A Prospective, Open-Label, Multicenter Randomized Phase III Study to Compare The Efficacy and Safety of A Combined Regimen of Venetoclax and Obinutuzumab Versus Fludarabine, Cyclophosphamide, and Rituximab (FCR)/Bendamustine and Rituximab (BR) in FIT Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without DEL(17P) or TP53 Mutation
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia (CLL)
Sponsor: Hoffmann-La Roche



 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Venetoclax and ObinutuzumabF. Hoffmann-La Roche Ltd 
Protocol CO41685, Version 5 
PROTOCOL 
TITLE: 
A PROSPECTIVE, OPEN-LABEL, MULTICENTER 
RANDOMIZED PHASE III STUDY TO COMPARE 
THE EFFICACY AND SAFETY OF A COMBINED 
REGIMEN OF VENETOCLAX AND OBINUTUZUMAB 
VERSUS FLUDARABINE, CYCLOPHOSPHAMIDE, 
AND RITUXIMAB (FCR)/ BENDAMUSTINE AND 
RITUXIMAB (BR) IN FIT PATIENTS WITH 
PREVIOUSLY UNTREATED CHRONIC 
LYMPHOCYTIC LEUKEMIA (CLL) WITHOUT 
DEL(17P) OR TP53 MUTATION 
PROTOCOL 
NUMBER: 
CO41685 
VERSION NUMBER: 
5 
TEST COMPOUND: 
Venetoclax (GDC-0199 [ABT-199]; RO5537382), 
Obinutuzumab (GA101, RO5072759) 
REGULATORY 
AGENCY 
IDENTIFIER 
NUMBERS:  
EUDRACT Number:  2019-003327-37 
IND Number:  115,045 
EU CT Number:  2023-504036-17-00 
NCT Number:  NCT04285567 
SPONSOR AND 
LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
2/Protocol CO41685, Version 5 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
5 
See electronic date stamp on final page of this document 
4 
19 April 2022  
3 
19 October 2021 
2 
12 April 2021 
1 
1 October 2019 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
3/Protocol CO41685, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol CO41685 has been amended primarily to update the planned statistical 
analyses.  Changes to the protocol, along with a rationale for each change, are 
summarized below: 
 
The advice for contraception for female patients following treatment with 
cyclophosphamide has been updated to 12 months (Section 4.1.1) to align with the 
guidance provided in the cyclophosphamide label. 
 
The guidance on collection of concomitant medications during the follow-up period 
of the study has been updated (Section 4.5.3) for clarity. 
 
Clarification on reporting of adverse events and serious adverse events that occur 
outside the adverse event reporting period to the Sponsor has been provided 
(Section 5.6). 
 
Response criteria has been updated (Section 4.5.11) to align with the iwCLL 
guidelines. 
 
The following updates were made to align with the SAP: 
 
Determination of sample size has been updated (Section 6.1). 
 
Analysis timing has been updated (Section 6.2). 
 
Intercurrent events identified in the study have been updated (Section 6.5.1.1). 
 
The secondary endpoints to be formally tested have been updated 
(Section 6.5.2). 
 
The planned progression-free survival interim and final analyses have been 
defined (Section 6.5.3, 6.8.1). 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitor has been removed from the protocol to align with Clinical Trial Regulation 
(CTR) requirements (front page and Section 5.4.1).  
 
A section describing duration of participation has been added to align with CTR 
requirements (Section 3.2.1) 
 
A comprehensive list of investigational medicinal products and auxiliary medicinal 
products have been added to align with CTR requirements (Section 4.3 and 
Appendix 18). 
 
The threshold for ionized calcium has been corrected in the Guidelines for Defining 
Tumor Lysis Syndrome (Appendix 15) to align with the threshold published in the 
Howard et al. 2018 publication. 
 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.17). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Section 4.5.17.4 
[Confidentiality]). 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
4/Protocol CO41685, Version 5 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Section 9.6 Dissemination of Data and Protection of Trade Secrets) 
 
The synopsis has been simplified to align with CTR and other guidelines. 
 
