hydration and to hospitalize the patient to 
facilitate monitoring and expedite response to electrolyte changes at initial dosing as well as at each first dose during the ramp-up period. 
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 withheld until the electrolyte 
abnormalities resolve.  Patients who develop electrolyte abnormalities should undergo aggressive management and further monitoring per Appendix 4.  Any time 
during the ramp-up period, if venetoclax was withheld 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).  The dose must be resumed at one lower dose-level if dose was 
withheld 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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Initial Doses:  Venetoclax 20 and 50 mg 
All patients, irrespective of their TLS risk category at the first dose of venetoclax, 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 to the end of the venetoclax 
ramp-up period (Cycle 3, Day 1). 
• 
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 prior to 
administering venetoclax (predose).  If clinically significant laboratory abnormalities 
are observed in this baseline laboratory assessment, the first dose of venetoclax 
must be delayed until resolution and management per the protocol and 
recommendations for Initial Management of Electrolyte Imbalances and Prevention 
of TLS must be initiated.  If needed, patient should receive additional prophylactic 
treatment prior to the initiation of dosing. 
Predose is defined as up to 4 hours before venetoclax administration, and 
results must be reviewed prior to dosing; if it is not possible to review results 
from a sample taken up to 4 hours predose, then it is acceptable to take a 
predose hematology and chemistry sample within 24 hours prior to dosing.  
The results of these samples must be reviewed prior to dosing.  If laboratory 
values from this sample have demonstrated no clinically significant 
abnormalities, the hematology and chemistry samples drawn on the day of 
venetoclax administration prior to dosing are not required to be reviewed prior 
to dose administration.  However, these predose (0−4 hours prior to dosing) 
laboratory samples should still be drawn, and these will serve as baseline for 
later laboratory values when assessing for laboratory evidence of TLS. 
 
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 venetoclax 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 obtained prior to administering 
venetoclax (predose) and 8 and 24 hours after dosing.  Laboratory samples should 
be sent and analyzed immediately. 

 
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Predose is defined as up to 4 hours before venetoclax administration, and 
results must be reviewed prior to dosing; if it is not possible to review results 
from a sample taken up to 4 hours predose, then it is acceptable to take a 
predose hematology and chemistry sample within 24 hours prior to dosing.  The 
results of these samples must be reviewed prior to dosing.  If laboratory values 
from this sample have demonstrated no clinically significant abnormalities, the 
hematology and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be reviewed prior to dose 
administration.  However, these predose (0−4 hours prior to dosing) laboratory 
samples should still be drawn, and these will serve as baseline for later 
laboratory values when assessing for laboratory evidence of TLS. 
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 CrCl ≥ 80 mL/min will receive their initial doses of 
20 and 50 mg venetoclax as outpatients.  Patients with CrCl < 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 obtained prior to administering 
venetoclax (predose) and 8 and 24 hours after dosing timepoints.  Laboratory 
samples should be sent and analyzed immediately.   
Predose is defined as up to 4 hours before venetoclax administration, and 
results must be reviewed prior to dosing; if it is not possible to review results 
from a sample taken up to 4 hours predose, then it is acceptable to take a 
predose hematology and chemistry sample within 24 hours prior to dosing.  The 
results of these samples must be reviewed prior to dosing.  If laboratory values 
from this sample have demonstrated no clinically significant abnormalities, the 
hematology and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be reviewed prior to dose 
administration.  However, these predose (0−4 hours prior to dosing) laboratory 
samples should still be drawn, and these will serve as baseline for later 
laboratory values when assessing for laboratory evidence of TLS. 
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.   

 
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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 
venetoclax.  Hospitalization will begin the evening prior to each initial dose of 
venetoclax and continue for 24 hours after each dose. 
• 
Upon admission, serum chemistry and hematology laboratory samples should be 
drawn, and IV hydration should be started with a target of 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 Howard et al. [2011] 
threshold of 8 mg/dL [475.8 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 the following:  
Please note that at room temperature, rasburicase causes enzymatic 
degradation of the uric acid in blood, plasma, and serum samples, which 
could potentially result in spuriously low plasma uric acid assay readings.  
The following special sample handling procedure must be followed to avoid 
ex vivo uric acid degradation:   
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).   
The plasma must be maintained in an ice water bath and analyzed for 
uric acid within 4 hours of collection. 
• 
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 obtained prior to administering 
venetoclax (predose) and at 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. 
Predose is defined as up to 4 hours before venetoclax administration, and 
results must be reviewed prior to dosing; if it is not possible to review results 
from a sample taken up to 4 hours predose, then it is acceptable to take a 

 
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predose hematology and chemistry sample within 24 hours prior to dosing.  The 
results of these samples must be reviewed prior to dosing.  If laboratory values 
from this sample have demonstrated no clinically significant abnormalities, the 
hematology and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be reviewed prior to dose 
administration.  However, these predose (0−4 hours prior to dosing) laboratory 
samples should still be drawn, and these will serve as baseline for later 
laboratory values when assessing for laboratory evidence of TLS. 
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 Venetoclax 
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 prior to 
administering venetoclax (predose).  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. 
Predose is defined as up to 4 hours before venetoclax administration, and 
results must be reviewed prior to dosing; if it is not possible to review results 
from a sample taken up to 4 hours predose, then it is acceptable to take a 
predose hematology and chemistry sample within 24 hours prior to dosing.  The 
results of these samples must be reviewed prior to dosing.  If laboratory values 
from this sample have demonstrated no clinically significant abnormalities, the 
hematology and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be reviewed prior to dose 
administration.  However, these predose (0 to 4 hours prior to dosing) 
laboratory samples should still be drawn, and these will serve as baseline for 
later laboratory values when assessing for laboratory evidence of TLS. 
 

 
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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 
venetoclax) as outpatients. 
• 
Serum chemistry, hematology, and vital signs will be obtained prior to administering 
venetoclax (predose) and at 8 and 24 hours after dosing.  Laboratory samples 
should be sent and analyzed immediately.   
Predose is defined as up to 4 hours before venetoclax administration, and 
results must be reviewed prior to dosing; if it is not possible to review results 
from a sample taken up to 4 hours predose, then it is acceptable to take a 
predose hematology and chemistry sample within 24 hours prior to dosing.  The 
results of these samples must be reviewed prior to dosing.  If laboratory values 
from this sample have demonstrated no clinically significant abnormalities, the 
hematology and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be reviewed prior to dose 
administration.  However, these predose (0 to 4 hours prior to dosing) 
laboratory samples should still be drawn, and these will serve as baseline for 
later laboratory values when assessing for laboratory evidence of TLS. 
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 CrCl ≥ 80 mL/min will receive their subsequent dose 
increases as outpatient.  Patients with CrCl < 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 obtained prior to administering 
venetoclax (predose) and at 8 and 24 hours after dosing.  Laboratory samples 
should be sent and analyzed immediately.   
Predose is defined as up to 4 hours before venetoclax administration, and 
results must be reviewed prior to dosing; if it is not possible to review results 
from a sample taken up to 4 hours predose, then it is acceptable to take a 
predose hematology and chemistry sample within 24 hours prior to dosing.  The 
results of these samples must be reviewed prior to dosing.  If laboratory values 
from this sample have demonstrated no clinically significant abnormalities, the 
hematology and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be reviewed prior to dose 
administration.  However, these predose (0 to 4 hours prior to dosing) 

 
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laboratory samples should still be drawn, and these will serve as baseline for 
later laboratory values when assessing for laboratory evidence of TLS. 
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 obtained prior to dosing (predose, defined as up 
to 4 hours before venetoclax dose) and 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 CrCl of ≥ 80 mL/min will receive the subsequent dose 
increases as outpatients.  Patients with CrCl < 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 continue for 24 hours after 
the dose. 
• 
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 who are not hospitalized, serum chemistry, hematology, and vital signs 
will be obtained prior to administering venetoclax and at 8 and 24 hours after dosing 
timepoints.  Laboratory samples should be sent and analyzed immediately. 
Predose is defined as up to 4 hours before venetoclax administration, and 
results must be reviewed prior to dosing; if it is not possible to review results 
from a sample taken up to 4 hours predose, then it is acceptable to take a 
predose hematology and chemistry sample within 24 hours prior to dosing.  The 
results of these samples must be reviewed prior to dosing.  If laboratory values 
from this sample have demonstrated no clinically significant abnormalities, the 
hematology and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be reviewed prior to dose 
administration.  However, these predose (0 to 4 hours prior to dosing) 
laboratory samples should still be drawn, and these will serve as baseline for 
later laboratory values when assessing for laboratory evidence of TLS. 
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 who are hospitalized during subsequent dose increases, serum 
chemistry, hematology, and vital signs will be obtained prior to dosing (predose, 
defined as up to 4 hours before venetoclax dose) and 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 withheld until the electrolyte 
abnormalities resolve.  Patients who develop electrolyte abnormalities should undergo 
aggressive management and further monitoring per Appendix 10, Recommendations for 
Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome.  
Any time during the ramp-up period, if venetoclax was withheld 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).  The dose must be resumed at one lower dose-level if interruption lasted more 
than 7 days, with the exception of the 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. 
For patients who are at high risk of TLS: 
• 
Hospitalized patients should receive TLS prophylaxis as described above for initial 
venetoclax dosing.  Nephrology (or acute dialysis service) must be 
consulted/contacted on admission (per institutional standards) to ensure emergency 
dialysis is available and the appropriate staff are aware and prepared to handle any 
necessary intervention for TLS.  Telemetry should also be considered. 
 
5.1.3.2 
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 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. 
5.1.3.3 
Prophylaxis for Infusion-Related Reactions 
The rate of infusion of obinutuzumab may need to be slowed for those patients that 
experience infusion reactions, and medications to treat IRRs (including epinephrine for 

 
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subcutaneous injections, corticosteroids, and diphenhydramine for IV injection) and 
resuscitation equipment should be available for immediate use during dosing. 
5.1.3.4 
Life-Threatening Infusion-Related Reactions and Anaphylaxis 
In the event of a life-threatening IRR (which may include pulmonary or cardiac events) or 
IgE-mediated anaphylactic reaction, obinutuzumab should be discontinued and no 
additional obinutuzumab should be administered.  Patients who experience any of these 
reactions should receive aggressive symptomatic treatment and will be discontinued 
from study treatment. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and 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. 
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 patient 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 5.3.5.10. 
• 
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). 
 

 
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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 5.3.5.11). 
• 
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) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE 
criteria; 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 Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor 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 will include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7) 

 
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• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
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 Sponsor 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 
(Section 5.3.3) and causality (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 
adverse events and serious adverse events caused by a protocol-mandated intervention 
(e.g., invasive procedures such as biopsies, discontinuation of medications) should be 
reported (see Section 5.4.2 for instructions for reporting serious adverse events). 
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 venetoclax, chlorambucil, or 
obinutuzumab.  Grade 3−4 adverse events should be reported for 6 months, and major 
infections (Grade 3−4) should be reported throughout the study and for 2 years after the 
last dose of study treatment, irrespective of causality (see Appendix 14 for duration and 
reporting of adverse events). 
Serious Adverse Events 
Throughout the study (including follow-up), all serious adverse events (regardless of 
causality) will be documented in the eCRF.  Details regarding the reporting period for 
SAEs are found in Appendix 14. 
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.   

 
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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 (v4.03) will be used for 
assessing adverse event severity.  Table 10 and Appendix 9 will be used for assessing 
severity for adverse events that are not specifically listed in the NCI CTCAE. 
Table 10 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
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 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National 
Cancer Institute. 
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 oneself, 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. 
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 5.4.2. 
 
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 

 
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• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as 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 
 
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 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after obinutuzumab administration 
should be captured as diagnosis of IRR on an Adverse Event eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
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 sign or symptom should be recorded on the 
Adverse Event eCRF.  If a diagnosis is subsequently established, all previously reported 
signs and symptoms should be nullified and replaced by a single diagnosis, with a 
starting date that corresponds to the starting date of the first symptom of the eventual 
diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are 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.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 

 
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• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
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 consequent 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. 
5.3.5.4 
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 (intensity) of the event will be recorded at the 
time the event is first reported.  If a persistent adverse event becomes more severe, the 
most extreme intensity should also be recorded on the Adverse Event eCRF.  If the 
event becomes serious, it should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning that the event became serious; see Section 5.4.2 for 
reporting instructions).  The Adverse Event eCRF should be updated by changing the 
event from "non-serious" to "serious," providing the date that the event became serious, 
and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
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 2 and Appendix 9.  Granulocyte 
colony-stimulating factor used as prophylaxis would not be considered an adverse event 
but should be reported as a concomitant medication. 

 
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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. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) 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 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. 
5.3.5.6 
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. 

 
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5.3.5.7 
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.  
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 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
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 and not on the Adverse Event eCRF.  All other 
on-study deaths, 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.  The term "sudden death" should be used only for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
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. 
During survival follow-up, deaths attributed to progression of CLL should be recorded 
only on the Survival eCRF. 
5.3.5.9 
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 General Medical History and Baseline 
Conditions eCRF. 

 
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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”). 
5.3.5.10 
Lack of Efficacy or Worsening of Chronic Lymphocytic 
Leukemia 
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. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient 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.   
The following hospitalization scenarios are not considered to be serious adverse events: 
• 
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 experienced an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours that is required per protocol 
or per local standard of care. 
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 

 
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associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills serious 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; Section 5.4.2). 
No safety data related to overdosing of venetoclax are available. 
5.3.5.13 
Patient-Reported Outcome Data 
Instructions on the PRO questionnaires in paper format 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 experienced.  Site 
staff will review PRO questionnaires for completeness only.  If it’s noted that the patient 
has written any words on the PRO instrument that is not a pre-defined response (e.g., 
comments in the margin of the questionnaire, comments in an open text field) that could 
be an adverse event or serious adverse event, 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 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 Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor 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 Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events 
• 
Adverse events of special interest 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor 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. 

 
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5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for All Sites  
Medical Monitor:  
 MB ChB 
Telephone No.: 
  
Mobile Telephone No.: 
  
 
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 
Monitor, 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 
Adverse Events of Special Interest 
Adverse events of special interest for this study will include the following (Appendix 14): 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
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.  
A paper Serious Adverse Event Reporting Form and fax cover sheet should be 
completed and faxed to Roche and AbbVie Safety Risk Management or its 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"). 
5.4.2.2 
Events That Occur after Study Drug Initiation 
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 venetoclax, chlorambucil, or 
obinutuzumab.  Grades 3 to 5 AEs should be reported for 6 months and major infections 
(Grades 3 to 5) for 2 years after last dose of study treatment irrespective of causality.  In 
all cases the reporting period will end when the next CLL treatment has been given.  
Related serious adverse events including all second primary malignancies will be 
reported indefinitely (Section 5.6).  For further details, see Appendix 14. 
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 

 
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via the EDC system.  A report will be generated and sent to AbbVie and Roche Safety 
Risk 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 to Roche and 
AbbVie Safety Risk Management or its 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. 
Instructions for reporting post-study adverse events are provided in Section 5.6. 
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 venetoclax (or within 18 months of the last dose of obinutuzumab).  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 and Roche Safety 
Risk Management.  In the event that the EDC system is unavailable, a Clinical Trial 
Pregnancy Reporting Form and fax cover sheet should be completed and faxed to 
AbbVie and Roche Safety Risk Management or its designee immediately (i.e., no more 
than 24 hours after learning of the pregnancy), using the fax numbers provided to 
investigators.  Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system. 
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 
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. 
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 
28 days after completing treatment with venetoclax or 18 months after the last dose of 
obinutuzumab.  Male patients who received study treatment should not attempt to father 
a child for at least 90 days after the last dose of venetoclax or 18 months after the last 
dose of obinutuzumab, whichever is longer, and agree to refrain from donating sperm 
during the treatment period and for at least 90 days after the last dose of venetoclax.  A 

 
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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 abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; 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 exposed to study 
drug or the 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 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
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. 

 
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5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events, 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 
If the investigator becomes aware of a serious adverse event with a suspected causal 
relationship to the study drug that occurs after the end of the study in a subject treated 
by him or her, the investigator should report the serious adverse event to the Sponsor. 
The investigator should report these events directly to AbbVie and Roche Safety Risk 
Management or designee via telephone, email or via fax machine using the Serious 
Adverse Event Reporting Form and fax cover sheet and via Email or eFax to AbbVie 
(see “Protocol Administrative and Contact Information & List of Investigators”). 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events 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 Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Combined Venetoclax /Obinutuzumab Investigator's Brochure  
• 
SmPC for chlorambucil 
 
The Sponsor 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 Sponsor as needed. 
Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study drug exposure and will be excluded from expedited 
reporting.  These anticipated events include known consequences of the underlying 
disease or condition under investigation (e.g., symptoms, disease progression) and 
events unlikely to be related to the underlying disease or condition under investigation 
but common in the study population independent of drug therapy (e.g., cardiovascular 
events in an elderly population).  These events are listed in Appendix 11. 

 
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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, is available upon request. 
Although exempted from expedited reporting to Health Authorities and IRBs as individual 
cases, these Serious Adverse Events (as defined in Section 5.4.2) must be reported 
within 24 hours of the site being made aware of the event. 
The iDMC will monitor the safety events in this study.  Any recommendations made by 
the iDMC during the study that do not favor the test product will be submitted to the 
health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
A detailed statistical analysis plan (SAP) will specify in more detail analyses that are 
outlined in this section of the protocol. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size for the study is determined given the requirements to perform a 
hypothesis test for clinically relevant statistical superiority in the primary endpoint of PFS. 
Estimates of the number of events required to demonstrate efficacy with regard to PFS 
are based on the following assumptions: 
• 
Log-rank test at the two-sided 0.05 level of significance 
• 
Median PFS for obinutuzumab and chlorambucil control arm (27 months) 
• 
80% power to detect HR = 0.65 for the comparison of obinutuzumab + venetoclax 
experimental arm versus GClb, with median PFS for obinutuzumab + venetoclax 
increased to 41.5 months  
• 
Exponential distribution of PFS 
• 
Annual drop-out rate of 10% 
• 
One interim analysis for efficacy after 75% of PFS events, utilizing a stopping 
boundary according to the γ family error spending function with parameter γ = −9.21. 
 
The addition of an optional early interim analysis requires no adjustment to the sample 
size, as the impact on the statistical power calculation is negligible. 
Based on these assumptions, a total of 170 PFS events are required for the final 
analysis of PFS.   
The minimum detectable difference at the final analysis corresponds approximately to an 
HR = 0.74. 

 
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The sample size calculation was performed using EAST version 6.2.  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, major protocol deviations, study drug administration, and patient disposition 
will be summarized by treatment arm in all randomized patients.  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 to evaluate 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 (ITT population). 
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 [2008]), or death from any cause, whichever occurs first.  
Progression-free survival on the basis of independent review committee (IRC) 
assessments will be considered primary for U.S. regulatory purposes (details will be 
provided in the SAP).  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.  All patients, including patients who discontinue all 
components of study therapy prior to disease progression (e.g., for toxicity), will continue 
in the study and will be followed for progressive disease and survival regardless of 
whether or not they subsequently receive new anti-leukemic therapy. 
The primary objective of the study is to test the following hypothesis: 
• 
Progression-free survival of obinutuzumab + venetoclax versus GClb (i.e., 
H0:  obinutuzumab + venetoclax = GClb versus 
H1:  obinutuzumab +  venetoclax ≠ GClb) 
 
Treatment comparisons will be made using a two-sided log-rank test (at 
0.05 significance-level, adjusted for the interim analyses), stratified by Binet stage.  If the 
null hypothesis is rejected and the observed HR is favorable for the 
obinutuzumab + venetoclax experimental arm, then it is concluded that 
obinutuzumab + venetoclax significantly lowers the risk of PFS events more than GClb.  

 
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A two-sided non-stratified log-rank test will be performed to support the primary analysis.  
Median PFS and the 95% confidence limits will be estimated using Kaplan-Meier 
survival methodology, with the Kaplan-Meier survival curve presented to provide a visual 
description.  PFS rates for 1, 2, and 3 years after randomization with 95% CIs will be 
reported.  Estimates of the treatment effect will be expressed as HR including 95% 
confidence limits estimated through a Cox proportional-hazards analysis stratified by 
Binet stage.  Primary analysis for FDA submission will be based on assessment of PFS 
by an Independent Review Committee (IRC). 
6.4.2 
Secondary Efficacy Endpoints 
The secondary endpoints of this study are: 
• 
PFS based on IRC-assessments (primary outcome for U.S. regulatory purposes), 
defined as the time from randomization to the first occurrence of progression or 
relapse or death from any cause 
• 
ORR (defined as rate of a clinical response of CR, Cri, or PR) at the completion of 
treatment assessment, as determined by the investigator according to the IWCLL 
guidelines (2008) 
• 
Complete response rate (CRR; defined as rate of a clinical response of CR or CRi) 
at the completion of treatment assessment, as determined by the investigator 
according to the IWCLL guidelines (2008) 
• 
MRD response rate (determined as the proportion of patients with MRD-negativity) 
measured in the peripheral blood at the completion of treatment assessment and 
also MRD response rate as measured in the bone marrow at the completion of 
treatment, both measured by ASO-PCR 
• 
OS, defined as the time between the date of randomization and the date of death 
due to 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. 
• 
MRD response rates in the peripheral blood at completion of combination treatment 
assessment (Cycle 9, Day 1 or 3 months after last IV infusion) and also MRD 
response rate as measured in the bone marrow, both measured by ASO-PCR 
• 
ORR at completion of combination treatment response assessment (Cycle 7, Day 1 
or 28 days after last IV infusion)  
• 
Duration of response, defined as the time from the first occurrence of a documented 
OR (CR, CRi or PR) to the time of progressive disease as determined by the 
investigator, or death from any cause 
• 
Best response achieved (CR, CRi, PR, stable disease, or PD) up to and including 
the assessment at completion of treatment assessment (within 3 months of last day 
of treatment) 
• 
EFS, defined as the time between date of randomization and the date of disease 
progression/relapse as assessed by the investigator, death, or start of a new 
anti-leukemic therapy.  Patients without an EFS event will be will be censored on the 
date of the last disease assessment. 

 
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• 
Time to new anti-leukemic treatment, defined as the time between the date of 
randomization and the date of first intake of new anti-leukemic therapy.  Patients 
who have not taken new anti-leukemic therapy will be censored at their last 
assessment prior to the analysis or date of death. 
 
The above secondary outcome measures of MRD will be on the basis of assessment 
performed centrally by ASO-PCR with MRD negativity defined using a cutoff of 10-4 (less 
than 1 cell in 10,000 leukocytes). 
MRD response rate will further be evaluated at completion of treatment using results of 
both peripheral blood and bone marrow where a patient will be considered MRD positive 
if either blood or bone marrow result is positive or both are missing.  A cross-tabulation 
will be provided of MRD status in peripheral blood and in bone marrow in patients with 
both samples available. 
MRD response rates at other timepoints during treatment and follow-up where MRD is 
measured in the peripheral blood (see Schedule of Assessments [Appendix 2 and 
Appendix 3]) will also be summarized.  Further details regarding MRD analyses will be 
provided in the SAP. 
Secondary time-to-event endpoints will be analyzed using the same statistical methods 
described for the primary analysis of PFS. 
Sensitivity analyses for PFS utilizing different censoring mechanism (such as for patients 
withdrawing due to toxicity) will be performed to assess the robustness of the primary 
analysis of PFS.  These will be described in the SAP. 
Response rates in the treatment groups will be compared using 
Cochran-Mantel-Haenszel test stratified by Binet stage.  Rates and 95% CIs will be 
reported for each treatment group. 
Type 1 error control for statistical testing of selected secondary endpoints will be 
specified in the SAP. 
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, obinutuzumab, or chlorambucil), 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 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.  

 
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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. 
6.6 
PHARMACODYNAMIC ANALYSES 
For each visit at which CD19 + CD5 + and CD19 + CD5 −  B-cell measurements are taken, 
B-cell data will be listed for individual patients by treatment arm: 
• 
Absolute counts 
• 
Percent relative to the baseline counts for the individual 
• 
Extent of CD19 + B-cell depletion (nadir) 
• 
Duration of depletion 
• 
Time to Recovery 
 
CD19+
 B-cell measurements will be summarized for each visit by the three treatment 
arms.  The parameters summarized will be CD19 + B-cell counts, percentage of baseline 
counts, nadir, time to nadir, duration of depletion, and time to recovery.  Exploratory 
analyses will be performed to assess the possible relationship between the 
pharmacokinetics of obinutuzumab and B-cell depletion. 
6.7 
PHARMACOKINETIC ANALYSES 
PopPK methods will be used to characterize the pharmacokinetics of venetoclax and 
obinutuzumab in this study in conjunction with appropriate historical data.  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 
popPK analysis may be reported separately from the Clinical Study Report. 
Concentrations of venetoclax and obinutuzumab may be summarized by timepoint.  
Additional PK analyses will be conducted as appropriate. 
6.8 
PATIENT-REPORTED OUTCOME ANALYSES 
The secondary PRO endpoints for the study are as follows: 
• 
To compare disease and treatment-related symptoms following treatment with the 
combination of obinutuzumab + venetoclax compared with GClb in patients with 
previously untreated CLL and coexisting medical conditions between arms as 
measured by MDASI-CLL. 

 
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• 
To evaluate changes in role functioning and health-related quality of life (HRQoL) 
following treatment with the combination of obinutuzumab + venetoclax compared 
with GClb in patients with previously untreated CLL and coexisting medical 
conditions between arms as measured by EORTC QLQ-C30  
 
The analysis of all other scales will be considered an exploratory endpoint. 
A repeated measures for mixed models will be used to compare changes from baseline 
between the arms. 
Scoring for the MDASI-CLL and EORTC QLQ-C30 questionnaires will be based on the 
corresponding user manual.  For scales with more than 50% of the constituent items 
completed, a pro-rated score will be computed that is 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-CLL and EORTC QLQ-C30 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 SAP. 
6.9 
HEALTH ECONOMICS ANALYSIS 
Health economics data, as assessed by the EQ-5D-3L, will be evaluated for patients 
with a baseline assessment and at least one post-baseline EQ-5D-3L 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 economics data analysis may be reported separately from 
the Clinical Study Report. 
6.10 
EXPLORATORY ANALYSES 
• 
The relationship between various baseline markers and clinical outcome parameters 
including the primary PFS outcome will be assessed in patients from both arms of 
the study (including but not limited to CLL FISH (17p-, 11q-, 13p-, + 12q), IGHV 
mutation status, p53 mutation status, serum parameters, Bcl-2 expression and other 
CLL disease markers.  
• 
Exploratory analyses of MRD negativity by timepoint will also be performed using 
new technologies including flow cytometry and Next-Generation Sequencing with 
MRD negativity defined using a cutoff of 10-4 (less than 1 cell in 10,000 leukocytes) 
for comparison with ASO-PCR and secondly by the limit of sensitivity of each of the 
above technologies. 
 
Also, exploratory analyses will be performed, including graphical analyses, of the 
relationship between MRD (on the basis of peripheral blood results by ASO-PCR) and 
PFS. 

 
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6.11 
INTERIM ANALYSES 
In addition to the periodic safety data reviews, the iDMC will evaluate efficacy and safety 
at the formal interim analysis of PFS and recommend if the study should be stopped 
early for efficacy (Section 9.4.2).  
Summaries and analyses will be prepared by an independent data coordinating center 
and presented by treatment arm for the iDMC's review.  
An interim efficacy analysis may be conducted at or after 1 year after the last patient’s 
last venetoclax dose (i.e., Month 37 of the study [August 2018]), provided that at least 
85 PFS events (50% of the total of 170 PFS events) have occurred.  If 85 PFS events 
have not been observed by 1 year after the last patient’s last venetoclax dose, then the 
interim analysis may be conducted once a minimum of 85 PFS events have occurred.  
PFS will be tested at the significance level determined using the gamma family error 
spending function with parameter γ=−21.12 so that the overall two-sided type I error 
rate will be maintained at the 0.05 level.  This gamma family boundary only allows the 
study to stop for efficacy if a treatment effect HR of 0.35 or better is observed when the 
interim analysis is based on 85 events. 
Because this option is added to mitigate a potential delay in the study read-out, the 
Sponsor’s decision to conduct this interim analysis will be based on a number of 
factors including, but not limited to, the number of events observed by 1 year after the 
last patient’s last venetoclax dose and the subsequent predicted time to reach 
110 events.  If the Sponsor does not conduct this interim analysis or if this interim 
analysis is conducted and is negative, then the Sponsor will proceed with the later 
original interim analysis as follows. 
Provided the above early interim analysis is not done or not passed, theoriginal interim 
analysis for efficacy will be performed once a minimum of 110 PFS events have 
occurred.  PFS will be tested at the significance level determined using the gamma 
family error spending function with parameter γ=−9.21 so that the overall two-sided type I 
error rate will be maintained at the 0.05 level.  If the early interim analysis (at a 
minimum of 85 events) is performed and is passed, thise later original interim analysis 
will not be undertaken. 
The final analysis is designed to be conducted after 170 events have occurred. The 
significance level will be adjusted to incorporate the α spent at either interim analysis 
done, so that the overall two-sided type I error rate will be maintained at the 0.05 level. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 

 
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eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory and other electronic 
data (i.e., IRC data) will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
Paper PRO questionnaires will be faxed or couriered from the site to a data entry center. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of 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 Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs 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 
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. 
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 

 
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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 7.5. 
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 study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study 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. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data, 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 Sponsor.  Written 
notification should be provided to the Sponsor 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 
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 

 
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applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s 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 Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's 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 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. 
The 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 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 updated or revised 
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 Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated 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. 

 
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For sites in the United States, each 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 (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 Sponsor maintains 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 be disclosed 
to third parties only 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. 
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. 

 
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8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor 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 (i.e., 5 years after last 
patient enrolled) 
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, including 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. 
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. 
9.4 
ADMINISTRATIVE STRUCTURE  
9.4.1 
Roles and Responsibilities 
Roles and responsibilities between GCLLSG, AbbVie Inc., F. Hoffmann-La Roche Ltd, 
and 
. will be described in separate documents. 
9.4.2 
Independent Data Monitoring Committee 
The iDMC will review the safety data once the randomization is opened.  A first safety 
analysis is planned to occur at the earliest of the following being reached: 
• 
100 patients randomized and treated for 3 months  
OR 
• 
9 months have elapsed since the first patient was randomized.   

 
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OR  
• 
a new case of treatment-related death 
 
Before the first safety analysis occurs the iDMC will review safety data approximately 
every month depending on the rate of initial recruitment into the study.  All further iDMC 
reviews will take place approximately twice per year and the iDMC will review all safety 
data collected during the study and the results of any interim analyses performed.  
For each review, the iDMC will be provided with: 
• 
General toxicity (NCI CTCAE):  Grade 3 and Grade 4 adverse events, all serious 
adverse events 
• 
Laboratory data (hematology and biochemistry) 
• 
Any adverse event that requires discontinuation of the study drug  
• 
Patient deaths  
• 
Concomitant medications 
 
Following each meeting, the iDMC will recommend to the Sponsor whether the study 
may continue according to the protocol, or the iDMC may suggest changes be made to 
the protocol on the basis of the outcome of the data review.  In exceptional cases, the 
iDMC may recommend stopping the study or closing a treatment arm due to safety 
reasons or an overwhelming benefit or lack of efficacy.  
An Independent Data Coordinating Center (iDCC) that is independent of the Sponsor will 
prepare analyses for review. 
Further details about the definition, the role as well as the responsibility of the iDMC will 
be provided in a separate document, the iDMC Charter. 
9.4.3 
Independent Review Committee 
Response will be assessed according to the IWCLL guidelines (2008).  The investigator 
assessment of response and progression will be considered primary for all endpoints 
described in the study, except for the U.S. regulatory purposes, where the primary 
endpoint will be IRC-assessed PFS.  The IRC will be composed of at least three experts 
(two reviewers and one adjudicator).  IRC assessment will be based on peripheral blood 
counts, bone marrow biopsy results, and reports of physical examination.  Further details 
about the responsibility and procedures of the IRC will be provided in a separate 
document, the IRC Charter. 
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 Sponsor 
prior to submission.  This allows the Sponsor to protect proprietary information and to 

 
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provide comments based on information from other studies that may not yet be available 
to the investigator. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor 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. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  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). 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
137/Protocol BO25323, Version 7 
10. 
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Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
141/Protocol BO25323, Version 7 
Appendix 1  
Schedule of Assessments Treatment-Period Visits (RAMP-UP to 400 mg) 
 
Screening 
Cycle 1 
Cycle 2 
Day −28 to −1 
1 a 
2 
8 
15 
22 
(20 mg) 
23 
1 
(50 
mg) 
2 
8 
(100 mg) 
9 
15 
(200 mg) 
16 
22 
(400 mg) 
23 
Informed Consent b 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent for 
GCLLSG biobanking  
(optional) b  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLS Lab-Based Risk 
Assessment and 
monitoring c 
x 
x 
x 
 
 
x 
x 
xd 
x 
x 
x 
x 
x 
x 
x 
General medical 
history, CIRS score, 
IADL and baseline 
conditions 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs e 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
Weight 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Staging f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphadenopathy 
(during physical 
exam/Binet staging 
at screening) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 1 
Schedule of Assessments Treatment Period Visits (RAMP-UP to 400 mg) (cont.) 
 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
142/Protocol BO25323, Version 7 
 
Screening 
Cycle 1 
Cycle 2 
Day −28 to −1 
1 a 
2 
8 
15 
22 
(20 mg) 
23 
1 
(50 
mg) 
2 
8 
(100 mg) 
9 
15 
(200 mg) 
16 
22 
(400 mg) 
23 
Liver/spleen (by 
physical 
examination) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 12 lead 
x 
As clinically indicated 
LVEF 
As clinically indicated 
ECOG performance 
status 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
B symptoms 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
CT scan 
assessment g 
x 
If PD is detected and confirmation of CR/PR at 3 months post treatment 
Bone marrow biopsy 
h 
(x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization 
 
(x) 
 
 
 
Mandatory hospitalization for patients at high-risk for TLS on Day 1 of 20-mg and 50-mg doses 
and possibly Day 1 of 100-mg, 200-mg, and 400-mg doses in treatment Arm A only 
Obinutuzumab 
(Arms A and B) i 
 
x 
(x) 
x 
x 
 
 
x 
 
 
 
 
 
 
 
Venetoclax Arm A 
 
 
 
 
 
Daily, as per dosing chart schedule (20, 50, 100, 200, 400mg) for 12 cycles starting 
C1D22 

Appendix 1 
Schedule of Assessments Treatment Period Visits (RAMP-UP to 400 mg) (cont.) 
 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
143/Protocol BO25323, Version 7 
 
Screening 
Cycle 1 
Cycle 2 
Day −28 to −1 
1 a 
2 
8 
15 
22 
(20 mg) 
23 
1 
(50 
mg) 
2 
8 
(100 mg) 
9 
15 
(200 mg) 
16 
22 
(400 mg) 
23 
Chlorambucil Arm B 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events b 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serious AEs and 
Grade 3 and 4 
infections b 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PRO questionnaires 
(MDASI-CLL, 
EQ-5D-3L, and 
EORTC-QLQ C30) t 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Local laboratory j 
Immunoglobulins 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV, HCV, HTLV1 
(if applicable)k 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coombs test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation (aPTT, 
PT, INR) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test l 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Urinalysis m 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

Appendix 1 
Schedule of Assessments Treatment Period Visits (RAMP-UP to 400 mg) (cont.) 
 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
144/Protocol BO25323, Version 7 
 
Screening 
Cycle 1 
Cycle 2 
Day −28 to −1 
1 a 
2 
8 
15 
22 
(20 mg) 
23 
1 
(50 
mg) 
2 
8 
(100 mg) 
9 
15 
(200 mg) 
16 
22 
(400 mg) 
23 
 Central Laboratory j 
Serum parameters 
(β2 microglobulin, 
thymidine kinase) 
 
xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
CLL markers 
(DNA/RNA) 
 
xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flow cytometry 
(BCL2 family and 
CLL counts) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional tumor 
tissue for Bcl-2 
family analysis by 
IHC (formalin fixed 
tissue) 
 
xq 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD (ASO-PCR)r 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD (NGS) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Laboratory j 
Evaluation of 
resistance by 
CD40L, simulation 
 
xp,s 
 
 
 
 
 
 
 
 
 
 
 
 
 
Metaphase 
cytogenetics 
 
xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCLLSG Biobanking 
sample 
 
xs 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 1 
Schedule of Assessments Treatment Period Visits (RAMP-UP to 400 mg) (cont.) 
 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
145/Protocol BO25323, Version 7 
 
Screening 
Cycle 1 
Cycle 2 
Day −28 to −1 
1 a 
2 
8 
15 
22 
(20 mg) 
23 
1 
(50 
mg) 
2 
8 
(100 mg) 
9 
15 
(200 mg) 
16 
22 
(400 mg) 
23 
Genetic analysis, 
(IGVH mutation 
status, cytogenetics 
(FISH), gene 
mutations and 
resistance markers 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for 
lymphocyte 
immunophenotyping 
(for diagnosis, safety 
monitoring, IRR 
prediction, 
ZAP70/CD38) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD (flow) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 1 
Schedule of Assessments Treatment Period Visits (RAMP-UP to 400 mg) (cont.) 
 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
146/Protocol BO25323, Version 7 
AE = adverse event; ASO-PCR = allele-specific oligonucleotide polymerase chain reaction; C = cycle; CIRS = Cumulative Illness Rating Scale; 
CLL = chronic lymphocytic leukemia; CR = complete response; CT = computed tomography; D = day; ECOG = Eastern Cooperative Oncology Group; 
eCRF = electronic Case Report Form; EORTC = European Organization for Research and Treatment of Cancer; EQ-5D-3L = EuroQol 5-Dimension 
questionnaire; GCLLSG = German CLL Study Group; IADL = Instrumental Activity of Daily Living IHC = immunohistochemistry; INR = international 
normalized ratio; IRR = infusion-related reaction; LVEF = left ventricular ejection fraction; MDASI-CLL = M.D. Anderson Symptom Inventory-Chronic 
Lymphocytic Leukemia; MRD = minimal residual disease; MRI = magnetic resonance imaging; NGS = next-generation sequencing; PD = disease 
progression; PR = partial response; PRO = patient-reported outcome; Tmt = treatment; TLS = tumor lysis syndrome. 
Notes:  All assessments during treatment period and at the follow-up Day 28 visit should be performed within 7 days of the scheduled visit, 
unless otherwise specified.  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  On treatment 
days:  pre-infusion laboratory samples should be drawn 0−4 hours before the start of infusion.  On Day 1 of each venetoclax dose ramp-up (e.g., 20 
mg [C1D22], 50 mg [C2D1], 100 mg [C2D8], 200 mg [C2D15], 400 mg [C2D22]), laboratory analyses will be required predose and at 8 and 
24 hours postdose to ensure that there are no abnormal changes.  If the patient is an inpatient, an additional 12 hours post-dose initiation 
hematology and chemistry is required. Laboratory values must be read by a clinician prior to taking the next venetoclax dose. 
a Samples should be taken after randomization number has been assigned. 
b After informed consent has been obtained but prior to initiation of study drug, only adverse events and serious adverse events caused by a 
protocol-mandated intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the last 
dose.  After this period, the investigator is not required to actively monitor patients for adverse events; however, the Sponsor should be notified if 
the investigator becomes aware of any post study serious adverse events or adverse events of special interest.  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. 
c Chemistry and hematology must also be assessed within 0−4 hours prior and 24 hours after the first obinutuzumab and venetoclax dose, and 
within 0−4 hours prior and 24 hours after each new (increased) venetoclax dose during the venetoclax dose-ramp up phase.  If it is not possible 
to review results from a sample taken up to 4 hours predose, then it is acceptable to take a predose hematology and chemistry sample within 
24 hours prior to dosing.  The results of these samples must be reviewed prior to dosing.  If laboratory values from this sample have 
demonstrated no clinically significant abnormalities, the hematology and chemistry samples drawn on the day of venetoclax administration prior 
to dosing are not required to be reviewed prior to dose administration.  However, these predose (0−4 hours prior to dosing) laboratory samples 
should still be drawn, and these will serve as baseline for later laboratory values when assessing for laboratory evidence of TLS. 
d For Cycle 2 only, in addition to Day 1, the TLS assessment must be performed on Day 8, Day 15, and Day 22.  
e Includes:  pulse rate and systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
High TLS risk subjects must have vital signs performed before and 8, 12, 24 hours after venetoclax 20mg and 50 mg dose ramp up. 