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics. This amendment represents cumulative 
changes to the original protocol. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
5/Protocol CO41685, Version 5 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 16 
PROTOCOL SYNOPSIS .................................................................................... 17 
1. 
BACKGROUND ............................................................................ 22 
1.1 
Background on Chronic lymphocytic Leukemia ....................... 22 
1.2 
Background on Venetoclax ...................................................... 23 
1.3 
Study Rationale and Benefit-Risk Assessment ........................ 24 
1.3.1 
Efficacy .................................................................................... 24 
1.3.2 
Safety ...................................................................................... 25 
1.3.3 
Benefit-Risk Assessment ......................................................... 26 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 27 
2.1 
Efficacy Objectives .................................................................. 27 
2.1.1 
Primary Efficacy Objective ....................................................... 27 
2.1.2 
Exploratory Efficacy Objective ................................................. 27 
2.1.3 
Secondary Efficacy Objective .................................................. 27 
2.2 
Safety Objectives ..................................................................... 28 
2.3 
Biomarker Objective ................................................................ 28 
2.4 
Patient-Reported Outcome Objectives .................................... 29 
2.5 
Health economic Objective ...................................................... 29 
3. 
STUDY DESIGN ........................................................................... 29 
3.1 
Description of the Study ........................................................... 29 
3.1.1 
Minimal Residual Disease Assessments ................................. 31 
3.1.2 
Disease Response Assessment .............................................. 31 
3.1.3 
Timing of Assessments ............................................................ 31 
3.1.3.1 
MRD Assessments .................................................................. 31 
3.1.3.2 
Tumor and Response Assessments ........................................ 32 
3.1.4 
Summary of Study Procedures ................................................ 33 
3.1.4.1 
Screening/Baseline Tests ........................................................ 33 
3.1.4.2 
Treatment Period ..................................................................... 34 
3.1.4.3 
Monitoring of Disease Progression during Treatment 
Period ...................................................................................... 36 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
6/Protocol CO41685, Version 5 
3.1.4.4 
Post-Treatment Follow-Up Visits ............................................. 36 
3.2 
End of Study and Length of Study ........................................... 36 
3.2.1 
Duration of Participation ........................................................ 36 
3.2.2 
Long-Term Follow Up .............................................................. 37 
3.3 
Rationale for Study Design ...................................................... 37 
3.3.1 
Rationale for Dose and Schedule ............................................ 37 
3.3.1.1 
Venetoclax ............................................................................... 37 
3.3.1.2 
Obinutuzumab ......................................................................... 38 
3.3.1.3 
Rationale for the Combination of Venetoclax with 
Obinutuzumab ......................................................................... 38 
3.3.2 
Rationale for Patient Population .............................................. 38 
3.3.3 
Rationale for Control Group ..................................................... 39 
3.3.4 
Rationale for MRD as the Primary Endpoint ............................ 39 
3.3.4.1 
MRD Negativity Leads to Improved Clinical Outcomes ........... 39 
3.3.4.2 
High and Promising Rates of MRD Negativity Achieved by 
Venetoclax ............................................................................... 40 
3.3.4.3 
Venetoclax in Combination with Obinutuzumab Show 
Compelling PFS and MRD Data in 1L CLL .............................. 41 
3.3.5 
Rationale for Biomarker Assessments ..................................... 43 
3.3.6 
Rationale for Chronic Lymphocytic Leukemia Diagnostic 
Laboratory Assessments ......................................................... 44 
3.3.6.1 
Lymphocyte Count ................................................................... 44 
3.3.6.2 
Lymphocyte Immunophenotyping ............................................ 44 
3.3.7 
Rationale for Not Assessing Pharmacokinetics in 
Study CO41685 ....................................................................... 45 
3.3.8 
Rationale for Patient-Reported Outcome (PRO) 
Assessments ........................................................................... 45 
4. 
MATERIALS AND METHODS ...................................................... 46 
4.1 
Patients .................................................................................... 46 
4.1.1 
Inclusion Criteria ...................................................................... 46 
4.1.2 
Exclusion Criteria ..................................................................... 47 
4.2 
Method of Treatment Assignment and Blinding ....................... 50 
4.2.1 
Treatment Assignment ............................................................. 50 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 50 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
7/Protocol CO41685, Version 5 
4.3.1 
Formulation, Packaging, and Handling .................................... 50 
4.3.1.1 
Venetoclax ............................................................................... 50 
4.3.1.2 
Obinutuzumab ......................................................................... 50 
4.3.1.3 
Fludarabine .............................................................................. 51 
4.3.1.4 
Cyclophosphamide .................................................................. 51 
4.3.1.5 
Rituximab ................................................................................. 51 
4.3.1.6 
Bendamustine .......................................................................... 52 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 52 
4.3.2.1 
Venetoclax ............................................................................... 52 
4.3.2.2 
Obinutuzumab ......................................................................... 53 
4.3.2.3 
Fludarabine, Cyclophosphamide plus Rituximab ..................... 59 
4.3.3 
Investigational Medicinal Product Accountability ..................... 61 
4.3.4 
Non-Investigational Medicinal Products ................................... 62 
4.3.4.1 
Non-Investigational Medicinal Products for this Study ............. 62 
4.3.4.2 
Rasburicase ............................................................................. 62 
4.3.5 
Continued Access to Venetoclax, Obinutuzumab, 
Fludarabine, Cyclophosphamide, Rituximab, and 
Bendamustine .......................................................................... 62 
4.4 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions .............................................................................. 63 
4.4.1 
Permitted Therapy ................................................................... 63 
4.4.1.1 
Premedication before Rituximab .............................................. 64 
4.4.1.2 
Concomitant administration with SARS-CoV-2 Vaccine .......... 64 
4.4.2 
Prohibited and Cautionary Therapy ......................................... 65 
4.4.2.1 
Drug-Drug Interaction .............................................................. 65 
4.4.2.2 
Herbal Therapies ..................................................................... 67 
4.4.3 
Prohibited Food ....................................................................... 67 
4.4.4 
Other Prohibited Medication .................................................... 67 
4.5 
Study Assessments ................................................................. 68 
4.5.1 
Informed Consent Forms and Screening Log .......................... 68 
4.5.2 
Procedures for Enrollment of Eligible Patients ......................... 68 
4.5.3 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 68 
4.5.4 
Physical Examinations ............................................................. 69 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
8/Protocol CO41685, Version 5 
4.5.5 
Performance Status ................................................................. 69 
4.5.6 
Clinical Staging ........................................................................ 69 
4.5.7 
Criteria for Initiation of First-Line Treatment ............................ 70 
4.5.8 
Vital Signs ................................................................................ 71 
4.5.9 
MRD Response Criteria ........................................................... 71 
4.5.9.1 
MRD Evaluation ....................................................................... 71 
4.5.9.2 
Additional Exploratory Assessments of MRD Response ......... 71 
4.5.10 
Tumor and Response Evaluations ........................................... 71 
4.5.11 
Response Criteria .................................................................... 73 
4.5.11.1 
Complete Response ................................................................ 73 
4.5.11.2 
Complete Response and Incomplete Bone Marrow 
Recovery.................................................................................. 74 
4.5.11.3 
Partial Response ..................................................................... 74 
4.5.11.4 
Progressive Disease ................................................................ 74 
4.5.11.5 
Stable Disease ......................................................................... 75 
4.5.12 
Other Disease-Specific Assessments ...................................... 75 
4.5.12.1 
Bone Marrow ........................................................................... 76 
4.5.12.2 
Lymphadenopathy and Hepatomegaly/Splenomegaly ............. 76 
4.5.12.3 
B-Symptoms ............................................................................ 76 
4.5.13 
Laboratory, Biomarker, and Other Biological Samples ............ 77 
4.5.13.1 
During Screening Only (Days 28 to 1) ................................. 77 
4.5.13.2 
Further Assessments ............................................................... 77 
4.5.14 
Electrocardiograms .................................................................. 80 
4.5.15 
Patient-Reported Outcome (PRO) Assessments and 
Health Economic Assessments ............................................... 81 
4.5.15.1 
MDASI-CLL .............................................................................. 81 
4.5.15.2 
EORTC QLQ-C30 .................................................................... 82 
4.5.15.3 
EQ-5D-5L................................................................................. 82 
4.5.16 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 83 
4.5.17 
Optional Samples for Research Biosample Repository ........... 83 
4.5.17.1 
Overview of the Research Biosample Repository .................... 83 
4.5.17.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 84 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
9/Protocol CO41685, Version 5 
4.5.17.3 
Sample Collection .................................................................... 84 
4.5.17.4 
Confidentiality .......................................................................... 85 
4.5.17.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 85 
4.5.17.6 
Withdrawal from the Research Biosample Repository ............. 86 
4.5.17.7 
Monitoring and Oversight ......................................................... 86 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 86 
4.6.1 
Study Treatment Discontinuation ............................................. 86 
4.6.2 
Patient Discontinuation from the Study .................................... 87 
4.6.3 
Study Discontinuation .............................................................. 87 
4.6.4 
Site Discontinuation ................................................................. 88 
5. 
ASSESSMENT OF SAFETY ......................................................... 88 
5.1 
Safety Plan .............................................................................. 88 
5.1.1 
Risks Associated with Venetoclax ........................................... 88 
5.1.1.1 
Tumor Lysis Syndrome ............................................................ 88 
5.1.1.2 
Serious Infections .................................................................... 89 
5.1.1.3 
Neutropenia and Cytopenias ................................................... 90 
5.1.1.4 
Effects on Cardiac Function ..................................................... 91 
5.1.1.5 
Effects on Fertility and Reproductive Toxicity .......................... 91 
5.1.1.6 
Drug Interactions ..................................................................... 91 
5.1.1.7 
Treatment-Emergent Malignancies 
(Second Primary Malignancies) ............................................... 92 
5.1.1.8 
Toxicity in Patients with Severe Hepatic Impairment ............... 92 
5.1.1.9 
Food Effect .............................................................................. 92 
5.1.2 
Risks Associated with Obinutuzumab ...................................... 92 
5.1.2.1 
Infusion-Related Reactions and Hypersensitivity Reactions .... 93 
5.1.2.2 
Tumor Lysis Syndrome ............................................................ 93 
5.1.2.3 
Neutropenia ............................................................................. 93 
5.1.2.4 
Lymphopenia ........................................................................... 94 
5.1.2.5 
Thrombocytopenia ................................................................... 94 
5.1.2.6 
Coagulation Abnormalities Including Disseminated 
Intravascular Coagulation ........................................................ 95 
5.1.2.7 
Infections ................................................................................. 95 
5.1.2.8 
Immunization ........................................................................... 97 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
10/Protocol CO41685, Version 5 
5.1.2.9 
Gastrointestinal Perforation ..................................................... 97 
5.1.2.10 
Worsening of Preexisting Cardiac Conditions .......................... 97 
5.1.2.11 
Risks Associated with the Combination of Venetoclax and 
Obinutuzumab ......................................................................... 97 
5.1.3 
Risks Associated with Rituximab ............................................. 98 
5.1.3.1 
Infusion-Related Reactions ...................................................... 98 
5.1.3.2 
Infections (Including Serious Infections) .................................. 98 
5.1.3.3 
Neutropenia ............................................................................. 98 
5.1.3.4 
Tumor Lysis Syndrome ............................................................ 99 
5.1.3.5 
Hepatitis B Reactivation ........................................................... 99 
5.1.3.6 
Progressive Multifocal Leukoencephalopathy .......................... 99 
5.1.3.7 
Severe Mucocutaneous Reactions .......................................... 99 
5.1.3.8 
Gastrointestinal Perforation ................................................... 100 
5.1.4 
Risks Associated with FCR/BR .............................................. 100 
5.1.4.1 
Tumor Lysis Syndrome .......................................................... 100 
5.1.4.2 