Appendix 1 
Schedule of Assessments Treatment Period Visits (RAMP-UP to 400 mg) (cont.) 
 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
147/Protocol BO25323, Version 7 
f Physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History 
and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  
Binet staging will be assessed using data collected at the screening visit.  Physical examinations may be performed 1 day prior to a planned 
treatment visit to facilitate scheduling. 
g CT Scan allowed 8 weeks prior to randomization and required as confirmation of CR/PR at 3months after end of treatment. MRI only if contrast 
enhanced CT not possible. 
h A bone marrow aspirate and biopsy is optional at screening (investigator discretion if clinically indicated) and must be taken at the end of 
treatment response assessment at the end of combination therapy at 9 months (Cycle 9) in patients with a CR or a PR. 
i Obinutuzumab may be given over two days if subject is considered high risk for infusion related reaction (IRR),or as per standard of care (SOC). 
j For samples drawn on days of study treatment, predose 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.  
k Certain patients (occult or prior HBV infection) require monthly DNA testing, although the data is not collected for the study. 
l All women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy test 
at screening. If serum pregnancy test has not been performed 14 days prior to the first dose, a urine pregnancy test must be performed 7 days 
prior to the first dose.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Further, all women who are not 
postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy test monthly while receiving 
study drug and at the Treatment Completion/Early Termination visit. 
m Includes:  dipstick pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria). 
n Includes:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells. 
o Includes:  sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and 
direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH. 
p Sample should be taken after randomization number is assigned and before first dose. 
q If formalin fixed specimen of bone marrow biopsy (also including lymph node or other biopsies) are collected at baseline by the site as per 
standard clinical assessment of the patient, a sample should be provided for IHC analysis of Bcl-2 family.  
r Blood. Additional bone marrow aspirate at completion of combination therapy (Cycle 9, Day 1 or 3 months after last IV infusion) and at the 
completion of treatment assessment (a minimum of 3 months after last treatment) for patients with CR/CRi and PR. 
s For patients who have signed the additional consent for GCLLSG biobanking, residual sample will be sent to the GCLLSG for analysis.  

Appendix 1 
Schedule of Assessments Treatment Period Visits (RAMP-UP to 400 mg) (cont.) 
 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
148/Protocol BO25323, Version 7 
t  PRO questionnaires scheduled for administration during a clinic visit should be completed prior to the performance of non-PRO assessments 
and the administration of study treatment. 
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
149/Protocol BO25323, Version 7 
Appendix 2  
Schedule of Assessments Cycle 3−Cycle 12 and Follow-Up Day 28 
Assessment 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C12 
Day 28 after 
Treatment 
Completion/Early 
Termination a 
General medical history 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (Day 1 of each cycle only) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Complete physical examination 
 
x 
 
 
x 
 
x 
 
 
 
x 
Lymphadenopathy (during physical 
examination) 
 
x 
 
 
x 
 
x 
 
 
 
x 
Liver and spleen by physical examination 
 
x 
 
 
x 
 
x 
 
 
 
x 
ECG 12 lead 
As clinically indicated 
 
LVEF 
As clinically indicated 
 
ECOG performance status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
B-symptoms 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
CT scan if PD is detected lymph nodes 
only 
x 
Bone marrow aspirate and biopsy (MRD) 
CR/PR 
 
 
 
 
 
 
x 
 
 
 
 
Obinutuzumab Arm A and B 
x 
x 
x 
x 
 
 
 
 
 
 
 
Chlorambucil Arm B (Days 1 and 15) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Venetoclax Arm A 
Daily dosing 400 mg for 10 cycles 
 
Staging and response assessment 
 
x 
 
 
x 
 
x 
 
 
 
x 
CT scan confirmation of CR/PR 
 
 
 
 
 
 
 
 
 
 
 

Appendix 2 
Schedule of Assessments Cycle 3−Cycle 12 and Follow-Up Day 28 (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
150/Protocol BO25323, Version 7 
Assessment 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C12 
Day 28 after 
Treatment 
Completion/Early 
Termination a 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
AEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SAEs/Grade3/4 infections 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PRO questionnaires (MDASI-CLL, EQ-
5D-3L, EORTC QLQ C30) b 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Local laboratory 
 
 
 
 
 
 
 
 
 
 
 
Hematology (Days 1 and 15) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Biochemistry (Days 1 and 15) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy Test c 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 Central Laboratory 
 
 
 
 
 
 
 
 
 
 
 
MRD (ASO-PCR) 
 
 
 
 
x 
 
x 
 
 
x 
 
MRD (NGS)  
 
 
 
 
x 
 
x 
 
 
x 
 
PK samples for obinutuzumab d 
 
x 
(Arm A 
only) 
 
 
 
 
 
 
 
 
 
PK samples for venetoclax d 
 
x 
(Arm A 
only) 
 
 
 
 
 
 
 
 
 
 Laboratory 
 
 
 
 
 
 
 
 
 
 
 
MRD (flow) 
 
 
 
 
x 
 
x 
 
 
x 
 
Blood for safety monitoring/B-cell 
recovery 
 
 
 
 
 
 
 
 
 
 
x 

Appendix 2 
Schedule of Assessments Cycle 3−Cycle 12 and Follow-Up Day 28 (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
151/Protocol BO25323, Version 7 
AE = adverse event; ASO-PCR = allele-specific oligonucleotide polymerase chain reaction; C = cycle; CR = complete response; CT = computed 
tomography; ECOG = Eastern Cooperative Oncology Group; EORTC = European Organization for Research and Treatment of Cancer; 
EQ-5D-3L = EuroQol 5-Dimension questionnaire; IRR = infusion-related reaction; LVEF = left ventricular ejection fraction; MDASI-CLL = M.D. 
Anderson Symptom Inventory-Chronic Lymphocytic Leukemia; MRD = minimal residual disease; NGS = next-generation sequencing; PD = disease 
progression; PK = pharmacokinetic; PR = partial response; PRO = patient-reported outcome; SAE = serious adverse event; TLS = tumor lysis 
syndrome. 
Notes:  For laboratory samples drawn on days on study treatment, predose 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. 
a Patients who discontinue all study drug prior to completing 12 cycles of treatment should have their early termination visit performed 28 days 
after the last dose of study drug was administered.  Patients who discontinue study drug prior to completing 12 cycles of therapy should continue 
to be followed for disease progression per the schedule in Appendix 3. 
b PRO questionnaires scheduled for administration during a clinic visit should be completed prior to the performance of non-PRO assessments 
and the administration of study treatment. 
c All women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy test 
monthly while receiving study drug and at the Treatment Completion/Early Termination visit. 
d See Appendix 4 for Schedule of PK Assessments. 
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
152/Protocol BO25323, Version 7 
Appendix 3 
Schedule of Assessments (Follow-Up Period) 
 
Follow-Up Visits 
Duration from Last Study Drug Administration until Disease Progression 
Survival 
(All Patients) 
Assessment 
+ 3 months after Treatment 
Completion/Early 
Termination a 
+ 6, 9, 12, 15 and18 months 
after Treatment 
Completion/Early Termination 
+ 24 months after Treatment 
Completion/Early Termination then every 
6 months until 5 years from last patient 
enrolled 
Every year after 
disease progression 
until 5 years from 
last patient enrolled 
Complete physical examination 
x 
x 
x 
 
Weight 
x 
x 
x 
 
Vital signs b 
x 
x 
x 
 
ECG 12-lead 
As clinically indicated 
As clinically indicated 
As clinically indicated 
 
LVEF 
As clinically indicated 
As clinically indicated 
As clinically indicated 
 
Lymphadenopathy during 
physical examination c 
x 
x 
x 
 
Liver/spleen (by physical 
examination) 
x 
x 
x 
 
ECOG performance status 
x 
x 
x 
 
B symptoms 
x 
x 
x 
 
CT scan assessment (or MRI if 
performed at screening) 
x 
 
 
 
CT scan of involved nodes at 
time of PD if determined by 
physical examination alone 
x 
x 
x 
 
Concomitant medications 
x 
x 
x 
x 
Response assessment 
x 
x 
x 
 

Appendix 3 
Schedule of Assessments (Follow-Up Period) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
153/Protocol BO25323, Version 7 
 
Follow-Up Visits 
Duration from Last Study Drug Administration until Disease Progression 
Survival 
(All Patients) 
Assessment 
+ 3 months after Treatment 
Completion/Early 
Termination a 
+ 6, 9, 12, 15 and18 months 
after Treatment 
Completion/Early Termination 
+ 24 months after Treatment 
Completion/Early Termination then every 
6 months until 5 years from last patient 
enrolled 
Every year after 
disease progression 
until 5 years from 
last patient enrolled 
Follow-up for PD/disease 
transformation 
x 
x 
x 
 
After PD continue to follow-up 
for NLT 
x 
x 
x 
x 
PRO questionnaire (MDASI-
CLL, EQ-5D-3L, and EORTC-
QLQ C30) until NLT d 
x 
x 
x 
 
Collection of NLT  
 
 
 
x 
Grade 3 and 4 adverse events 
(until 6 months after the end of 
treatment) 
x 
x 
 
 
Unrelated SAEs  
x 
x 
x 
 
Grade 3 and 4 infections (until 
2 years after the end of 
treatment) 
x 
x 
x 
 
Related SAEs and secondary 
malignancies, indefinitely 
x 
x 
x 
x 
Hematology e 
x 
x 
x 
 
Chemistry f 
x 
x 
x 
 
Immunoglobulin (IgA, IgG, IgM) 
x 
x 
x 
 
Urinalysis g 
x 
 
 
 
GCLLSG biobanking h 
x (at timepoint of refractory disease or PD only) 

Appendix 3 
Schedule of Assessments (Follow-Up Period) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
154/Protocol BO25323, Version 7 
 
Follow-Up Visits 
Duration from Last Study Drug Administration until Disease Progression 
Survival 
(All Patients) 
Assessment 
+ 3 months after Treatment 
Completion/Early 
Termination a 
+ 6, 9, 12, 15 and18 months 
after Treatment 
Completion/Early Termination 
+ 24 months after Treatment 
Completion/Early Termination then every 
6 months until 5 years from last patient 
enrolled 
Every year after 
disease progression 
until 5 years from 
last patient enrolled 
Genetic analysis (IGHV 
mutation status, Cytogenetics 
[FISH], gene mutations and 
resistance markers) 
x (at time point of refractory disease or PD only) 
Evaluation of resistance by 
CD40L stimulation 
x (at time point of refractory disease or PD only) 
Flow cytometry (BCL2) 
x (at time point of refractory disease or PD only) 
BCL2 family and CLL markers 
(DNA/RNA) 
x (PD only) 
MRD (blood) 
x i 
x i 
x j 
 
Bone Marrow Aspirate 
x k 
 
 
 
Bone Marrow Biopsy 
x k 
 
 
 
Blood for safety monitoring/ 
B-cell recovery l  
 
x 
(12 and 18 months only) 
x 
 
AE = adverse event; ASO-PCR  = allele-specific oligonucleotide polymerase chain reaction; CLL = chronic lymphocytic leukemia; CR = complete 
response; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic Case Report Form; EORTC = European 
Organization for Research and Treatment of Cancer; EQ-5D-3L = EuroQol 5-Dimension questionnaire; FISH = fluorescence in situ hybridization; 
GCLLSG = German CLL Study Group; MDASI-CLL = M.D. Anderson Symptom Inventory-Chronic Lymphocytic Leukemia; MRD = minimal 
residual disease; MRI = magnetic resonance imaging; NLT = next anti-leukemia treatment; PD = progressive disease; PK = pharmacokinetic; 
PR = partial response; PRO = patient-reported outcome; RCR = Roche Clinical Repository; SAE = serious adverse event. 

Appendix 3 
Schedule of Assessments (Follow-Up Period) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
155/Protocol BO25323, Version 7 
Notes:  All assessments during treatment period and at the follow-up Day 28 visit should be performed within 7 days of the scheduled visit, 
unless otherwise specified.  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  Following the 
end of treatment assessment (3 months after treatment completion/early termination) all other follow-up assessments, whether tumor 
assessments or other study assessments, will be done within ±14 days for 3-monthly and within a month for 6-monthly assessments of the 
scheduled visits. 
a Visit should be performed no earlier than 2 months and no later than 3 months after end of treatment.  If the patient is in CR or PR following the 
CT scan a bone marrow examination should be performed a minimum of 3 months after the end of the treatment.  This visit also correlates to 
2 months after the Day 28 after Treatment Completion/Early Termination visit. 
b Includes pulse rate, respiratory rate and systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
c Physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History 
and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF 
d PRO questionnaires scheduled for administration during a clinic visit should be completed prior to the performance of non-PRO assessments 
and the administration of study treatment. 
e Includes: WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells. 
f Includes: sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and 
direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH. 
g Includes: dipstick pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria). 
h For patients who have signed the additional consent for GCLLSG biobanking, residual sample will be sent to the GCLLSG for analysis. 
i Blood for MRD assessment will include 10 mL of blood at all timepoints for ASO-PCR; 5 or 6 mL at baseline and 10 mL at other timepoints for 
analysis by NGS and flow cytometry 
j Blood for MRD assessment will include 10 mL of blood for ASO-PCR and 10 mL for analysis by NGS at 24 months after treatment 
completion/early termination and then every 6 months thereafter (until 5 years from last patient enrolled). 
k A bone marrow aspirate must be taken within 8 weeks from patients who achieve a CR/PR for central assessment of MRD.  Bone marrow 
aspirate (separate sample, assessed at a local laboratory) and biopsy to confirm CR is required. 
l For samples drawn on days of study treatment, predose 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 ≥ 24 hours after dose should be obtained within a ± 2-hour window of the scheduled time.  
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
156/Protocol BO25323, Version 7 
Appendix 4 
Schedule of Pharmacokinetic Assessments 
Pharmacokinetics is defined in this protocol as a dual timepoint drug level testing (18 mL 
blood at Cycle 4, Day 1 in all venetoclax [GDC-0199] patients [Arm A]). 
Blood samples to assess venetoclax and obinutuzumab concentrations in plasma and 
serum, respectively, will be collected at the following timepoints in patients who are 
randomized to Treatment A: 
Visit 
Timepoint 
Sample type and analyte 
Cycle 4, Day 1 
Pre venetoclax dose 
Plasma for venetoclax 
 
4 hours (± 1 hour) post- venetoclax dose 
Plasma for venetoclax 
 
Pre-obinutuzumab infusion 
Serum for obinutuzumab 
 
End of obinutuzumab infusion 
Serum for obinutuzumab 
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
157/Protocol BO25323, Version 7 
Appendix 5  
Sample List of Excluded and Cautionary Medications for 
Patients Randomized to Arm A (Venetoclax + Obinutuzumab) 
Type 
Medication 
Excluded during the venetoclax ramp-up period and cautionary after patients are on 400 mg/day 
of venetoclax  
Strong CYP3A inducers  
Avasimibe, carbamazepine (Tegretol), phenobarbital, 
phenytoin (Dilantin), rifampin (Rifadin), and St. John's 
wort 
Moderate CYP3A inducers  
Bosentan, efavirenz, etravirine, modafinil, and nafcillin 
Strong CYP3A inhibitors a 
Boceprevir, clarithromycin, conivaptan, indinavir, 
itraconazole, ketoconazole, mibefradil, lopinavir/ritonavir, 
nefazodone, nelfinavir, ritonavir, posaconazole, saquinavir, 
telaprevir, telithromycin, and voriconazole 
Moderate CYP3A inhibitors a 
Amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinibb, 
darunavir/ritonavir, diltiazem, erythromycin, fluconazole, 
fosamprenavir, imatinib b, and verapamil 
Cautionary throughout the study 
Warfarin 
 
Weak CYP3A inducers 
Amprenavir, aprepitant, armodafinil, clobazamechinacea, 
pioglitazone, prednisone, rufinamide, and vemurafenib b 
Weak CYP3A inhibitors 
Alprazolam, amiodarone, amlodipine, atorvastatin, 
bicalutamideb, cilostazol, cimetidine, cyclosporine b, 
fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, 
nilotinibb, oral contraceptives, pazopanibb, ranitidine, 
ranolazine, tipranavir/ritonavir, ticagrelor, and zileuton 
P-gp substrates 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, 
digoxin, everolimusb, fexofenadine, lapatinibb, loperamide, 
maraviroc, nilotinibb, ranolazine, saxagliptin, sirolimusb, 
sitagliptin, talinolol, tolvaptan, and topotecan b 
BCRP substrates 
Methotrexateb, mitoxantroneb, irrinotecanb, lapatinibb, 
rosuvastatin, sulfasalazine, and topotecanb 
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, 
dronedarone, felodipine, quercetin, ronalzine, and ticagrelor 
 

 
Appendix 5 
Sample List of Excluded and Cautionary Medications for 
Patients Randomized to Arm A (Venetoclax + Obintuzumab) 
(cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
158/Protocol BO25323, Version 7 
Type 
Medication 
BCRP inhibitors 
Gefitinibb, cyclosporineb 
OATP1B1/B3 inhibitors 
Gemfibrozil, eltrombopag, cyclosporineb, tipranavir 
Note:  This is not an exhaustive list.  For an updated list, see the following link:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm  In addition to the medications listed in this table, subjects receiving 
venetoclax should not consume grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges), or star fruits. 
a 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. 
b These are anticancer agents; contact Medical Monitor before use. 
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
159/Protocol BO25323, Version 7 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) 
Body system 
Score 
1. Cardiac (heart only) 
0 
1 
2 
3 
4 
2. Hypertension (rating is based on severity; organ damage is rated 
separately) 
0 
1 
2 
3 
4 
3. Vascular (blood, blood vessels and cells, bone marrow, spleen, 
lymphatics) 
0 
1 
2 
3 
4 
4. Respiratory (lungs, bronchi, trachea below the larynx) 
0 
1 
2 
3 
4 
5. EENT (eye, ear, nose, throat, larynx) 
0 
1 
2 
3 
4 
6. Upper GI (esophagus, stomach, and duodenum; pancreas; do not 
include diabetes) 
0 
1 
2 
3 
4 
7. Lower GI (intestines, hernias) 
0 
1 
2 
3 
4 
8. Hepatic (liver and biliary tree) 
0 
1 
2 
3 
4 
9. Renal (kidneys only) 
0 
1 
2 
3 
4 
10. Other GU (ureters, bladder, urethra, prostate, genitals) 
0 
1 
2 
3 
4 
11. Muscolo-skeletal-integumentary (muscle, bone, skin) 
0 
1 
2 
3 
4 
12. Neurological (brain, spinal cord, nerves, do not include dementia) 
0 
1 
2 
3 
4 
13. Endocrine-Metabolic (includes diabetes, thyroid; breast; systemic 
infections; toxicity) 
0 
1 
2 
3 
4 
14. Psychiatric/Behavioral (includes dementia, depression, anxiety, 
agitation/delirium, psychosis) 
0 
1 
2 
3 
4 
 