Cytopenias and Infections ..................................................... 100 
5.1.4.3 
Worsening of Preexisting Cardiac Conditions ........................ 101 
5.1.4.4 
Teratogenicity and Mutagenicity ............................................ 101 
5.1.5 
Potential Risks with Bendamustine ........................................ 102 
5.1.6 
Management of Patients Who Experience Adverse Events ... 102 
5.1.6.1 
Guidelines for Management of Specific Adverse Events in 
ARM A (Venetoclax + Obinutuzumab) ................................... 103 
5.1.6.2 
Guidelines for Management of Specific Adverse Events in 
ARM B (FCR/BR) ................................................................... 106 
5.1.7 
Dose Modifications of Fludarabine and Cyclophosphamide 
Due to Decreased Renal Function ......................................... 109 
5.1.7.1 
Prophylaxis and Management of Tumor Lysis Syndrome 
for Patients Being Treated with Venetoclax ........................... 110 
5.1.7.2 
Prophylaxis for Infections ....................................................... 122 
5.1.7.3 
Prophylaxis for Infusion-Related Reactions ........................... 122 
5.1.7.4 
Life-Threatening Infusion-Related Reactions and 
Anaphylaxis ........................................................................... 123 
5.2 
Safety Parameters and Definitions ........................................ 123 
5.2.1 
Adverse Events ...................................................................... 123 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
11/Protocol CO41685, Version 5 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ................................................................................ 123 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 124 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 125 
5.3.1 
Adverse Event Reporting Period ............................................ 125 
5.3.2 
Eliciting Adverse Event Information ....................................... 125 
5.3.3 
Assessment of Severity of Adverse Events ........................... 125 
5.3.4 
Assessment of Causality of Adverse Events.......................... 126 
5.3.5 
Procedures for Recording Adverse Events ............................ 127 
5.3.5.1 
Infusion-Related Reactions .................................................... 127 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................. 127 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ........... 128 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 128 
5.3.5.5 
Abnormal Laboratory Values ................................................. 129 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 129 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 130 
5.3.5.8 
Deaths ................................................................................... 130 
5.3.5.9 
Pre-existing Medical Conditions ............................................. 131 
5.3.5.10 
Lack of Efficacy or Worsening of Chronic Lymphocytic 
Leukemia ............................................................................... 131 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 131 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ........................................................................... 132 
5.3.5.13 
Patient-Reported Outcome Data ............................................ 134 
5.3.5.14 
Safety Biomarker Data ........................................................... 134 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 134 
5.4.1 
Emergency Medical Contacts ................................................ 135 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 135 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 135 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 135 
5.4.3 
Reporting Requirements for Pregnancies .............................. 136 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
12/Protocol CO41685, Version 5 
5.4.3.1 
Pregnancies in Female Patients ............................................ 136 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 136 
5.4.3.3 
Abortions................................................................................ 137 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 137 
5.5 
Follow-Up of Patients after Adverse Events........................... 137 
5.5.1 
Investigator Follow-Up ........................................................... 137 
5.5.2 
Sponsor Follow-Up ................................................................ 137 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 138 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 138 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 139 
6.1 
Determination of Sample Size ............................................... 139 
6.2 
Analysis Timing ...................................................................... 140 
6.3 
Summaries of Conduct of Study ............................................ 140 
6.4 
Summaries of Demographic and Baseline Characteristics .... 140 
6.5 
Efficacy Analyses ................................................................... 141 
6.5.1 
Primary Efficacy Endpoint ...................................................... 141 
6.5.1.1 
Target of Estimation for the Primary Efficacy Endpoint .......... 141 
6.5.2 
Secondary Efficacy Endpoints ............................................... 142 
6.5.3 
Type-1 Error Control .............................................................. 143 
6.5.4 
Supplementary Analyses ....................................................... 143 
6.6 
Safety Analyses ..................................................................... 144 
6.6.1 
Patient-Reported Outcome Analyses ..................................... 144 
6.6.2 
Health Economic Analyses .................................................... 145 
6.7 
Exploratory analyses ............................................................. 145 
6.8 
Interim Analysis ..................................................................... 146 
6.8.1 
Planned Interim Analysis ....................................................... 146 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 146 
7.1 
Data Quality Assurance ......................................................... 146 
7.2 
Electronic Case Report Forms ............................................... 147 
7.3 
Electronic Patient-Reported Outcome Data ........................... 147 
7.4 
Source Data Documentation .................................................. 147 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
13/Protocol CO41685, Version 5 
7.5 
Use of Computerized Systems .............................................. 148 
7.6 
Retention of Records ............................................................. 148 
8. 
ETHICAL CONSIDERATIONS .................................................... 149 
8.1 
Compliance with Laws and Regulations ................................ 149 
8.2 
Informed Consent .................................................................. 149 
8.3 
Institutional Review Board or Ethics Committee .................... 150 
8.4 
Confidentiality ........................................................................ 150 
8.5 
Financial Disclosure ............................................................... 151 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 152 
9.1 
Study Documentation ............................................................ 152 
9.2 
Protocol Deviations ................................................................ 152 
9.3 
Management of Study Quality ................................................ 152 
9.4 
Site Inspections ..................................................................... 152 
9.5 
Administrative Structure ......................................................... 152 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 153 
9.7 
Protocol Amendments ........................................................... 154 
10. 
REFERENCES............................................................................ 155 
 
 
LIST OF TABLES 
Table 1 
Treatment Arm A:  VEN  G Doses per Study Visit .................... 34 
Table 2 
Administration of First Infusion of Obinutuzumab, if Split 
Over Two Days, and Subsequent Infusions of Obinutuzumab .... 58 
Table 3 
Administration of First and Subsequent Infusions of 
Rituximab .................................................................................... 60 
Table 4 
Excluded and Cautionary Medications for Patients 
Randomized to Arm A (Venetoclax  Obinutuzumab) ................. 66 
Table 5 
Venetoclax Dose Reductions for Strong and Moderate 
CYP3A Inhibitors ......................................................................... 67 
Table 6 
Management of Hepatitis B Virus Reactivation ........................... 96 
Table 7 
National Cancer Institute Grading Scale for Chronic 
Lymphocytic Leukemia ............................................................. 103 
Table 8 
Guidelines for Management of Specific Adverse Events for 
Patients Randomized to Arm A ................................................. 104 
Table 9 
Venetoclax Dose Reduction ...................................................... 105 
Table 10 
Bendamustine Dose Reduction ................................................. 107 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
16/Protocol CO41685, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PROSPECTIVE, OPEN-LABEL, MULTICENTER 
RANDOMIZED PHASE III STUDY TO COMPARE 
THE EFFICACY AND SAFETY OF A COMBINED 
REGIMEN OF VENETOCLAX AND 
OBINUTUZUMAB VERSUS FLUDARABINE, 
CYCLOPHOSPHAMIDE, AND RITUXIMAB (FCR)/ 
BENDAMUSTINE AND RITUXIMAB (BR) IN FIT 
PATIENTS WITH PREVIOUSLY UNTREATED 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) 
WITHOUT DEL(17P) OR TP53 MUTATION 
PROTOCOL NUMBER: CO41685 
VERSION NUMBER: 
5 
TEST COMPOUNDS: 
Venetoclax (GDC-0199 [ABT-199]; RO5537382), 
Obinutuzumab (GA101, RO5072759) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to the Sponsor or their designee. 
 