PHILOSOPHY AND DEVELOPMENT OF THE SCALE 
Compiling and quantifying medical problems in the elderly population would allow 
meaningful comparison of medical burden and treatment outcomes in elderly patients 
with variable and complex medical problems. 
The Cumulative Illness Rating Scale (CIRS) was initially developed by Linn et al. and 
published in JAGS 1968; it appeared immediately a user friendly but comprehensive 
review of medical problems by organ systems, based on a 0−4 rating, yielding a 
cumulative score. 
This scale was successively revised by Miller et al. to reflect common problems of the 
elderly with an emphasis on morbidity using specific examples and was renamed CIRS 
for Geriatrics (CIRS-G) (Miller et al. 1992); moreover, Miller and Towers provided also a 
manual of guidelines for scoring their version (Miller et al. 1991). 
Then, in 1995, Parmelee et al. validated a Modified CIRS version, based on a 1−5 rating 
and with some differences in categories, in a geriatric residential population 
(Parmelee et al. 1995). 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
160/Protocol BO25323, Version 7 
Finally, Mistry et al. used this latter Modified CIRS version with a 0 thru 4 rating to 
measure medical burden in psychogeriatric participants of the UPBEAT program, 
showing that inclusion of acute medical conditions did not undermine the usefulness of 
the CIRS (Mistry et al. 2004). 
Based on the version of Miller and Towers, current guidelines were adapted to the 
Modified CIRS version and updated. 
EDUCATION OF RATER 
Nurses, physician assistants, nurse practitioners, or physicians are required to have a 
necessary background for completing this scale.  Due to the judgment required, some 
physician consultation may be necessary to clarify complex medical problems or 
their severity. 
THE MINIMUM DATABASE REQUIRED 
It is expected that every patient should have a complete history and physical 
examination with a detailed problem list, height and weight (to calculate body mass 
index, BMI), and baseline labs including a complete blood count and differential, 
chemistry profile to include electrolytes, liver and kidney function, serum B12, thyroid 
function, cholesterol level, hemoglobin A1c (for diabetic patients), and an EKG.  For 
rating psychiatric conditions, the rater is expected to be familiar with the Mini Mental 
Status Examination (Folstein et al. 1975), and the Diagnostic and Statistical Manual IV 
(DSM IV) APA 1994).  A checklist of needed information is available in the Appendix. 
RATING SUGGESTIONS (GENERAL PRINCIPLES) 
Every single disease must be classified in the appropriate system.  If there are several 
problems in the same system, only the most severe is rated.  Example:  for a patient 
suffering from a well-controlled angina (Rated 2) and terminal heart failure (Rated 4), 
only the higher rated condition would be scored in the Cardiac system (e.g., rating is 4). 
The spread of a cancer may lead to rate the condition in more than one category.  
For example, a lung cancer with bone metastases treated with nonsteroidal 
anti-inflammatory drugs (NSAIDs) is Rated 4 in Respiratory and 2 in Musculoskeletal. 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
161/Protocol BO25323, Version 7 
General rules for severity rating: 
1. 
 No problem affecting that system or past problem without clinical relevance. 
2. 
Current mild problem or past significant problem. 
3. 
Moderate disability or morbidity and/or requires first line therapy. 
4. 
Severe problem and/or constant and significant disability and/or hard to control 
chronic problems (complex therapeutic regimen). 
5. 
Extremely severe problem and/or immediate treatment required and/or organ failure 
and/or severe functional impairment. 
 
LEVEL 0 
No problem or healed minor injuries; past childhood illnesses (chickenpox); 
minor surgery (carpal tunnel completely healed, caesarean); uncomplicated healed 
fractures; other past problems healed without sequel, residual or complication 
(pneumonia). 
LEVEL 1 
Any current medical problem that causes mild discomfort or disability, or has occasional 
exacerbations, having only minor impact on morbidity (asthma controlled with PRN 
bronchodilators, occasional heartburn relieved with PRN antacids).  Medical problems 
that are not currently active but were significant problems in the past (passage of a 
kidney stone) or required major surgery (hysterectomy, cholecystectomy, 
appendectomy). 
LEVEL 2 
Medical conditions that require daily treatment or first line therapy (asthma controlled 
with inhaled steroids, gastro-esophageal reflux treated with daily medication, 
osteoarthritis requiring daily NSAID, etc.) and/or have moderate disability or morbidity. 
LEVEL 3 
Chronic conditions that are not controlled with first line therapy (asthma needing 
continuous corticosteroid therapy, symptomatic angina despite medical regimes,  
heart failure with symptoms or uncontrolled hypertension despite complex therapeutic 
regimen) and/or constant significant disability, but not severe disability. 
LEVEL 4 
Any acute condition that requires immediate treatment or hospitalization 
(unstable angina, acute myocardial infarction, stroke, but also bladder outlet obstruction) 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
162/Protocol BO25323, Version 7 
and/or extremely severe problems; organ failure (end-stage renal disease needing 
dialysis, oxygen-dependent chronic obstructive pulmonary disease, terminal 
heart failure); severe sensory impairment (almost complete blindness or deafness, 
being wheelchair bound) and/or severely affected quality of life, severe impairment in 
function; delirium by medical (organic) conditions. 
RATING MALIGNANCIES 
Consistent scoring of severity ratings for various malignancies is a difficult problem.  
Each malignancy has its own rating system and prognostic indicators, the complexity of 
which would quickly exceed the aim of the intended simplicity and ease of use of CIRS. 
The following general guidelines are intended to provide a reasonably accurate 
delineation of medical burden for cancer without excessive complexity. 
• 
Level 1:  Cancer diagnosed in the remote past without evidence of recurrence or 
sequel in the past 10 years or skin cancer excised in the past without major sequel 
(other than melanoma). 
• 
Level 2:  No evidence of recurrence or sequel in the past 5 years. 
• 
Level 3:  Required chemotherapy, radiation, hormonal therapy or surgical procedure 
for cancer in the past 5 years. 
• 
Level 4:  Recurrent malignancy or metastasis (other than to lymph glands) or 
palliative treatment stage. 
 
These ratings are to be made in the appropriate organ category for a given malignancy. 
ORGAN-SPECIFIC CATEGORIES 
The following organ-specific categories will attempt to provide guidelines for consistent 
rating of comparable severity.  Common conditions will be stressed with the focus on the 
“judgment strategy” that can be applied to other problems not listed.  
If there are several problems in the same system, only the most severe is rated. 
HEART 
In this category, only heart and coronary disease have to be considered (not vascular):  
coronary arteries disease, heart failure, valvular heart diseases, heart disease 
secondary to hypertension, endocardities, miocardities, pericardities, arrhythmias 
(extrasystoles, bundle-branch blocks, atrial fibrillation, PMK placement), 
heart malignancies.  Functional impact must be considered too (e.g., NYHA II heart 
failure has different value between dependent and independent persons). 
0. 
No problems 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
163/Protocol BO25323, Version 7 
1. 
Remote MI (> 5 years ago); occasional [exertion] angina; asymptomatic 
valvular disease 
2. 
CHF compensated with meds (NYHA I-II); daily anti-angina meds; left ventricular 
hypertrophy; atrial fibrillation, bundle branch block, daily anti-arrhythmic drugs (even 
for prophylaxis); PMK placement for asymptomatic bradycardia (relieved by Holter 
EKG monitoring); valvular disease requiring medical treatment 
3. 
Previous MI (< 5 years ago); abnormal stress test; status post (previous) 
percutaneous coronary angioplasty, coronary artery bypass graft surgery or other 
cardiac surgery (valve replacement); moderate CHF (NYHA II−III) or complex 
medical treatment; bifascicular block; PMK placement for cardiogenic syncope; 
pericardial effusion or pericarditis 
4. 
Acute coronary syndrome, unstable angina or acute MI; intractable CHF 
(NYHA III−IV acute or chronic); marked restriction to the normal activity of daily 
living secondary to cardiac status 
 
HYPERTENSION 
Consider only hypertension severity; organ damage (complications) should be 
considered into the respective categories. 
0. 
Normotension 
1. 
Borderline hypertension; hypertension compensated with salt restriction and weight 
loss, drug free (when drug therapy is indicated, but the patient does not take meds, 
the score is at least 2) 
2. 
Daily antihypertensive meds:  hypertension controlled by 1 pill therapy (even fixed 
doses combinations) 
3. 
Hypertension requiring two or more pills for control 
4. 
Malignant hypertension, or hypertension non-controlled by complex 
therapeutic regimen 
 
VASCULAR-HEMATOPOIETIC 
Artery disease:  carotid atherosclerosis, peripheral arteries disease (PAD), 
aneurysms (every site); 
Venous disease:  venous insufficiency, varices, deep venous thrombosis (DVT), 
pulmonary embolism, primary pulmonary hypertension; 
Hematopoietic disease:  anemia, leucopenia, thrombocytopenia, 
hematological malignancy; 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
164/Protocol BO25323, Version 7 
Lymphopoietic disease:  chronic lymphatic edema, lymphoma, spleen and 
thymus disease; 
Immunologic disease:  systemic lupus erythematosus, systemic sclerosis (scleroderma), 
sarcoidosis, hypersensitivity 
5. 
No problem 
6. 
Venous insufficiency, varices, lymphedema; carotid stenosis  < 70%; hemoglobin 
10−12 g/dL (in females), 12−14 g/dL (in males); anemia of chronic 
“inflammatory” disease 
7. 
Previous DVT; one symptom of atherosclerosis disease (claudication, bruit, 
amaurosis fugax, absent pedal pulses) or daily meds (e.g., anti-platelets drugs); 
PAD IIa−IIb by Fontaine; carotid stenosis > 70%; aortic aneurysm < 4 cm; 
hemoglobin 8−10 g/dL (in females), 10−12 g/dL (in males); anemia secondary to 
iron, B12 vitamin or folate deficiency, or to chronic renal failure; total white blood cell 
(WBC) 2000−4000/mmc; mild thrombocytopenia (50000−150000/mmc) 
8. 
DVT or recent DVT (< 6 months ago); two or more symptoms of atherosclerosis 
(see above); PAD Fontaine III or recent/previous angioplasty (with or without 
stenting); hemoglobin < 8g/dL (in females), <10 g/dL (in males); dyserythropoietic 
anemia; WBC < 2000/mmc; severe thrombocytopenia (< 50000/mmc) 
9. 
Pulmonary embolism (acute or recent/previous); atherosclerosis requiring surgical 
intervention (e.g., aortic aneurysm > 4 cm, symptomatic carotid stenosis > 70%, 
PAD Fontaine IV or amputation for vascular causes, etc.); recent/previous vascular 
surgery; any hematological or vascular malignancy (including multiple myeloma) 
 
In case of immunological disease, score should be assigned by considering blood 
abnormalities, stadium of organ damage and/or functional disability (2:  symptoms 
controlled by daily meds; 3:  symptoms not well controlled; 4:  symptoms impossible to 
be controlled or short time poor prognosis). 
RESPIRATORY 
In this category COPD, asthma, emphysema, restrictive pulmonary interstitial lung 
diseases, malignancies of lung and pleura, pneumonia, and smoking status are 
considered. 
10. No problem 
11. Recurrent episodes of acute bronchitis; currently treated asthma with prn inhalers 
when required; cigarette smoker > 10 but < 20 pack years 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
165/Protocol BO25323, Version 7 
12. Instrumental diagnosis of COPD or pulmonary interstitial disease (X-ray, 
TC, spirometry); daily prn inhalers (≤ 2 pharmacological classes); two or more 
episodes of pneumonia in the last 5 years; cigarette smoker < 20 but 
< 40 pack-years 
13. Exertion dyspnea secondary to limited respiratory capacity, not well controlled by 
daily meds; required oral steroids for lung disease; daily prn inhalers 
(3 pharmacological classes); acute pneumonia treated as an outpatient 
14. Chronic supplementation of oxygen; respiratory failure requiring assisted ventilation, 
or previous (at least one episode); any lung or pleural neoplasm; acute pneumonia 
requiring hospitalization 
 
Smoking is an important respiratory and cardiovascular risk, so it is considered as a 
disease, and it is rated according to lifetime pack-years:  
Number of cigarette packs smoked per day × Number of years smoked in their lifetime 
e.g., 1 pack-year = 20 cigarettes/die (1 pack) × 1 year 
 
Ex-smokers should be rated too, but those who have been smoke-free for the most 
recent 20 years would merit a lower rating than those who are currently smoking. 
Examples: 
a) Patient smoking 20 cig/die (1 pack) for 25 years = 25 pack-years − CIRS score:  2 
b) Patient smoking 40 cig/die (2 packs) for 25 years = 50 pack-years − CIRS score:  3 
c) 
Ex-smoker of 20 cig/die (1 pack) for 25 years, he stopped 5 years ago − CIRS 
score:  2 
d) Ex-smoker of 20 cig/die (1 pack) for 25 years, he stopped 20 years ago − CIRS 
score:  1 
 
Classification of COPD could be more specific when instrumental data (objective 
evidence) are available:  blood gases, forced expiratory volume in 1 second (FEV1), etc. 
EYES, EARS, NOSE & THROAT, AND LARYNX 
To simplify the potential complexity of this category it was decided to score according to 
the severity of the disability created by sensory diseases (degree of limited autonomy 
and communication), and avoid rating each type of pathology.  Sensory impairments 
should be rated after instrumental correction (corrective lenses, hearing aid, etc.). 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
166/Protocol BO25323, Version 7 
Eyes:  glaucoma, cataracts, macular degeneration (diabetic/hypertensive retinopathy), 
any other pathology 
Ears:  otitis, dizziness, any cause of hearing impairment 
Nose & Throat:  rhinitis, pharyngitis, nasal polyps, sinusitis, malignancies 
Larynx:  dysphonia, acute and chronic laryngitis, malignancies 
15.  No problems 
16. Corrected vision with glasses; mild hearing loss; chronic sinusitis 
17. Difficulty in reading newspaper or drive although glasses; required hearing aid; 
chronic sinonasal complaints requiring medication; vertigo/dizziness requiring 
daily meds 
18. Severe low vision, partially blind (required an escort to venture out, unable to  
read newspaper); severe ear impairment (conversational heading still impaired with   
hearing aid); laryngeal dysphonia (not neurological dysarthria) 
19. Functional blindness/deafness:  unable to read, recognize a familiar face, unable to 
conversational heading, even if “organically” he is not completely blind or deaf; 
laryngectomy (every cause, especially malignancies); required surgical intervention 
for vertigo; aphonia secondary to laryngeal impairment. 
 
UPPER GASTROINTESTINAL SYSTEM 
This category is comprehensive of the intestinal tract from esophagus to duodenum, 
and pancreatic trees:  dysphagia, GERD, hiatal hernia, esophageal diverticula, any type 
of gastritis (consider also H. Pylori eradication or not), gastric/duodenal ulcer, acute or 
chronic pancreatitis, malignancies (comprehensive of gastric lymphoma). 
Ensure that type 1 diabetes is rated under “metabolic.” 
20. No problem 
21. Hiatal hernia, GERD or gastritis requiring prn meds; previous ulcer (> 5 years ago); 
previous H. Pylori eradication therapy (> 5 years ago) 
22. Daily proton pump inhibitor/anti-acid meds; documented gastric or duodenal ulcer or 
H. Pylori eradication therapy within 5 years 
23. Active gastric or duodenal ulcer; positive fecal occult blood test; any swallowing 
disorder or dysphagia; chronic pancreatitis requiring supplemental pancreatic 
enzymes for digestion; previous episode of acute pancreatitis 
24. Any type of malignancies (see “Rating Malignancies”); previous gastric surgery 
because of cancer; history of perforated ulcer (gastric surgery not because of 
cancer, ulcorrhaphy); melena/heavy bleeding from upper GI source; acute 
pancreatitis 
 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
167/Protocol BO25323, Version 7 
LOWER GASTROINTESTINAL SYSTEM 
Comprehensive of the rest of the GI system, from small bowel to anus:  
Whipple’s disease, diverticulosis, irritable bowel, malignancies.  Constipation is rated, 
too, by type and frequency of laxatives required, or by history of impaction. 
25. No problems, previous appendectomy, previous hernia repair (without  
complications) 
26. Constipation managed with prn meds; active hemorrhoids; intestinal hernia requiring 
surgery; previous hernia repair with complications (intestinal adherences, 
laparocele, etc.); irritable bowel syndrome (few symptoms) 
27. Constipation requiring daily bulk laxatives (psyllium, policarbophil, sterculia, guar 
gum, etc.), or stool softeners; diverticulosis (previous diverticulitis); 
inflammatory bowel disease in remission with meds (> 5 years ago) 
28. Bowel impaction/diverticulitis within the last year; daily use of stimulant (irritant) 
or osmotic laxatives (bisacodyl, senna, glycerol, sodium docusate; lactulose, 
polyethylene glycol) or enemas; chronic bowel inflammation in remission with meds 
(< 5 years ago) 
29. Diverticulitis flare up; active inflammatory disease; current impaction; 
hematochezia/active bleeding from lower GI source; bowel carcinoma 
 
LIVER AND BILIARY TREES 
Comprehensive of liver, gallbladder, biliary trees, portal system:  acute and chronic 
hepatitis (viral, alcoholic, toxic, autoimmune, idiopathic), cirrhosis, portal hypertension, 
hemochromatosis, primary biliary cirrhosis, cholelithiasis, cholangitis, 
primary malignancies.  As the hepato-biliary system is difficult to assess through the 
physical examination, therefore, laboratory results must be used. 
30. No problem 
31. History of hepatitis (actually normal values of transaminases); cholecystectomy 
32. Cholelithiasis; chronic hepatitis or previous hepatitis (< 5 years ago) or any other 
liver disease (hemochromatosis, primary biliary cirrhosis) with mildly elevated 
transaminases (within 3-times normal values); heavy alcohol use within 5 years 
(to rate in “psychiatric”, too) 
33. Chronic hepatitis or any other liver disease with marked elevation of  transaminases 
(> 3-times normal values); elevated bilirubin 
34. Acute cholecystitis; any biliary obstruction; active hepatitis/liver cirrhosis; any liver or 
biliary tree carcinoma 
 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
168/Protocol BO25323, Version 7 
RENAL 
This category is exclusive of kidney:  kidney stones, acute/chronic renal failure, 
glomerulonephritis; nephrosic/nephritic syndrome; active/chronic pyelonephritis, 
diabetic or hypertensive nephropathy (albuminuria/proteinuria), renal carcinoma.  
Bence-Jones proteinuria in multiple myeloma should not be considered. 
35. No problem 
36. Asymptomatic kidney stone; kidney stone passage within the last ten years; 
pyelonephritis within 5 years; kidney cysts without hematuria 
37. Serum creatinine > 1.5 but < 3 mg/dL without diuretic or antihypertensive medication 
(particularly ACE-inhibitors or SRAA blockers); kidney calculi requiring daily meds 
38. Serum creatinine > 3 mg/dL or < 1.5 mg/dL in conjunction with diuretics, 
antihypertensive, or bicarbonate therapy; active pyelonephritis; nephrosic syndrome; 
colic symptoms treated as an outpatient 
39. Required dialysis; renal carcinoma; colic symptoms requiring hospitalization 
 