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
17/Protocol CO41685, Version 5 
PROTOCOL SYNOPSIS 
TITLE: 
A PROSPECTIVE, OPEN-LABEL, MULTICENTER RANDOMIZED 
PHASE III STUDY TO COMPARE THE EFFICACY AND SAFETY 
OF A COMBINED REGIMEN OF VENETOCLAX AND 
OBINUTUZUMAB VERSUS FLUDARABINE, 
CYCLOPHOSPHAMIDE, AND RITUXIMAB (FCR)/ 
BENDAMUSTINE AND RITUXIMAB (BR) IN FIT PATIENTS WITH 
PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA 
(CLL) WITHOUT DEL(17P) OR TP53 MUTATION 
PROTOCOL NUMBER: 
CO41685 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
EUDRACT Number:  2019-003327-37 
IND Number:  115,045 
EU CT Number:  2023-504036-17-00 
NCT Number:  NCT04285567  
TEST PRODUCT: 
Venetoclax (GDC-0199 [ABT-199]; RO5537382),  
Obinutuzumab (GA101, RO5072759) 
PHASE: 
III 
INDICATION: 
Chronic Lymphocytic Leukemia (CLL) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
STUDY RATIONALE 
This study will evaluate the efficacy and safety of venetoclax (Venclexta or Venclyxto) in 
combination with obinutuzumab (Gazyva or Gazyvaro) (VEN  G) compared with fludarabine, 
cyclophosphamide, and rituximab (FCR), and bendamustine and rituximab (BR) in FIT patients 
(FIT defined by a CIRS/score 6 and a normal creatinine clearance of 70 mL/min) with 
previously untreated chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutations.  
Specific objectives and corresponding endpoints for the study are outlined in this section. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
18/Protocol CO41685, Version 5 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Corresponding Endpoint 
 Evaluate the efficacy of VEN  G compared 
with FCR/BR 
 MRD response rate, determined as the 
proportion of patients with MRD-negativity 
(defined as 1 CLL cell in 
10,000 leukocytes), measured in PB using 
NGS at Month 15 
 evaluate the safety of VEN  G compared 
with FCR/BR 
 Nature, frequency, and severity of adverse 
events and serious adverse events  
 Changes in vital signs, physical findings, and 
clinical laboratory test results during and 
following study treatment 
 Premature withdrawals 
Secondary Objective 
Corresponding Endpoint 
 Evaluate the efficacy of VEN  G compared 
with FCR/BR 
 PFS, defined as the time from randomization 
to the first occurrence of disease 
progression, or death from any cause; 
disease progression assessed by the 
investigators using the iwCLL criteria  
 MRD response rate, in PB at the end of 
treatment response visit (812 weeks after 
the last dose of FCR/BR [~9 months] vs. 
812 weeks after last dose of VEN  G 
[~15 months]) 
MRD response rate in BM at the end of 
treatment response visit (9 months FCR/BR 
vs. 15 months VEN  G) vs. 812 weeks 
after last dose of VEN  G [approximately 
15 months from first dose]) ORR, which 
includes CR, complete remission with CRi, 
and PR at the Month 15 assessment 
 CR rate, which includes CR and CRi at the 
Month 15 assessment 
 MRD response rate in PB of patients with a 
CR/CRi at Month 15MRD response rate in 
the BM of patients with a CR/CRi at the end 
of treatment visit (812 weeks after the last 
dose of FCR/BR [~9 months] vs. 
812 weeks after the last dose of VEN  G 
[~15 months]) 
 DOR, defined as the time from the first 
response to the time of PD or death from 
any cause, whichever comes first 
 Best response achieved (CR, CRi, PR, SD, 
or PD) up to and including the assessment 
at Month 15 
 EFS, defined as the time between the date 
of randomization and the date of disease 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
19/Protocol CO41685, Version 5 
Secondary Objective 
Corresponding Endpoint 
 
progression/relapse, death, or start of a new 
anti-leukemic therapy  
 OS, defined as the time from randomization 
to the date of death from any cause 
TLS risk reduction rate in Arm A, defined as 
the reduction in the proportion of participants 
who were TLS high-risk after 3 doses of 
obinutuzumab compared to the proportion of 
participants who were TLS high-risk at 
baseline 
 Reduction in mandatory hospitalizations 
during venetoclax ramp-up in Arm A 
participants, defined as the actual number of 
protocol‑mandated hospitalizations for TLS 
monitoring during venetoclax ramp-up 
periodafter 3 doses of obinutuzumab 
compared to the number of 
protocol‑mandated hospitalizations for TLS 
monitoring during venetoclax ramp-up 
expected at baseline 
BM  bone marrow; BR  bendamustine and rituximab; CLL  chronic lymphocytic leukemia; 
CRi  incomplete blood count recovery; DOR  duration of objective response; EFS  event-
free survival; FCR  fludarabine, cyclophosphamide, and rituximab; iwCLL  International 
Workshop on CLL; MRD  minimal residual disease; NGS  next generation sequencing; 
OS  overall survival; PB  peripheral blood; PD  progressive disease; PFS  progression-free 
survival; PR  partial response; SD  stable disease; TLS  tumor lysis syndrome; 
Ven  G  Venetoclax (Venclexta or Venclyxto) in combination with Obinutuzumab (Gazyva or 
Gazyvaro)  
  