GENITOURINARY 
Ureters, bladder, urethra.  Genitals, prostate, testicles, penis, seminal vesicles. 
Uterus, ovaries.  Mammary gland is rated under “metabolic”. 
This category is comprehensive of all GU tract impairments:  ureteral or bladder stones, 
benign prostate hypertrophy (BPH), urinary tract infections (UTI’s), prolapses, etc.  
Urinary incontinence and indwelling catheter should also be considered. 
40. No problem 
41. Stress incontinence; BPH without urinary symptoms; hysterectomy or ovariectomy 
(uterine fibroma, benign neoplasm) 
42. Pathological pap smear (or 2 consecutives abnormal); frequent UTIs (3 or more in 
the past year) in female or current UTIs; urinary incontinence (not stress) in females; 
BPH with urinary symptoms (frequency, urgency, hesitancy); status post TURP; 
any urinary diversion procedure; indwelling catheter; bladder calculi 
43. Prostatic cancer in situ (e.g., incidentally found during TURP); vaginal bleeding; 
cervical carcinoma in situ; hematuria (any cause); urinary incontinence (not stress) 
in males; bladder polyps 
44. Acute urinary retention; current urosepsis; any GU malignancies except as above 
 
MUSCULOSKELETAL/INTEGUMENT 
This is a very broad category, including:  osteoarthritis, osteoporosis, any bone fracture; 
primary neoplasm (bone, muscle, connective tissue, skin), distinguishing melanoma from 
other localized skin cancers; rheumatoid arthritis and polymyalgia rheumatica; muscular 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
169/Protocol BO25323, Version 7 
injuries (rotator cuff, long head of the biceps); pressure sores; any dermatological 
disease. 
The scores of this category are strictly correlated to the disability they cause; for the 
evaluation of the level of disability, refer to BADL and IADL. 
NOTICE:  Score the severity of each illness according to the level of disability caused by 
the same illness in this category, without considering the disability caused by 
other diseases.  For example:  a patient affected both by osteoarthritis and hemiplegia 
from a previous stroke has a high level of disability, but you have to score 2 for disability 
by osteoarthritis (in this category) and 4 for disability by stroke (in the neurological 
category); for a patient with both a deforming rheumatoid arthritis and a previous stroke 
without remaining outcomes you have to score 4 for disability from arthritis 
(in this  category) and 2 for disability from stroke (in the neurological category). 
45. No problem 
46. Requires PRN meds for osteoarthritis (NSAID) or has mildly limited IADL from joint 
pathology; excised skin cancers (except melanoma); skin infections requiring 
antibiotics within a year 
47. Daily anti-osteoarthritis meds (NSAID) or use of assistive devices or little limitation 
in ADL (previous arthroprosthesis or treated fracture with a low level of remaining 
disability); osteoporosis without vertebral fractures; daily meds for chronic skin 
diseases (even local, as psoriasis or pressure sores); non-metastatic melanoma; 
daily meds for rheumatoid arthritis (except steroids) with a low level of  disability 
48. Osteoarthritis with a moderate level of disability in ADL; requires chronic treatment 
with steroids for arthritic conditions or joints’ deformities or severely impaired; 
osteoporosis with vertebral compression fractures 
49. Wheelchair bound for osteomuscular disease; severe joint deformities or severely 
impaired usage; osteomyelitis; any bone or muscle or connective tissue neoplasm 
(see “Rating Malignancies”); metastatic melanoma. 
 
Fractures and/or arthroprosthesis (both recent and old) have to be scored according to 
the level of disability they cause (considering outcomes too), in order to avoid confusion 
about possible classifications of different fractures or joints.  The same is true for 
muscular diseases. 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
170/Protocol BO25323, Version 7 
CENTRAL AND PERIPHERAL NERVOUS SYSTEM 
This category includes the “somatic” pathologies of the central and peripheral nervous 
system:  any kind of stroke, neurodegenerative diseases (Parkinson’s disease and 
parkinsonism, multiple sclerosis, amyotrophic lateral sclerosis, etc.), myelopathies, 
traumas with neurological outcomes, primary or secondary epilepsy, neuropathies 
(diabetic, alcoholic, any other etiology), primary tumors, chronic headaches (migraine), 
insomnia, etc.  It must carefully estimate the severity and prognosis of the illness but 
also the functional impairment that the illness causes. 
50. No problem (or fewer convulsions in childhood) 
51. Frequent headaches requiring PRN meds without impairment in Advanced ADL; 
previous TIA (one event); previous epilepsy, actually not treated, without crisis since 
more than 10 years ago. 
52. Chronic headache requiring daily meds (even for prophylaxis) or with regularly 
functional impairment in Advanced ADL (bed rest, job withdrawal, etc.); actual TIA 
or more than one previous TIA; previous stroke without significant residual; 
mild severity neurodegenerative diseases (see above), treated and well controlled; 
epilepsy controlled with drugs. 
53. Previous stroke with mild residual dysfunction (hemiparesis, dysarthria); 
any neurosurgical procedure; moderate severity neurodegenerative diseases 
(see above), not well controlled by meds; epilepsy in treatment but with 
periodic crisis. 
54. Acute stroke or previous stroke with severe residual dysfunction (hemiplegia, 
aphasia, severe vascular dementia) or more than one previous stroke (multi-infarct 
encephalopathy); severe neurodegenerative diseases (see above) causing disability 
in ADL; neurological coma. 
 
Alzheimer’s disease and dementia should not be rated into this category 
(Psychiatric and behavioral diseases):  Alzheimer’s disease should be listed only under 
psychiatric disorders; if dementia stems from vascular and/or mixed dementia and/or 
other neurological condition (e.g., Parkinson’s Disease), both “neurologic” 
and “psychiatric” categories should be endorsed at the appropriate level for severity, 
considering in this category the stroke and the multi-infarct encephalopathy responsible 
for the cognitive impairment (score 3 for stroke with remaining outcomes, score 4 for 
multi-infarct encephalopathy). 
ENDOCRINE-METABOLIC SYSTEM AND BREAST (SYSTEMIC INFECTIONS 
AND POISONINGS) 
Type 1 and Type 2 diabetes (organ damage should be considered into the respective 
categories, like for hypertension), obesity and dyslipidemia (hypercholesterolemia) 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
171/Protocol BO25323, Version 7 
represent the core of this category; it includes also hypo- and hyper-thyroidism, 
hypo- and hyper-parathyroidism, adrenal pathologies (Cushing’ or Addison’ disease), 
hypogonadism, hypopituitarism, etc.  Malignancies of these glands, both benignant 
(like thyroid nodules) and malignant (like thyroid or adrenal cancer, vipoma, etc.) 
are included too. 
Even if it is an exocrine gland, breast was included in this category because the authors 
did not find a more appropriate one; so it also includes breast cancer. 
Moreover, it includes:  electrolyte disorders, sepsis, systemic infections (like 
tuberculosis, syphilis, AIDS) scored according to their severity and the functional 
impairment they cause (see general indications) and poisonings (chronic by metals or 
acute by pesticides or carbon monoxide). 
55. No problem 
56. Diabetes and/or dyslipidemia compensated with diet; mild obesity (BMI 
30-35 kg/m2); hypothyroidism in replacement therapy (L-thyroxin); hyperthyroidism 
caused by Plummer’ adenoma surgically treated. 
57. Diabetes compensated with oral hypoglycemic drugs or insulin (hemoglobin 
A1c < 7%); dyslipidemia well controlled by daily meds (c-LDL lower than the 
recommended target according to the individual global cardiovascular risk); 
moderate obesity (BMI 35−45 kg/m2); hyperthyroidism in pharmacologic treatment; 
asymptomatic or surgically treated hyperparathyroidism; fibrocystic breast disease. 
58. Diabetes not well compensated by therapy (hemoglobin A1c 7−8.5%, presence of 
complications); dyslipidemia not well controlled (c-LDL higher than the 
recommended target according to the individual global cardiovascular risk; for 
instance, c-LDL > 100 mg/dL in patients with previous myocardial infarction or 
stroke); severe obesity (BMI > 45 kg/m2); symptomatic hyperparathyroidism (e.g., 
hypercalcaemia); replacement therapy for adrenal failure; any electrolytes disorder 
requiring hospitalization. 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
172/Protocol BO25323, Version 7 
59. Uncontrolled diabetes (hemoglobin A1c > 8.5%) or one diabetic ketoacidosis or 
nonketotic hyperosmolar coma during the past year; genetic uncontrolled 
dyslipidemia; acute adrenal failure during hormonal replacement therapy; 
any neoplasm of thyroid, breast, adrenal gland (see “Rating Malignancies”). 
 
NOTICE:  when the patient is not treated with drug therapy for diabetes or dyslipidemia 
but he should be for the optimal control of the pathology (for instance, hemoglobin 
A1c > 7%, total cholesterol > 250 mg/dL), score the pathology according to the laboratory 
values, which really define its severity. 
PSYCHIATRIC AND BEHAVIORAL DISEASES 
This category includes both dementia and related behavioral disorders 
(psychosis, anxiety, depression, agitation) and all the pre-existing and/or not related to 
dementia psychiatric disorders.  Since this is the only item analyzing patient’s mental 
status (all the others refer to physical status), it is very important to evaluate it 
considering carefully further information derived from the Comprehensive Geriatric 
Assessment (MMSE; Geriatric Depression Scale, Neuro-Psychiatric Inventory 
if available). 
60. No psychiatric problem or history thereof 
61. Minor psychiatric condition or history thereof:  previous (occasional) 
psychiatric treatment without hospitalization; major depressive event and/or use of 
antidepressants more than 10 years ago without hospitalization; occasional use of 
minor tranquilizers (e.g., BDZ; even if as hypnotherapy for insomnia); mild cognitive 
impairment (MMSE 25-28). 
62. A history of major depression (according to DSM-IV criteria) within the last 10 years 
(treated or untreated); mild dementia (MMSE 20-25); previous admission to 
Psychiatric Department for any reason; history of substance abuse (more than ten 
years ago, including alcoholism). 
63. Current major depression (according to DSM-IV criteria) or more than two previous 
major depression episodes in the past 10 years; moderate dementia (MMSE 
15−20); current and usual usage of daily anti-anxiety meds (even as hypnotherapy 
for insomnia); current or within the past ten years substance abuse or dependence 
(according to DSM-IV criteria); requires daily antipsychotic medication; previous 
attempt at suicide. 
64. Current mental illness requiring psychiatric hospitalization, institutionalization, 
or intensive outpatient management (psychiatric emergency, as attempt at suicide 
or severe depression with suicide purpose, acute psychosis or acute 
decompensation of chronic psychosis, severe substance abuse; severe agitation 
from dementia); severe dementia (MMSE < 15); delirium (acute confusion or altered 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
173/Protocol BO25323, Version 7 
mental status for medical (organic) reasons:  in this case you have to codify also the 
medical cause in its own category with the appropriate level of severity). 
It could be requested psychiatric consult for this category; dementia and depression, the 
most frequent diseases in the elderly, can be scored in details using the MMSE and 
GDS.  The severity of any mental disorder (dementia, depression, anxiety, psychosis, 
substance abuse and all the others) has to be scored according to the level of functional 
impairment or disability they cause. 
REFERENCES 
Linn BS, Linn MW, Gurel L. Cumulative Illness Rating Scale. J Am Geriatr Soc 1968; 
16:622-6. 
Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai H, Mulsant B, Reynolds 
CF III. Rating chronic medical illness burden in geropsychiatric practice and research: 
application of the Cumulative Illness Rating Scale. Psychiatry Res 1992; 41:237-48. 
Miller MD, Towers A. A manual guidelines for scoring the Cumulative Illness Rating 
Scale for Geriatrics (CIRS-G). Pittsburg, PA: University of Pittsburgh; 1991. 
Parmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the Cumulative Illness 
Rating Scale in a geriatric residential population. J Am Geriatr Soc 1995; 43:130-7. 
Mistry R, Gokhman I, Bastani R, Gould R, Jimenez E, Maxwell A, McDermott C, 
Rosansky J, Van Stone W, Jarvik L; UPBEAT Collaborative Group. Measuring medical 
burden using CIRS in older veterans enrolled in UPBEAT, a psychogeriatric treatment 
program: a pilot study. J Gerontol A Biol Sci Med Sci 2004; 59:1068-75. 
Folstein MF, Folstein SE, McHugh PR. “Mini Mental State”: a pratical method for grading 
the cognitive state of patients for the clinician. J Psichiatr Res 1975; 12:189-98. 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: 
DSM-IV. 4th ed. Washington: Amer. Psychiatric Assn., 1994. 
Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric 
depression screening scale: a preliminary report. J Psichiatr Res 1983; 17:37-49. 
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. 
Neurology 1994; 44:2308-14. 
 
CHECKLIST 
Medical history 
1. 
Timing of events and/or interventions (how long ago underwent surgery for…; 
how long ago had myocardial infarction or stroke, etc.) and evaluation of 
functional impairment 

 
Appendix 6 
The Modified Cumulative Illness Rating Scale (CIRS) (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
174/Protocol BO25323, Version 7 
2. 
Drugs list (fundamental), including laxatives and tranquilizers (even hypnoinducent) 
3. 
Symptoms of atherosclerotic disease (TIA, angina, claudication, amaurosis) 
4. 
Etiological diagnosis (reasonably reliable) of anemia 
5. 
Degree of vascular stenosis or aneurism dimension (by Doppler and/or ultrasound 
and/or TC data, when available) 
6. 
Information about smoking status (how many cigarettes per day for how many years, 
when stopped) 
7. 
Glasses use? With this aid, the patient is able to read a newspaper? Requires an 
escort to venture out? 
8. 
Any hearing aid? (you should evaluate possibility to communicate with patient) 
9. 
“Peptic history” of the patient (including previous eradication therapy for H. Pylori) 
10. Urinary symptoms, incontinence, presence of bladder catheter (even from BADL) 
 
PHYSICAL EXAMINATION 
a) Height (m2) and weight (kg) (measured, not reported, if possible) to calculate BMI 
b) Blood pressure, heart rate, cardiac murmurs, peripheral arterial pulses 
c) 
Joint pain or passive stiffness limitation (non−X-ray-based diagnosis of 
osteoarthritis) 
d) Neurological residual (dysarthria/aphasia, hemiparesis/hemiplegia) 
 
BASELINE LABORATORY SAMPLES 
• 
Blood count:  hemoglobin, WBC and platelets 
• 
Creatinine, electrolytes 
• 
Cholesterol levels (total, HDL) and triglycerides 
• 
AST, ALT, fractioned bilirubin 
• 
Thyroid function and serum B12 (when indicated) 
• 
Hemoglobin A1c (for diabetic patients) 
 
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
175/Protocol BO25323, Version 7 
Appendix 7 
Standard Cockcroft and Gault Formula for Calculated Creatinine 
Clearance 
For serum creatinine concentration in mg/dL: 
CrCl  
=  
(140-age + ) × (wt) x 0.85 (if female), or  × 1.0 (if male) 
 
(mL/min) 72 × serum creatinine (mg/dL) 
For serum creatinine concentration in µmol/L: 
CrCl  
=  
(140-age + ) × (wt) × 0.85 (if female), or × 1.0 (if male) 
(mL/min) 0.81 × serum creatinine 
=  
 
 
(µmol/L) 
+ age in years, weight (wt) in kilograms 
Reference:  Cockcroft and Gault 1976 
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
176/Protocol BO25323, Version 7 
Appendix 8 
Body Surface Area Calculation (BSA) Calculation Using the 
Mosteller Formula 
The following formula is to be used when calculating BSA: 
BSA(m2) = ([Height (cm) × Weight (kg)]/3600)½ 
 
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
177/Protocol BO25323, Version 7 
Appendix 9 
National Cancer Institute Common Terminology Criteria 
In the present study, toxicities will be graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 
A pdf of the NCI CTCAE v4.03 can be downloaded from the following Website: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 
 
Investigators who do not have access to Internet can contact the Data Center to receive 
a hard copy of this document by mail. 
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
178/Protocol BO25323, Version 7 
Appendix 10  
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome  
PRIOR TO OBINUTUZUMAB INFUSION 
Patients with a high tumor burden (absolute lymphocyte count ≥ 25 × 109/L or bulky 
lymphadenopathy) must receive prophylaxis for tumor lysis syndrome (TLS) prior to the 
initiation of treatment.  These patients must be well-hydrated.  It is desirable to maintain 
a fluid intake of approximately 3 liters/day, 1−2 days before the first dose of 
obinutuzumab.  All such patients with a high tumor burden must be treated with 
allopurinol or a suitable alternative treatment starting 12-24 hours prior to the first 
infusion.  Patients should continue to receive repeated prophylaxis with allopurinol and 
adequate hydration prior to each subsequent infusion, if deemed appropriate by the 
investigator. 
FIRST DOSE OF VENETOCLAX OR DOSE ESCALATION 
• 
Within the first 24 hours after either the first dose or dose escalation, if any 
laboratory criteria below are met, the patient should be hospitalized for monitoring 
and the investigator notified.  No additional venetoclax doses should be 
administered until resolution.  A rapidly rising serum potassium 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).  
• 
Intravenous (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 150−200 mL/hr; 
not < 50 mL/hr).  Modification of fluid rate should also be considered for individuals 
with specific medical needs.  
• 
Monitor for symptoms or signs of tumor lysis syndrome (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 
multidisciplinary management will be as per institutional protocols.  
 
In addition to the recommendations for patients with chronic lymphocytic leukemia/ small 
lymphocytic lymphoma 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 first guideline.  

 
Appendix 10  
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (cont.) 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
179/Protocol BO25323, Version 7 
• 
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.  
 

 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
180/Protocol BO25323, Version 7 
Appendix 11  
Adverse Events Commonly Associated with Chronic 
Lymphocytic Leukemia Study Population and/or Progression of 
Chronic Lymphocytic Leukemia 
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) 
 

 
Appendix 11  
Adverse Events Commonly Associated with Chronic 
Lymphocytic Leukemia (CLL) Study Population and/or 
Progression of CLL (cont.) 
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POPULATION-RELATED COEXISTING MEDICAL CONDITIONS 
• 
Hypertension 
• 
Rheumatoid arthritis/osteoarthritis 
• 
Hyperlipidemia 
• 
Peptic ulcer 
• 
Inflammatory bowel disease 
• 
Coronary artery disease 
• 
Peripheral vascular disease 
• 
Cardiomyopathy  
• 
Valvular disease 
• 
Atrial fibrillation 
• 
Diabetes mellitus 
• 
Chronic obstructive pulmonary disease 
• 
Cerebrovascular accident 
• 
Transient ischemia attack 
 
 

 
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Appendix 12  
International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) Guidelines 

Fr o m  t h e  Kli ni k  I  f ür  I n n ere  Me dizi n,  U ni versität  z u  K öl n,  K öl n,  Ger ma n y;  t he  Ge or get o w n  
U ni versit y H os pital, L o m bar di Ca ncer Ce nter, Was hi n gt o n, D C; t h e I nstit ute of Ca ncer Researc h, 
L o n d o n,  U nite d  Ki n g d o m;  t h e  U ni versita  Vita- Sal ute  Sa n  Raffaele,  Mila n o,  Ital y;  t h e  I nstit ute  
Paste ur, M o nte vi d e o, Ur u g ua y; t he U ni versit y of Ul m, Ul m, Ger ma n y; t he Pi n d erfiel ds H os pital, 
Wa k efiel d,  U nite d  Ki n g d o m;  t he  De part me nt.  of  Le u ke mia,  U ni versit y  of  Te xas,  M D  A n ders o n  
Ca ncer  Ce nter,  H o ust o n,  T X;  t he  H os pital  Cli nic,  Barcel o na,  S p ai n;  t he  Di visi o n  of  
He mat ol o g y/ O nc ol o g y, L o n g Isla n d Je wis h Me dical Ce nter, Ne w H y de Par k, N Y; a n d t he Re becca 
a n d J o h n M o ores Ca ncer Ce nter, U ni versit y of Calif or nia, Sa n Die g o, La J olla, C A. 
A d dress f or c orres p o n de nce: 
Mic hael Halle k, M D 
Kli ni k I f ür In n ere Me dizi n 
U ni versität z u K öl n 
J ose p h- Stelz ma n n Str. 9 
5 0 9 2 4 K öl n 
Tel.: 0 2 2 1/ 4 7 8 4 4 0 0 
Fa x: 0 2 2 1/ 4 7 8 5 4 5 5 
E mail: mic hael. halle k @ u ni- k oel n. de 
 
C o p yri g ht © 2 0 0 8 A m eri c a n S o ci et y of H e m at ol o g y
Bl o o d Fir st E diti o n P a p er, pr e p u bli s h e d o nli n e J a n u ar y 2 3, 2 0 0 8; D OI 1 0. 1 1 8 2/ bl o o d- 2 0 0 7- 0 6- 0 9 3 9 0 6  
G ui d eli n e s f o r t h e Di a g n o si s a n d  T r e a t m e n t  of C hr o ni c  L y m ph o c y ti c  
L e u k e mi a: A  Re p o r t f r o m t h e I n t e r n a ti o n al W o r k s h o p  o n C h r o ni c 
L y m p h o c y ti c L e u k e mi a (I W C L L)  u pd a ti n g  t h e N a ti o n al  C a n c e r I n s ti t u t e-
W o r ki n g G r o u p  ( NCI- W G)  1 99 6 g ui d eli n e s  
Mic hael Halle k, Br uce D. C h es o n, Da niel Cat o vs k y, Fe d eric o Cali garis- Ca p pi o, G uilla u me Di g hier o, 
Hart m ut D ö h ner, Peter Hill me n, Mic h ael J. Keati n g, E mili M o ntserrat, Ka nti R. Rai, T h o mas J. Ki p ps 
O bi n ut u z u m a b a n d V e n et o cl a x ( G D C -0 1 9 9) F. H off m a n -L a R o c h e Lt d  
1 8
/Pr ot o c ol B O 2 5 3 2 3 , V er si o n 7 

In 1988 and 1996, a National Cancer Institute-sponsored Working Group (NCI-WG) on chronic 
lymphocytic leukemia (CLL) published guidelines for the design and conduct of clinical trials for 
patients with CLL to facilitate comparisons between different treatments and to establish 
definitions that could be used in scientific studies on the biology of this disease.
1,2 The Food and 
Drug Administration (FDA) also adopted these guidelines in their evaluation and approval of new 
drugs. During the last decade, considerable progress has been made in defining new prognostic 
markers, diagnostic parameters and treatment options, prompting the IWCLL-sponsored Working 
Group to revise the 1996 criteria (Tables 1-4). 
1. Diagnosis of CLL
The World Health Organization (WHO) classification of hematopoietic neoplasias describes CLL as
leukemic, lymphocytic lymphoma, being only distinguishable from SLL (small lymphocytic
lymphoma) by its leukemic appearance.
3 In the WHO classification CLL is always a disease of
neoplastic B-cells, while the entity formerly described as T-CLL is now called T-cell prolymphocytic
leukemia (T-PLL). 4
It is important to verify that the patient has CLL and not some other lymphoproliferative disease 
that can masquerade as CLL, such as hairy cell leukemia, or leukemic manifestations of mantle cell 
lymphoma, marginal zone lymphoma, splenic marginal zone lymphoma with circulating villous 
lymphocytes or follicular lymphoma. To achieve this, it is essential to evaluate the blood count, 
blood smear, and the immune phenotype of the circulating lymphoid cells (see below,1.1. and 1.2.). 
1.1. Blood 
The diagnosis of CLL requires the presence of 
≥ 5000 B-lymphocytes/µL in the peripheral blood 
for the duration of at least 3 months. The clonality of the circulating B-lymphocytes needs to be 
confirmed by flow cytometry. The leukemia cells found in the blood smear are characteristically 
small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking 
discernable nucleoli and having partially aggregated chromatin. These cells may be found 
admixed with larger or atypical cells, cleaved cells or prolymphocytes, which may comprise up 
to 55% of the blood lymphocytes.
5 Finding prolymphocytes in excess of this percentage would 
favor a diagnosis of prolymphocytic leukemia (B-cell PLL). Gumprecht nuclear shadows, or 
smudge cells, found as cell debris, are other characteristic morphologic features found in CLL. 
CLL or SLL might be suspected in otherwise healthy adults who have an absolute increase in the 
clonal B lymphocytes, but who have less than 5000 B-lymphocytes/µL in the blood. However, in 
the absence of lymphadenopathy or organomegaly (as defined by physical examination and CT 
scans), cytopenias, or disease-related symptoms, the presence of fewer than 5000 B-lymphocytes 
per µL blood is defined as “monoclonal B-lymphocytosis” (MBL).
6 The presence of a cytopenia 
caused by a typical marrow infiltrate defines the diagnosis of CLL regardless of the number of 
peripheral blood B-lymphocytes or of the lymph node involvement. MBL seems to progress to 
frank CLL at a rate of 1-2 % per year.
7 
The definition of SLL requires the presence of lymphadenopathy and the absence of cytopenias 
caused by a clonal marrow infiltrate. Moreover, the number of B-lymphocytes in the peripheral 
blood should not exceed 5000/µL. In SLL, the diagnosis should be confirmed by histopathological 
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evaluation of a lymph node biopsy whenever possible. 
1.2. lmmunophenotype 
CLL cells co-express the T-cell antigen CD5 and B-cell surface antigens CD19, CD20, and CD23. 
The levels of surface immunoglobulin, CD20, and CD79b are characteristically low compared to 
those found on normal B cells.
8,9 Each clone of leukemia cells is restricted to expression of either 
kappa or lambda immunoglobulin light chains.
8 Variations of the intensity of expression of these 
markers may exist and do not prevent inclusion of a patient in clinical trials for CLL. 
In contrast, B-cell PLL cells do not express CD5 in half of the cases, and typically express high 
levels of CD20 and surface Ig.
10 Also, the leukemia cells of mantle cell lymphoma, despite also 
expressing B cell surface antigens and CD5, generally do not express CD23. 
1.3. Other tests performed at diagnosis 
The tests described in section 1.3. are not needed to establish the diagnosis of CLL, but may help 
to predict the prognosis or to assess the tumor burden. With the exception of molecular genetics 
(FISH), the application of these tests should not be used in routine practice to influence therapy 
and is not generally recommended. However, certain parameters, such as immunoglobulin 
mutational status, are useful for predicting the clinical course in individual cases. These tests can 
be recommended for patients who want a better prediction of the rate at which their disease 
might progress but it should be emphasized that the indication for treatment does 
not depend on 
any of these tests but on the clinical stage and the disease activity (see Section 4). 
1.3.1 Molecular Genetics 
Using interphase fluorescence-in situ hybridization (FISH), cytogenetic lesions can be identified 
in more than 80% of all CLL cases.
11 The most common deletions are in the long arm of 
chromosome 13 (del(13q14.1)). Additional, frequent chromosomal aberrations comprise deletions 
and/or trisomy of chromosome 12, deletions in the long arm of chromosomes 11 (del(11q)) and 6 
(del(6q)), and in the short arm of chromosome 17 (del(17p)).
11 When stimulated in vitro, CLL 
cells can have detectable chromosomal translocations, which are of potential prognostic 
significance.12 However, certain translocations can help distinguish other lymphoproliferative 
diseases from CLL (e.g. t(11;14), which generally is found in mantle cell lymphoma). 
There is increasing evidence from prospective clinical trials that detection of certain 
chromosomal deletions has prognostic significance. Patients with leukemia cells that have 
del(17p) have an inferior prognosis and appear resistant to standard chemotherapy regimens 
employing alkylating drugs and/or purine analogues.
13,14 In a retrospective analysis on several 
chromosomal aberrations as detected by FISH, patients who had CLL cells with chromosomal 
aberrations del(11q) and del(17p) had an inferior outcome compared to patients who had 
leukemia cells with a normal karyotype or del(13q) as the sole genetic abnormality.
11 On the 
other hand, patients with leukemia cells having del(17p) may respond to therapy with 
alemtuzumab, either alone or in combination with other anti-leukemia agents.
15,16 Detection of 
these cytogenetic abnormalities has apparent prognostic value and may influence therapeutic 
decisions. For clinical trials, it is recommended that cytogenetics be performed prior to treating a 
patient on protocol. Additional genetic defects may be acquired during the course of the disease;
17 
therefore, the repetition of FISH analyses seems justified prior to subsequent, second- and third-
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line treatment. 
1.3.2 Mutational status of IgV
H, VH3.21 usage, and expression of ZAP-70 or CD38 
The leukemia cells express immunoglobulin that may or may not have incurred somatic mutations 
in the immunoglobulin heavy chain variable region genes (IgV
H genes). The outcome of patients 
with leukemia cells that use an unmutated IgV
H gene is inferior to those patients with leukemia 
cells that use a mutated IgV
H gene. 18,19 In addition, the VH3.21 gene usage is an unfavorable 
prognostic marker independent of the IgV
H mutational status. 20 Leukemia-cell expression of ZAP-
70 and CD38 was found to correlate with the expression of unmutated IgV
H genes and to predict a 
poor prognosis. 21-27 However, the association between expression of ZAP-70 or CD38 with the 
expression of unmutated IgV
H genes is not absolute. It is uncertain whether leukemia-cell 
expression of unmutated IgV
H genes or ZAP-70 predict the response to treatment or overall 
survival, once therapy is required.
14,28 Taken together, further clinical trials are needed to 
standardize the assessment of these parameters and to determine whether they should affect the 
management of patients with CLL.
1.3.3 Serum markers 
Several studies have found that serum markers CD23, thymidine kinase, and ß
2-microglobulin 
may predict survival or progression-free survival.
29-35 Assays for these markers should be 
standardized and used in prospective clinical trials to validate their relative value to the 
management of patients with CLL. 
1.3.4 Marrow Examination 
Characteristically more than 30% of the nucleated cells in the aspirate are lymphoid. Although 
the type of marrow infiltration (diffuse versus non-diffuse) reflects the tumor burden and 
provides some prognostic information, recent studies of the German and Spanish study groups 
suggest that the prognostic value of BM biopsy may now be superseded by new prognostic 
markers. 
A marrow aspirate and biopsy generally are 
not required for the diagnosis of CLL. However, a 
marrow biopsy and aspirate can help evaluate for factors that might contribute to cytopenias 
(anemia, thrombocytopenia) that may or may not be directly related to leukemia-cell infiltration 
of the marrow. Because such factors could influence the susceptibility to drug-induced 
cytopenias, a marrow biopsy is recommended prior to initiating therapy. It is recommended to 
repeat a marrow biopsy in patients with persisting cytopenia after treatment to uncover disease- 
versus therapy-related causes. 
2. Clinical Staging
There are two widely accepted staging methods for use in both patient care and clinical trials: the
Rai36 and the Binet system.
37 The original Rai classification was modified to reduce the number
of prognostic groups from five to three.
38 As such, both systems now describe three major
subgroups with discrete clinical outcomes. These two staging systems are simple, inexpensive,
and can be applied by physicians worldwide. Both solely rely on a physical examination and
standard laboratory tests, and do not require ultrasound, computed tomography, or magnetic
resonance imaging. These two systems are outlined in the following.
2.1. Rai staging system 
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T h e m o difi e d R ai classific ati o n d efi nes l o w-ris k dis eas e as pati e nts w h o ha ve l y m p h oc yt osis wit h 
le u k e mi a c ells i n t h e bl o o d a n d/ or marr o w (l y m p h oi d c ells > 3 0 %) (f or m erl y c o nsi d er e d R ai st a g e 
0).  Pati e nts  wit h  l y m p h oc yt osis,  e nlar ge d  n o des  i n  a n y  site,  a n d  s ple n o m e gal y  a n d/ or  
h e pat o m e gal y (l y m p h n o d es b ei n g pal pa ble or n ot) ar e d efi n e d as ha vi n g i nt er m e diat e ris k dis eas e 
(f or m erl y c o nsi d er e d R ai sta g e I or sta g e II). Hi g h ris k dis eas e i ncl u d es pati e nts wit h dis eas e-
r elat e d a n e mia ( as d efi n e d b y a h e m o gl o bi n ( H b) le v el less t h a n 1 1 g/ dl) (f or m erl y sta g e III) or 
t hr o m b oc yt o p e nia (as d efi n e d b y a plat elet c o u nt of less t ha n 1 0 0 x 1 0 9/ L) (f or m erl y sta g e I V).  
2. 2. Bi net st a gi n g syste m 
Sta gi n g is b as e d o n t h e n u m b er of i n v ol v e d ar eas, as d efi n e d b y t h e pr es e n c e of e nlar g e d l y m p h 
n o d es of gr eat er t ha n 1 c m i n dia met er or or ga n o m e gal y, a n d o n w h et h er t h er e is a n e mia or 
t hr o m b oc yt o p e nia.  
Ar e a of i n v ol v e m e nt c o n si d er e d f or st a gi n g 
( 1)  H ea d a n d n ec k, i ncl u di n g t h e Wal d e yer ri n g (t his c o u nts as o n e ar ea, e ve n if m or e t ha n
o n e gr o u p of n o d es is e nlar g e d).
( 2)  A xilla e (i n v ol ve m e nt of b ot h a xilla e c o u nts as o n e area).
( 3)  Gr oi ns, i n cl u di n g s u p erfi ci al f e m orals (i n v ol v e m e nt of b ot h gr oi ns c o u nts as o n e ar ea).
( 4) P al p a ble  s plee n.
( 5) P al p a ble li v er (cli nic all y e nlar g e d).
St a g e A. H b ≥ 1 0 g/ d L a n d plat elets ≥ 1 0 0 X 1 0 9/ L a n d u p t o t w o of t h e a b o ve i n v ol ve d. 
St a g e B. H b ≥ 1 0 g/ d L a n d plat elets ≥ 1 0 0 X 1 09/ L a n d or ga n o m e gal y gr eat er t ha n t hat d efi n e d 
f or sta g e A (i. e. t hr e e or m or e ar e as of n o d al or or g a n e nlar g e m e nt). 
St a g e C. All p ati e nts w h o ha ve H b of less t ha n 1 0 g/ d L a n d/ or a plat elet c o u nt of less t ha n 1 0 0 x 
1 0 9/ L, irres p ecti v e of or ga n o m e gal y.  
3. Eli gi bilit y Crit eria f or Cli nical Trials
T h e  s electi o n  of  C L L  p ati e nts  f or  cli nical  trials  is  si milar  t o  t hat  f or  p ati e nts  wit h  ot h er
m ali g n a n ci es.  P h as e  I-II  cli nical  trials  c o m m o nl y,  alt h o u g h  n ot  i n varia bl y,  ar e  i nt e n d e d  f or
pati e nts w h o ha ve ha d pri or t h era p y. It ma y b e w ort h c o nsi d eri n g t h e i ncl usi o n of pati e nts wit h
S L L i n s o m e p h as e I-II tri als e x pl ori n g n e w a g e nts i n C L L. H o we v er, f or S L L t h e r es p o ns e
ass ess m e nt  s h o ul d  b e d o n e acc or di n g  t o  t h e l y m p h o ma  g ui d eli n es.  T h e c o m bi nati o n of  n e w
a g e nts wit h st a n dar d t h era p y as part of p has e II st u di es ma y b e i n vesti gate d i n b ot h u ntreat e d a n d
pr e vi o usl y tr eat e d p ati e nts. P h as e III cli nical trials are us e d t o c o m p are t h e cli nical o utc o m e
e m pl o yi n g  n e w  tr eat m e nt  m o daliti es  wit h  t hat  usi n g  c urre nt  sta n dar d  t h era p y.  Ot h er
re q uir e m e nts  f or  eli gi bilit y  wit h  res p ect  t o  a g e,  cli ni c al  sta g e,  p erf or ma n c e  stat us,  or ga n
f u ncti o n, or st at us of dis eas e acti vit y s h o ul d b e d efi n e d f or ea c h st u d y.
3. 1. Perf or m a nce St at us a n d Fit n ess 
Pri or  t o  i ncl usi o n  i n  a  trial,  t h e  perf or ma nc e  stat us  as  d efi n e d  b y  t he  East er n  C o o p erati v e  
O nc ol o g y Gr o u p ( E C O G) s h o ul d b e 0- 3. F ut ure cli nical trials i n v ol vi n g el d erl y p ati e nts i d eall y 
s h o ul d ass ess t h e c o m or bi dit y (fit n ess) a n d/ or f u ncti o n al acti vit y of p ati e nts (e. g. s u c h as t hat 
d efi n e d b y “c u m ulati v e ill n ess rati n g s cale” ( CI R S) or t h e “ C h arls o n ” sc ore). 3 9, 4 0  
3. 2. Or g a n F u ncti o n Eli gi bility f or Cli nic al Tri als 
M ost c h e m ot h er a p y a g e nts h a v e p ote ntial t o xicit y f or t h e li v er, ki d n e ys, h eart, l u n gs, n er v o us 
O bi n ut u z u m a b a n d V e n et o cl a x ( G D C -0 1 9 9) F. H off m a n -L a R o c h e Lt d  
1 8
/Pr ot o c ol B O 2 5 3 2 3 , V er si o n 7 

system, or other organ systems. Therefore, organ function requirements should be guided by the 
known or suspected toxicity of each agent based on preclinical studies or prior clinical studies. 
Patients enrolled on protocols evaluating agents with known or suspected toxicity for a given 
organ(s) should have documented the specific organ function prior to therapy.  
3.3. Infectious Disease Status 
The status of specific infectious diseases as outlined in section 3.5 should be documented. 
Patients with active infections requiring systemic antibiotics, antifungal or antiviral drugs should 
have their infection resolved prior to initiating therapy in a clinical trial. 
3.4. Second Malignancies 
Patients with a second malignancy, other than basal cell carcinoma of the skin or in situ 
carcinoma of the cervix or the breast, generally are not considered candidates for entry into 
clinical trials unless the tumor was successfully treated with curative intent at least 2 years prior 
to trial entry. 
3.5. Required Pretreatment Evaluation 
Parameters considered necessary for a complete pretreatment evaluation may differ depending on 
whether or not the patient is treated in a clinical protocol. Therefore, a clear distinction is made in 
sections 3.5 and 5 between recommendations for general practice and the requirements for 
clinical trials (Tables 1, 2, and 3). If not indicated otherwise, recommendations are identical for 
clinical trials and general practice. In general, studies for defining these parameters should be 
performed within 2 weeks of clinical trial enrollment (except for marrow aspirate and biopsy and 
computed tomography (CT) scans (see sections 3.5.1 and 3.5.2). 
3.5.1. Essential pretreatment tests (see Table 1) 
3.5.1.1. Physical examination: The bidimensional diameters of the largest palpable lymph nodes 
in each of the following sites should be recorded: cervical, axillary, supraclavicular, inguinal, and 
femoral. The size of the liver and spleen, as assessed by palpation, should also be recorded.  
3.5.1.2. Assessment of performance status (ECOG score). 
3.5.1.3. A complete blood cell count (CBC; white blood cell count, hemoglobin and hematocrit, 
platelet count) and differential count, including both percent and absolute number of 
lymphocytes, and reticulocyte count should be performed. Reporting the proportion of prolymphocytes 
is desirable when these are present. 
3.5.1.4. Marrow biopsy: Prior to initiating treatment in a clinical trial with potentially 
myelosuppressive agents, patients should undergo a unilateral marrow aspirate and biopsy. 
Repeat marrow biopsies may be compared with the pre-treatment marrow specimen. 
3.5.1.5. Serum chemistry (e.g., creatinine, bilirubin, LDH, transaminases, alkaline 
phosphatase).  
3.5.1.6. Serum immunoglobulin levels. 
3.5.1.7. Direct antiglobulin test (DAT). 
3.5.1.8. Chest radiograph. 
3.5.1.9. Human immunodeficiency virus (HIV) 
Patients who are infected with HIV should be given special consideration because of the potential 
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risks for immune suppression with most anti-leukemia therapies and the potential for 
compounded myelotoxicity of treatment with anti-retroviral therapy. 
3.5.1.10. Cytomegalovirus (CMV) 
Therapies associated with the potential for reactivation of infection with CMV, such as 
alemtuzumab or allogeneic stem cell transplantation, should include plans for monitoring for active 
CMV disease and/or for providing anti-CMV therapy.
41 These should cover screening or early 
diagnosis of CMV reactivation and its subsequent management. However, a positive CMV 
serology does not represent a contraindication for alemtuzumab treatment or allogeneic stem cell 
transplantation. As a general recommendation for patients treated with alemtuzumab, close 
monitoring and/or therapy for active CMV disease should be considered for patients found to 
have evidence for increased levels of CMV in the blood by the polymerase chain reaction (PCR), 
even in the absence of clinical symptoms. Also, evaluation and therapy for CMV is recommended 
for any patient with clinical symptoms of active CMV infection. 
3.5.1.11. Hepatitis B and Hepatitis C 
Before initiating treatment, the evaluation for infection with hepatitis B virus (HBV) and hepatitis 
C virus (HCV) is recommended, since reactivation of HBV and HCV infections may occur under 
therapy with immunosuppressive or myelosuppressive drugs. Chronic HBV carriers as defined by 
positive surface antigen (HBsAg) undergoing chemotherapy should receive prophylactic therapy 
with nucleoside analogs such as lamivudine to prevent HBV reactivation.
42,43 
3.5.2 Additional pretreatment tests (Table 1) 
The following tests may be performed in clinical trials or in the presence of specific clinical 
problems. 
3.5.2.1. The assessment of molecular cytogenetics (FISH) prior to therapy is recommended. 
3.5.2.2. Computed tomography (CT) scans: CT scans generally are 
not required for the initial 
evaluation, or follow up. Moreover, the staging of CLL does not use CT scans but relies on 
physical examination and blood counts. A recent study has found that patients in Rai stage 0 but 
with detectable abdominal disease by CT scans may have a more aggressive disease.
44 Therefore, 
clinical studies evaluating the use of CT scans in CLL are strongly encouraged. Moreover, 
enlarged lymph nodes if detected only by CT scan do not change the clinical Binet or Rai stage. 
In clinical trials  where the treatment intent is to maximize complete remissions chest, 
abdominal and pelvic CT scans are recommended to evaluate the response to therapy. CT scans 
should be performed prior to the start of therapy and at the first restaging following therapy if 
previously abnormal. 
3.5.2.3. Other imaging methods: Except in some patients with Richter’s transformation, positron 
emission tomography (PET) scans do 
not provide information that is useful in the management of 
CLL. Similarly, nuclear magnetic resonance imaging and other imaging techniques are generally
not useful in the management of CLL.
3.5.2.4. Abdominal ultrasound: In some countries, the use of abdominal ultrasound is popular to 
assess the extent of lymphadenopathy and organomegaly in CLL. While it may be used in the 
clinical management of individual patients, this methodology is strongly investigator-dependent 
and should therefore not be used for the response evaluation in clinical trials. 
3.5.2.5. A lymph node biopsy is generally 
not required, unless such tissue is necessary for 
companion scientific studies or in rare cases with difficult diagnosis. A lymph node biopsy is 
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requested to establish the diagnosis of a transformation into an aggressive lymphoma (Richter’s 
syndrome). 
4. Indications for Treatment
4.1. Primary Treatment Decisions (Table 2)
Criteria for initiating treatment may vary depending on whether or not the patient is treated in a
clinical trial. In general practice, newly diagnosed patients with asymptomatic early-stage disease
(Rai 0, Binet A), should be monitored without therapy unless they have evidence of disease
progression. Studies from both the French Cooperative Group on CLL,
45 the Cancer and
Leukemia Group B (CALGB),
46 the Spanish Group Pethema,
47 and the Medical Research Council
(MRC)48 in the UK in patients with early-stage disease confirm that the use of alkylating agents
in patients with such early-stage disease does not prolong surviva1. This result was confirmed by
a meta-analysis. 49 In one study, treated patients with early-stage disease had an increased
frequency of fatal epithelial cancers compared to untreated patients.
45 Therefore, the potential
benefit, if any, of an early-intervention therapy with anti-leukemia drugs, alone or in combination
with monoclonal antibodies, requires further study.
Whereas patients at intermediate (stage I and II) and high risk (stage III and IV) according to the 
modified Rai classification or at Binet stage B or C usually benefit from the initiation of 
treatment, some of these patients (in particular Rai intermediate risk or Binet stage B) can be 
monitored without therapy until they have evidence for progressive or symptomatic disease. 
Active disease should be clearly documented for protocol therapy. At least one of the following 
criteria should be met: 
(1)
Evidence of progressive marrow failure as manifested by the development of, or worsening
of, anemia and/or thrombocytopenia
(2)
Massive (i.e., > 6 cm below the left costal margin) or progressive or symptomatic
splenomegaly
(3)
Massive nodes (i.e., >10 cm in longest diameter) or progressive or symptomatic
lymphadenopathy
(4)
Progressive lymphocytosis with an increase of >50% over a 2-month period, or lymphocyte
doubling time (LDT) of less than 6 months. LDT can be obtained by linear regression
extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of two weeks over
an observation period of 2-3 months; patients with initial blood lymphocyte counts of less
than 30.000/µl may require a longer observation period to determine the LDT. Also, factors
contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should
be excluded.
(5)
Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or other
standard therapy (see 10.2).
(6)
A minimum of any one of the following disease-related symptoms must be present:
(a)
Unintentional weight loss ≥ 10% within the previous 6 months.
(b)
Significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform
usual activities).
(c)
Fevers of greater than 100.5° F or 38.0° C for 2 or more weeks without other
evidence of infection.
(d)
Night sweats for more than 1 month without evidence of infection.
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Hypogammaglobulinemia or monoclonal or oligoclonal paraproteinemia does not by itself 
constitute a basis for initiating therapy. However it is recommended to assess the change of these 
protein abnormalities, if patients are treated. 
Patients with CLL may present with a markedly elevated leukocyte count; however, the 
symptoms associated with leukocyte aggregates that develop in patients with acute leukemia 
rarely occur in patients with CLL. Therefore, the absolute lymphocyte count should not be used 
as the sole indicator for treatment 
4.2. Second-Line Treatment Decisions 
In general, second-line treatment decisions follow the same indications as those used for 
initiation of first-line treatment. Patients who have resistant disease, a short time to progression 
after the first treatment, and/or leukemia cells with del(17p) often do not respond to standard 
chemotherapy and have a relatively short surviv
al. Therefore, such patients should be offered 
investigative clinical protocols including allogeneic hematopoietic stem cell transplantation.
50-54 
5. Definition of Response, Relapse and Refractory Disease (Tables 3 and 4)
Assessment of response should include a careful physical examination and evaluation of the
blood and marrow. Imaging studies, in particular CT scans, generally are not required except to 
monitor the response to therapy in clinical trials (Table 3). 
5.1. Complete remission (CR) requires all of the following criteria as assessed at least 3 months 
after completion of therapy: 
5.1.1. Absence of clonal lymphocytes in the peripheral blood (as defined in section 1.1 and 1.2). 
5.1.2. Absence of significant lymphadenopathy (e.g. lymph nodes greater than 1,5 cm in 
diameter) by physical examination. In clinical trials a CT scan of the abdomen, pelvis and 
thorax should be performed if previously abnormal. Lymph nodes should not be larger than 
1,5 cm in diameter. 
5.1.3. No hepatomegaly or splenomegaly by physical examination. In clinical trials a CT scan of 
the abdomen should be performed at response assessment if found to be abnormal prior to 
therapy or if physical exam is inconclusive at the time of evaluation. 
5.1.4. Absence of constitutional symptoms. 
5.1.5. Blood counts above the following values: 
 
5.1.5.1. Polymorphonuclear leukocytes 
≥ 1.500/µL. 
5.1.5.2. Platelets > 100.000/µL. 
5.1.5.3. Hemoglobin > 11,0 g/dL (untransfused). 
5.1.6. For patients in clinical trials (Table 3): a marrow aspirate and biopsy should be performed 
at least 3 months after the last treatment and if clinical and laboratory results listed in 5.1.1 to 
5.1.5 demonstrate that a CR has been achieved. The marrow should be analyzed by flow 
cytometry and/or immunohistochemistry to demonstrate that the marrow is free of clonal B-
CLL cells. Cases with residual CLL cells by conventional (not 4-colour; see below) flow 
cytometry or immunohistochemistry are defined as PR. 
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In some cases, lymphoid nodules can be found (formerly used to define nodular PR), 
which often reflect residual disease.
55,56 Therefore, these nodules should be assessed by 
immunohistochemistry to define whether they are comprised primarily of T cells or 
lymphocytes other than CLL cells or of CLL cells. The category of “nodular PR” should no 
longer be used. If the marrow is found to be hypocellular, a repeat marrow biopsy should be 
performed after 4-6 weeks, provided that the blood counts have recovered, as defined in 5.1.5. 
Marrow biopsies should be compared with that of the pre-treatment marrow. In some cases, it 
is necessary to postpone the marrow biopsy until after all the other criteria to define a CR 
(5.1.1 to 5.1.5) have been satisfied. However, this time interval should not exceed 6 months 
after the last treatment. 
5.1.7. A controversial issue is how best to categorize the response of patients who fulfill all
 the 
criteria for a CR (including the marrow examinations described in 5.16), but who have a 
persistent anemia or thrombocytopenia or neutropenia apparently unrelated to CLL, but 
related to drug toxicity. We recommend that these patients should be considered as a different 
category of remission, CR with incomplete bone marrow recovery (CRi). For the definition of 
this category, CRi, the marrow evaluation (see 5.1.6.) should be performed with scrutiny and 
not show any clonal infiltrate. In clinical trials, CRi patients should be monitored 
prospectively to determine whether their outcome differs from that of patients with detectable 
residual disease or with non-cytopenic CR. 
5.2. Partial remission (PR) is defined by the criteria described in 5.21, 5.22, and/or 5.23 (if 
abnormal prior to therapy), as well as one or more of the features listed in 5.24. To define a PR 
at least one  of these parameters needs to be documented for a minimal duration of 2 months 
(Table 4). Constitutional symptoms persisting for more than 1 month should also be 
documented. 
5.2.1. A decrease in the number of blood lymphocytes by below 50% or more from the value 
prior to therapy. 
5.2.2. Reduction in lymphadenopathy (to be assessed by CT scans in clinical trials
57 and by 
palpation in general practice) as defined by: 
5.2.2.1 A decrease lymph node size by below 50% or more in 
•
the sum products of up to 6 lymph nodes, or
•
in one lymph node diameter if only a single lymph node was present prior to
therapy.
5.2.2.2 No increase in any lymph node, and no new enlarged lymph node. In small lymph 
nodes (< 2 cm), an increase of < 25% is not considered to be significant. 
5.2.3. A decrease in the size of the liver and/or spleen by 50% more as defined by CT scan in 
clinical trials or by palpation or ultrasound in general practice. 
5.2.4. The blood count should show one of the following results: 
5.2.4.1. Polymorphonuclear leukocytes at 1.500/
µL or more or 50% improvement over baseline 
without G-CSF support. 
5.2.4.2. Platelet counts greater than 100.000/µL or 50% improvement over baseline. 
5.2.4.3. Hemoglobin greater than 11,0 g/dL or 50% improvement over baseline without red blood 
cell transfusions or erythropoietin support. 
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5.3. Progressive disease is characterized by at least one of the following: 
5.3.1. Lymphadenopathy: progression of lymphadenopathy is discovered almost uniformly by 
blood counts. Therefore, imaging methods are not needed to follow CLL progression. 
Progression of lymphadenopathy may be documented by physical examination. Disease 
progression occurs, if one of the following events is observed: 
•
Appearance of any new lesion such as enlarged lymph nodes (> 1,5 cm), splenomegaly,
hepatomegaly or other organ infiltrates.
•
An increase by 50% or more in greatest determined diameter of any previous site. A
lymph node of 1-1,5 cm must increase by 50% or more to a size greater than 1,5 cm in the
longest axis. A lymph node of more than 1,5 cm must increase to more than 2,0 cm in the
longest axis.
•
An increase of 50% or more in the sum of the product of diameters of multiple nodes.
5.3.2. An increase in the liver or spleen size 
by 50% or more or the de novo appearance of 
hepatomegaly or splenomegaly. 
5.3.3. 
An increase in the number of blood lymphocytes by 50% or more with at least 5,000 B 
lymphocytes per µL. 
5.3.4. Transformation to a more aggressive histology (e.g. Richter's syndrome). Whenever 
possible, this diagnosis should be established by lymph node biopsy. 
5.3.5. Occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to CLL. 
5.3.5.1 During therapy: cytopenias may occur as a side effect of many therapies and should be 
assessed according to Table 5. During therapy, cytopenias cannot be used to define disease 
progression. Each protocol should define the amount of drug(s) to be administered with such 
cytopenias. 
5.3.5.2. Post treatment: The progression of any cytopenia (unrelated to autoimmune cytopenia), 
as documented by a decrease of Hb levels by more than 2 g/dl or to less than 10 g/dl, or by a 
decrease of platelet counts by more than 50% or to less than 100.000/µl, which occurs at least 
3 months after treatment, defines disease progression, if the marrow biopsy demonstrates an 
infiltrate of clonal CLL cells. 
5.4. Stable disease: Patients who have not achieved a CR or a PR, and who have not exhibited 
PD, will be considered to have stable disease (which is equivalent to a non-response). 
5.5. Responses that should be considered clinically beneficial include CR and PR; all others (e.g. 
stable disease, non-response, progressive disease, or death from any cause) should be rated as 
a treatment failure. 
5.6. Duration of response and progression-free survival 
 Duration of response should be measured from the end of the last treatment until evidence of 
progressive disease (as defined above). Progression-free survival (PFS) is defined as the interval 
between the first treatment day to the first sign of disease progression.  Event-free survival is 
defined as the interval between the first treatment day to the first sign of disease progression, or 
treatment for relapse, or death (whichever occurs first). Survival duration is defined as the 
interval between the first treatment day to death. 
5.7. Relapse 
Relapse is defined as a patient who has previously achieved the above criteria (5.1-5.2) of a CR 
or PR, but after  a period of 6 or more months, demonstrate evidence of disease progression (see 
5.3). 
5.8. Refractory disease 
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[0]Refractory disease is defined as treatment failure (as defined in 5.5) or disease progression
within 6 months to the last anti-leukemic therapy. For the definition of “high risk CLL”
justifying the use of allogeneic stem cell transplantation,
58 the disease should be refractory to a
purine-analogue based therapy or to autologous hematopoietic stem cell transplantation.
5.9. Minimal residual disease 
The complete eradication of the leukemia is an obvious desired endpoint. New detection 
technologies such as multicolor flow cytometry and real-time quantitative PCR have determined 
that many patients who achieved a complete response by the 1996 NCI-WG guidelines have 
detectable minimal residual disease (MRD). While eradication of MRD may improve prognosis, 
prospective clinical trials are needed to define whether additional treatment intended solely to 
eradicate MRD provides a significant benefit to clinical outcome. The techniques for assessing 
MRD have undergone a critical evaluation and have become fairly standard.
59 Either four-color 
flow cytometry (MRD Flow) or allele-specific oligonucleotide PCR are reliably sensitive down 
to a level of approximately one CLL cell in 10.000 leukocytes. As such, patients will be defined 
as having a clinical remission in the absence of MRD when they have blood or marrow with less 
than one CLL cell per 10.000 leucocytes. The blood generally can be used for making this 
assessment except during the period within 3 months of completing therapy, particularly for 
patients treated with alemtuzumab, rituximab and other antibodies targeting CLL. In such cases 
it is essential to assess the marrow for MRD. Therefore, future clinical trials that aim toward 
achieving long-lasting complete remissions should include at least one test to assess MRD, 
because the lack of leukemia persistence using these sensitive tests seems to have a strong, 
positive prognostic impact 
60-62. 
6. Factors Requiring Stratification at Inclusion in a Clinical Phase III Trial
6.1. Patients ideally should be stratified with regard to previous treatment versus no previous
treatment, and  as purine analogue-sensitive versus purine-analogue refractory in studies for 
which prior therapy is allowed. 
6.2. If more than one clinical stage is allowed, patients ideally should be stratified for stage. 
6.3. Patients ideally should be stratified based upon whether or not they have leukemia cells with 
del(17p) or del(11q). 
7. Assessment of Toxicity
Evaluation of treatment-related toxicity requires careful consideration of both the manifestations
of the underlying disease and the anticipated adverse reactions to the agents used in therapy. For
this reason, some of the conventional criteria used for assessing toxicity are not applicable to
clinical studies involving patients with hematological malignancies in general, or CLL in
particular. An example is hematological toxicity; patients with advanced CLL generally have
cytopenias that may be caused by the underlying CLL and/or prior therapy. A few guidelines are
presented to help evaluate for treatment-induced toxicity in CLL.
7.1. Hematological Toxicity 
Evaluation of hematological toxicity in patients with CLL must take into consideration that many 
patients have low blood cell counts at the initiation of therapy. Therefore, the standard criteria 
used for solid tumors cannot be applied, as many CLL patients then would be considered to have 
grade II to IV hematological toxicity at the initiation of treatment. Furthermore, the absolute 
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blood neutrophil counts rarely are used at the initiation of therapy to modify the treatment dose, 
since these values typically are unreliable in CLL patients with lymphocytosis. However, the 
increasing use of more effective therapeutic agents, particularly those with neutropenia as a dose-
limiting toxicity (e.g. nucleoside analogs), can result in clinically significant myelosuppression. 
Therefore, the 1996 guidelines proposed a new dose-modification scheme for quantifying 
hematological deterioration in patients with CLL, which included alterations in the dose of 
myelosuppressive agents based on the absolute neutrophil count. This dose modification scheme 
has proven very helpful in the context of several large prospective trials in CLL and should be 
retained (Table 5). 
7.2. Infectious Complications 
Patients with CLL are at increased risk for infection because of compromised immune function, 
which might be related to the disease itself and/or to the consequences of therapy. Nevertheless, 
the rate(s) of infection following treatment can be used in assessing the relative immune-
suppressive effects of a given therapy. The etiology of the infection should be reported and 
categorized as bacterial, viral, or fungal, and as proven or probable. The severity of infections 
should be quantified as minor (requiring either oral antimicrobial therapy or symptomatic care 
alone), major (requiring hospitalization and systemic antimicrobial therapy), or fatal (death as a 
result of the infection). 
Particular attention should be given to monitoring for symptoms or laboratory evidence of 
infection with CMV in patients treated with agents like alemtuzumab (alone or in combination) 
or with allogeneic stem cell transplantation. In contrast, the infection rate seems low in patients 
younger than 65 years treated with fludarabine-based first line therapy, where no monitoring or 
routine anti-infective prophylaxis is required.
63 
7.3. Tumor lysis syndrome 
CLL patients rarely experience tumor lysis syndrome after therapy with a purine analogue 
based regimen. 64 However, this might not be the case following treatment with newer agents or 
novel treatment modalities. For this reason, patients in early phase clinical trials should be 
monitored for possible tumor lysis syndrome, which should be treated appropriately. If observed, 
the occurrence and severity of tumor lysis syndrome should be recorded in clinical trials. 
7.4. Non-hematological Toxicities 
Other non-hematological toxicities should be graded according to the latest version of the NCI 
Common Toxicity Criteria (CTC). 
8. Reporting of Clinical Response Data
Clear and careful reporting of data is an essential part of any clinical trial. In clinical studies
involving previously treated patients, patients who are relapsed or refractory should be clearly 
distinguished. Relapse and refractory disease are defined above (5.7 and 5.8). For those patients 
who have relapsed, it is also useful to describe the quality and duration of their prior response. 
9. Treatment endpoints
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 Given the recent increase of treatment options for CLL patients, the choice of treatment and the 
endpoints of clinical trials may depend on the fitness of the patients (see 3.1). For example, the 
number of MRD negative complete remissions or the overall survival might be appropriate 
endpoints in physically fit patients. In contrast, trials on patients with reduced physical fitness 
might choose the time to progression or health-related quality of life as trial endpoints. Moreover, 
recent data suggest that the quality of life in CLL patients is reduced as compared to the normal 
population and only moderately increased by some of the current treatment options.
65-68 
Therefore, further studies assessing the health-related quality of life in CLL are strongly 
encouraged. 
10. Supportive care and management of complications
10.1. Indications for growth factors in CLL 
While under myelosuppressive (chemo-)therapy, growth factors such as granulocyte-colony-
stimulating factor (G-CSF) should be given according to the guidelines of the American Society 
of Clinical Onclogy. 69 The use of G-CSF also might benefit patients who experience prolonged 
cytopenias following treatment with alemtuzumab. Similarly, some CLL patients with anemia 
may benefit from erythropoiesis stimulating factors, if used according to recently published 
guidelines.70,71 However, it should be pointed out that CLL-related cytopenias are often 
efficiently corrected by an appropriate anti-leukemic therapy.
 
10.2. Autoimmune hemolytic anemia (AIHA)
 or autoimmune thrombocytopenia (ITP) 
ITP and AIHA as a single abnormality caused by CLL initially should be treated with 
glucocorticoids and not chemotherapy. Second line treatment options for AIHA include 
splenectomy, intravenous immunoglobulins, and/or immunosuppressive therapy with agents such 
as cyclosporine A, azathioprin, or low-dose cyclophosphamide. Good responses also have been 
obtained with antibody therapy using agents as rituximab or alemtuzumab.
72-74 Treatment 
refractory 
autoimmune 
cytopenias 
can 
be 
an 
indication 
for 
chemotherapy 
or 
chemoimmunotherapy directed at the underlying CLL.
75 In this regard, the Binet or Rai staging 
systems do not distinguish between ITP/AIHA or marrow infiltration as the cause for anemia or 
thrombocytopenia that results in classifying a patient as having stage C or high-risk disease. 
ACKNOWLEDGMENT 
This work was supported in part by the Competence Network Malignant Lymphoma of the German 
Ministery for Education and Research (BMBF). 
The following colleagues are credited for their active participation in the original version of the Guidelines: 
Charles A. Schiffer, Martin M. Oken, David H. Boldt, Sanford J. Kempin, and Kenneth A. Foon. The following 
colleagues are credited for their active participation of the second, 1996 version of the guidelines: John M. 
Bennett, Michael Grever, Neil Kay, and Susan O’Brien. 
We wish to thank the following colleagues for reading and commenting on the current version of the 
guidelines: Drs Francesc Bosch (Barcelona, Spain), John Byrd (Columbus, Ohio, USA), Barbara Eichhorst 
(Cologne, Germany), Terry Hamblin (London, UK), Neil Kay (Rochester, Minnesota, USA), Eva Kimby 
(Stockholm, Sweden), Estella Matutes (London , UK), Stefano Molica (Catanzaro, Italy), Stephen Mulligan 
(Sydney, Australia), Susan O’Brien (Houston, Texas, USA), David Oscier (Bournemouth, UK), John 
Seymour (Melbourne, Australia). 
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We acknowledge the support of the German Cancer Aid (Deutsche Krebshilfe), the Kompetenznetz Maligne 
Lymphome (Competence Network Malignant Lymphoma) of the German Ministry for Education and 
Research (BMBF) and the European Leukemia Network (ELN) to Michael Hallek and Hartmut Döhner, of 
the National Institutes of Health PO1-CA081534 to
 the CLL Research Consortium (CRC), the Arbib 
Foundation to Daniel Catovsky, the Karches Family Foundation, Prince Family Foundation and the Nash 
Family Foundation to Kanti R. Rai. 
Authorship 
Michael Hallek, Bruce D. Cheson, Daniel Catovsky, Federico Caligaris-Cappio, Guillaume 
Dighiero, Hartmut Döhner, Peter Hillmen, Michael Keating, Emili Montserrat, Kanti R. Rai, 
Thomas J. Kipps all wrote the paper. 
Conflict of Interest Disclosure 
The authors declare no competing financial interests. 
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TABLES 
Table 1. Pretreatment Evaluation of Patients with CLL 
Diagnostic test 
Section of 
guidelines
General 
practice 
Clinical 
trial 
Tests to establish the diagnosis 
1. 
Complete blood count and differential count 
1.1 
Always 
Always 
Immunophenotyping of lymphocytes 
1.2. 
Always 
Always 
Assessment prior to treatment 
3.5.1 
History and physical, performance status 
3.5.1.1, 
3.5.1.2 
Always 
Always 
Complete blood count and differential 
3.5.1.3 
Always 
Always 
Marrow aspirate and biopsy 
3.5.1.4 
Desirable
Desirable 
Serum chemistry, 
serum immunoglobulin, 
direct antiglobulin test 
3.5.1.5, 
3.5.1.6, 
3.5.1.7 
Always 
Always 
Chest radiograph 
3.5.1.8 
Always 
Always 
Infectious disease status 
3.3 
Always 
Always 
Additional tests prior to treatment 
3.5.2 
Cytogenetics (FISH) for del(13q), del(11q), del(17p), 
add(12), del(6q) in the peripheral blood lymphocytes 
3.5.2.1 
Desirable
Always 
IgVH mutational status, ZAP-70, and CD38 
1.2 
No 
Always 
CT scan of chest, abdomen, and pelvis 
3.5.2.2 
No 
Desirable; 
always if 
CR is the 
desired 
endpoint. 
MRI, Lymphangiogram, gallium scan, PET scans 
3.5.2.3 
No 
No 
Abdominal ultrasound 
3.5.2.4 
Possible 
No 
General practice is defined as the use of accepted treatment options for a CLL patient not 
enrolled on a clinical trial. 
Abbreviations: No, not generally indicated; RQ, indicated if a research question; PBS, 
peripheral blood smear; MRI, magnetic resonance imaging; PET, positron emission tomography; 
FISH, fluorescence in situ hybridization. 
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Table 2. Recommendations Regarding Indications for Treatment in CLL 
General 
practice 
Clinical 
trial 
Treat with Rai stage 0 
No* 
RQ 
Treat with Binet stage A 
No* 
RQ 
Treat with Binet stage B or Rai stage I or 
Rai stage II 
Possible* 
Possible* 
Treat with Binet stage C or Rai stage III 
or Rai stage IV 
Yes
Yes
Treatment of active/progressive disease 
Yes 
Yes 
Treat without active/progressive disease 
No 
RQ 
General practice is defined as 
the use of accepted treatment options for a CLL patient not 
enrolled on a clinical trial. 
Abbreviations: No, not generally indicated; RQ, indicated if a research question. 
*Treatment is indicated, if the disease is active as defined in section 4.
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Table 3. Recommendations regarding the response assessment in CLL patients 
Diagnostic test 
Section of 
guidelines 
General 
practice 
Clinical trial 
History, physical examination 
5.1.2, 5.1.3, 
5.1.4, 5.2.2, 
5.2.3, 5.3.1, 
5.3.2 
Always
Always
Immunophenotyping of peripheral blood 
lymphocytes 
5.1.1 
If clinical and 
hematological 
response 
indicates CR 
If 
clinical 
response and 
hematological 
response 
indicates CR 
CBC and differential count 
5.1.5, 5.2.4, 
5.3.3, 5.3.5 
Always
Always
Marrow aspirate and biopsy 
5.1.6 
At cytopenia 
of 
uncertain 
cause 
At 
CR 
or 
cytopenia of 
uncertain 
cause 
Assessment for minimal residual disease 
5.9 
No 
If 
a 
long-
lasting CR is 
the 
desired 
endpoint 
Ultrasound of the abdomen 
5.1.2, 5.1.3, 
5.2.2, 5.2.3, 
5.3.1, 5.3.2 
Possible, 
if 
previously 
abnormal 
No 
CT scans of chest, pelvis, and abdomen 
5.1.2, 5.1.3, 
5.2.2, 5.2.3, 
5.3.1, 5.3.2 
No
Indicated
if previously 
abnormal and 
otherwise in 
CR 
General practice is defined as 
the use of accepted treatment options for a CLL patient not 
enrolled on a clinical trial. 
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Table 4 - Response definition after treatment for CLL patients, using the parameters of 
Tables 1 and 3 
Parameter
CR
PR
PD
SD
Lymphadenopathy 1) None above 1,5 
cm 
Decrease ≥ 50% 
Increase ≥ 50% 
Change of -49% 
to +49% 
Liver and/or spleen 
size 
Normal size 
Decrease ≥ 50% 
Increase ≥ 50% 
Change of -49% 
to +49% 
Constitutional 
symptoms 
None
Any
Any
Any
Polymorphonuclear 
leukocytes 
> 1500/µl
> 1500/µl or >
50%
improvement
over baseline
Any
Any
Circulating 
clonal 
B-lymphocytes
Nil
Decrease ≥ 50% 
from baseline 
Increase ≥ 50% 
over baseline 
Change of -49% 
to +49% 
Platelet count 
> 100.000/µl
> 100.000/µl or
increase ≥ 50%
over baseline
Decrease of 
≥ 
50%
from 
baseline 
secondary 
to 
CLL 
Change of -49 to 
+49%
Hemoglobin 
>
11,0
g/dl 
(untransfused 
and 
without 
erythropoietin) 
>
11 g/dl or 
increase ≥ 50%
over baseline
Decrease of > 2 
g/dl
from 
baseline 
secondary 
to 
CLL 
Increase < 11,0 
g/dl or < 50% 
over baseline, or 
decrease < 2 g/dl
Marrow
Normocellular, <
30% 
lymphocytes, no 
B-lymphoid
nodules.
Hypocellular
marrow defines
CRi (5.1.6.).
≥
30% 
lymphocytes, or 
B-lymphoid
nodules, or not 
done
Increase 
of 
lymphocytes 
to 
more than 30% 
from normal 
No 
change 
in 
marrow infiltrate
1)
sum of the products of multiple lymph nodes (as evaluated by CT scans in clinical trials, or by physical
exam or ultrasound in general practice).
CR: complete remission, all of the criteria have to be met; PR: partial remission, at least one of the criteria has to be 
met; PD: progressive disease: at least one of the above criteria has to be met; SD; all of the above criteria have to be 
met. 
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Table 5. Grading Scale for Hematological Toxicity in CLL Studies 
Grade# 
Decrease in Platelets* or Hb° (nadir) 
From Pretreatment value (%) 
absolute 
neutrophil 
count/µL§ (nadir) 
0 
No change to 10% 
≥ 2,000 
1
11%-24%
≥ 1,500 and < 2,000 
2
25%-49%
≥ 1,000 and < 1,500 
3
50%-74%
≥ 500 and < 1,000 
4 
≥ 75% 
< 500 
* Platelet counts must be below normal levels for grades 1-4. If, at any level of decrease the
platelet count is <20.000/µL, this will be considered grade 4 toxicity, unless a severe or life-
threatening decrease in the initial platelet count (e.g., 20.000/µL) was present pretreatment, in
which case the patient is not evaluable for toxicity referable to platelet counts.
° Hb levels must be below normal levels for grades 1-4. Baseline and subsequent Hb 
determinations must be performed before any given transfusions. The use of erythropoietin is 
irrelevant for the grading of toxicity, but should be documented. 
# Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal. Death occurring as a 
result of toxicity at any level of decrease from pretreatment will be recorded as grade 5. 
§ If the absolute neutrophil count (ANC) reaches less than 1,000/µL, it should be judged to be
grade 3 toxicity. Other decreases in the white blood cell count, or in circulating granulocytes, 
are not to be considered, since a decrease in the white blood cell count is a desired therapeutic end 
point. A gradual decrease in granulocytes is not a reliable index in CLL for stepwise grading of 
toxicity. If the ANC was less than 1,000/µL prior to therapy, the patient is not evaluable for 
toxicity referable to the ANC. The use of G-CSF is irrelevant for the grading of toxicity, but 
should be documented. 
Obinutuzumab and Venetoclax (GDC-0199)F. Hoffman-La Roche Ltd 
202/Protocol BO25323, Version 7 

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doi:10.1182/blood-2007-06-093906
Prepublished online January 23, 2008; 
Hartmut Dohner, Peter Hillmen, Michael J. Keating, Emili Montserrat, Kanti R. Rai and Thomas J. Kipps
Michael Hallek, Bruce D. Cheson, Daniel Catovsky, Federico Caligaris-Cappio, Guillaume Dighiero,
Institute-Working Group (NCI-WG) 1996 guidelines
Lymphocytic Leukemia (IWCLL) updating the National Cancer
leukemia: a report from the International Workshop on Chronic 
Guidelines for the diagnosis and treatment of chronic lymphocytic
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Copyright 2011 by The American Society of Hematology; all rights reserved.
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Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of
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Appendix 13  
Schedule of Response and Minimal Residual Disease Assessments 
 
BM = bone marrow aspirate and biopsy; CR = complete response; CT = computed tomography; D = day; FUM = follow-up months; 
GClb = obinutuzumab + chlorambucil; IWCLL = International Workshop on Chronic Lymphocytic Leukemia; MRD = minimal residual disease; 
PB = peripheral blood; PE = physical exam; PR = partial response.
From last 
patient enrolled
From last 
patient enrolled

 
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Appendix 14 
Duration and Reporting of Adverse Events 
 
RELATED 
UNRELATED 
Post-Treatment 
Reporting 
Period 
Follow-up 
Post-treatment 
Reporting 
Period 
Follow-up 
AEs Grades 1 and 
2 
28 days  
Not required 
28 days 
Not required 
AEs Grades 3 and 
4 
6 months or NLT 
Until resolution 
to ≤ Grade 2 
6 months or NLT 
Until resolution 
to ≤ Grade 2 
Major infections 
(Grades 3 and 4) 
2 years or NLT 
Until resolution 
stabilization or 
end of study 
2 years or NLT 
Until resolution 
stabilization or 
1 year after onset 
SAEs 
Indefinitely 
Until resolution 
stabilization or 
end of study 
Throughout 
follow-up 
period 
Until resolution 
stabilization or 
1 year after onset 
Secondary 
malignancies 
Indefinitely 
Not required 
Indefinitely 
Not required 
AE = adverse event; SAE = serious adverse event; NLT = next leukemia treatment. 
 

 
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Appendix 15 
EQ-5D-3L Questionnaire 
 
 
 

 
Appendix 15 
EQ-5D-3L Questionnaire (cont.) 
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Appendix 16  
Eastern Cooperative Oncology Group Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (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 
 

 
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Appendix 17  
Matutes Scoring System 
Flow cytometric analysis of peripheral blood or bone marrow is performed for expression 
of the cell surface markers listed in the table below. The scores for each marker are 
summed. 
 
0 Points 
1 Point 
CD5 
Negative 
Positive 
CD23 
Negative 
Positive 
FMC7 
Positive 
Negative 
S Ig  
Strong 
Weak 
CD22 
Strong 
Weak 
Note:  A score of ≥ 4 is indicative of CLL; a 
score ≤ 3 should prompt consideration of an 
alternative diagnosis. 
Source:  http://bloodref.com/lymphoid/cll/cll-score 
 
Matutes E, Owusu-Ankomah K, Morilla R, et al. The immunological profile of B-cell 
disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia 
1994;8:1640−5. 
 
 

 
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Appendix 18  
M.D. Anderson Symptom Inventory (MDASI-CLL) 

 
Appendix 18  
M.D. Anderson Symptom Inventory (MDASI-CLL) (cont.) 
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Appendix 19  
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) 
 

 
Appendix 19  
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) (cont.) 
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Appendix 20  
Guidelines for Defining Tumor Lysis Syndrome 
All tumor lysis syndrome events should be graded per the National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.03 criteria. 
Howard et al. (2011) defined laboratory tumor lysis syndrome as the presence of two or 
more electrolyte changes above or below the thresholds described above occurring 
during the same 24-hour period within 3 days before the start of therapy or 7 days after 
the start of therapy.  For the purposes of this study, this window applies to the initiation 
of any study therapy and each dose escalation of venetoclax.  Furthermore, this 
assessment assumes that a patient has or will receive adequate hydration 
(± alkalinization) and a hypouricemic agent(s). 
Table 1 
Howard Definition of Laboratory Tumor Lysis Syndrome 
Laboratory Assessment 
Range 
Uric acid 
> 476 µmol/L (> 8.0 mg/dL) 
Potassium 
> 6.0 mmol/L (> 6.0 mEq/L) 
Phosphorous 
> 1.5 mmol/L (> 4.5 mg/dL) 
Corrected calcium 
< 1.75 mmol/l (< 7.0 mg/dL) or ionized 
calcium < 1.12 (0.3 mmol/L) a 
Note:  Howard et al. (2011) defined laboratory tumor lysis syndrome as the presence of two or 
more electrolyte changes above or below the thresholds described above occurring during the 
same 24-hour period within 3 days before the start of therapy or 7 days afterward.  For the 
purposes of this study, this window applies to the initiation of any study therapy and each dose 
escalation of venetoclax.  Furthermore, this assessment assumes that a patient has or will 
receive adequate hydration (± alkalinization) and a hypouricemic agent(s). 
a The corrected calcium level in mg/dL is the measured calcium in mg/dL + (0.8 × [4-albumin 
in g/dL]). 
 

 
Appendix 20 
 
Guidelines for Defining Tumor Lysis Syndrome (cont.) 
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Table 2 
Howard Definition of Clinical Tumor Lysis Syndrome 
The presence of laboratory TLS and one or more of the following criteria: 
Creatininea:  An increase in serum creatinine level of 0.3 mg/dL (26.5 µmol/L); a single value 
> 1.5 times the ULN of the age appropriate normal range if no baseline creatinine measurement 
is available; or the presence of oliguria, defined as average urine output of < 0.5 mL/kg/hour for 
6 hours 
Cardiac dysrhythmia or sudden death probably or definitely caused by hyperkalemia 
Cardiac dysrhythmia, sudden death, seizure, neuromuscular irritability (tetany, paresthesias, 
muscle twitching, carpopedal spasm, Trousseau’s sign, Chvostek’s sign, layngospasm or 
bronchospasm), hypotension, or heart failure probably or definitely caused by hypocalcemiab 
TLS = tumor lysis syndrome; ULN = upper limit of normal. 
a Acute kidney injury is defined as an increase in the creatinine level of ≥ 0.3 mg/dL 
(26.5 umol/L) or a period of oliguria lasting ≥ 6 hours.  By definition, if acute kidney injury is 
present, the patient has clinical TLS. 
b Not directly attributable to a therapeutic agent. 
 
REFERENCE 
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. New Engl J Med 
2011;364:1844−54. 

 
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Appendix 21  
The Lawton Instrumental Activities of Daily Living Scale 
 
Source:  Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental 
activities of daily living. Gerontologist 1969;9(3):179−86.