Primary and selected secondary objectives for the study are expressed using the estimand 
framework in accordance with the International Conference on Harmonization E9 (R1) 
statistical principles for clinical trials (ICH 2020) in Section 3. 
 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
20/Protocol CO41685, Version 5 
Overall Design and Study Population 
Several key aspects of the study design and study population are summarized below. 
 
Phase: 
Phase III 
Population Type: 
Adult Patients 
Control Method: 
Active Comparator 
Population Diagnosis 
or Condition: 
FIT patients with 
previously untreated 
CLL without del(17p) 
or TP53 mutation 
requiring treatment 
Interventional 
Model: 
Parallel 
Population Age: 
 65 or 65 years 
Test Compounds}: Venetoclax/RO5537382 
Obinutuzumab/RO5072759 
Site Distribution: 
Multi-site and 
multi-region 
Active Comparator: Fludarabine, 
Cyclophosphamide, and 
Rituximab 
(FCR)/Bendamustine and 
Rituximab (BR) 
Study Intervention 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
2 
Number of 
Participants to Be 
Enrolled: 
165 
  
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are venetoclax, obinutuzumab, 
fludarabine, cyclophosphamide, bendamustine, and rituximab. 
ARM A 
Patients randomized to Arm A (VEN  G) will receive 12 cycles of treatment, each with a precise 
duration of 28 days.  During the first cycle, obinutuzumab will be administered intravenously on 
Days 1 (and 2), 8, and 15 as well as on Day 1 of Cycles 26.  Continuous daily administration, 
with a 5-week ramp-up period, of venetoclax starts on Cycle 1, Day 22.  Venetoclax will be 
administered until the end of Cycle 12.   
Because it is possible that de-bulking from obinutuzumab therapy before starting venetoclax 
dosing already significantly reduces the risk of tumor lysis syndrome (TLS), TLS prophylactic 
measures will be re-assessed at the time of starting the first dose of venetoclax. 
Arm B 
Patients randomized to Arm B (FCR/BR 50:50) will receive 6 cycles of FCR consisting of a single 
cycle of a single infusion of rituximab on Day 1 and fludarabine and cyclophosphamide infusions 
on Days 13 of each 28-day cycle or bendamustine as infusions on Days 1 and 2 and a single 
cycle of rituximab on Day 1 of each 28-day cycle. 
All patients in Arm B can be considered for treatment with BR, whereas only patients 65 years 
of age will be eligible for FCR.  The choice between FCR or BR in Arm B will be at the 
investigator’s discretion.  
During this study, adverse events will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 5.0. 
The primary endpoint for assessing efficacy will be MRD response rate in PB at Month 15 in both 
arms (~3 months after the last dose of venetoclax in Arm A and approximately 9 months after the 
last cycle of FCR/BR in Arm B).  The primary MRD assessment will be conducted in 
approximately 165 patients enrolled in the study. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
21/Protocol CO41685, Version 5 
All patients will be assessed for minimal residual disease (MRD) response in PB samples using 
next generation sequencing (NGS) and will also be assessed for MRD response in the BM 
sample using NGS.  For both, response is defined as achieving MRD negativity at a cutoff of 
10-4 (1 CLL cell in 10,000 leukocytes). 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual is expected to be approximately 
3.5 years after the last patient is enrolled, allowing for completion of the maximum duration of 
planned therapy (in the absence of disease progression) as well as at least 2.5 years of follow 
up for all patients in order to reach the estimated number of events needed for the PFS final 
analysis. 
Patients are expected to be on study for a minimum of 3.5 years up to a maximum of 6.2 years, 
subject to their date of enrollment in relation to the last patient enrolled. 
Committees 
Independent Committees: 
independent Data Monitoring Committee 
Other Committees: 
Not Applicable 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
22/Protocol CO41685, Version 5 
1. 
BACKGROUND 
1.1 
BACKGROUND ON CHRONIC LYMPHOCYTIC LEUKEMIA 
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, 
representing approximately 30% of all adult leukemias.  The incidence of CLL varies by 
race and geographic location, with a lower incidence in Asia (5% of leukemias) 
compared with Western countries.  The incidence is higher in males than females and 
increases with age (NIH SEER 2018).  CLL is a clonal disease of unknown etiology, 
characterized by the accumulation of mature B cells in the blood, lymph nodes, spleen, 
liver, and bone marrow (BM). 
The disease has a characteristic immunophenotype, which includes co-expression of 
CD5 (T-cell antigen) and the B-cell surface antigens CD19, CD20, and CD23, and low 
levels of surface immunoglobulin, CD20, and CD79b compared with normal B cells 
(Hallek et al. 2008).  The clonality of the disease is confirmed by the presence of a single 
immunoglobulin light chain.  
CLL generally follows an indolent course.  Treatment is usually associated with a high 
rate of initial responses followed inevitably by relapse.  Subsequent treatments can 
induce remissions, but at a progressively lower rate with responses of shorter duration.  
Although the median survival of patients with CLL is around 10 years, the disease has 
an extremely variable clinical course, and the prognosis depends on disease stage and 
a range of prognostic biomarkers.  Two clinical staging systems have been developed by 
Rai et al. (1975) and Binet et al. (1977).  Both systems are widely used and are an 
accepted prognostic tool, albeit with limitations (notably for predicting disease 
progression in early stage disease).  In both systems, patients are classified into low-, 
intermediate-, and high-risk groups on the basis of the degree of lymphocytosis, 
presence of lymphadenopathy, hepatomegaly or splenomegaly, anemia, and 
thrombocytopenia.  There are also a number of biomarkers that can predict the patient 
prognosis with CLL.  Patients with del(17p) or TP53 mutations have the poorest 
prognosis.  Approximately 5%10% of patients with early stage CLL have del(17p) 
and/or TP53 mutations, and this rate increases with treatment lines up to 40% in 
advanced refractory CLL (Zenz et al. 2008; Stilgenbauer and Zenz 2010; Zenz et al. 
2010).  Other biomarkers, such as mutations in NOTCH1, SF3B1, MYD88, or BIRC3, 
may also be predictive of an unfavorable prognosis in the absence of a TP53 mutation.  
Patients with CLL cells with unmutated immunoglobulin heavy chain variable region 
(IgVH/IGHV) have a higher risk of unfavorable genetic mutations and, therefore, a 
poorer prognosis.  
In the United States, a recent Surveillance, Epidemiology, and End Results (SEER) 
report estimated an overall age-adjusted mortality rate for CLL of 1.3 per 
100,000 persons per year with the median age at diagnosis of 70 years, the median age 
at death of 80 years, and an approximate 5-year survival rate of 84.2% for the period of 
20082014 (NIH SEER 2018).  The mortality estimates of the total number of CLL 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
23/Protocol CO41685, Version 5 
deaths in Europe are limited; therefore, survival estimates are also presented.  The 
5-year mortality rate for Spanish patients diagnosed with CLL between 1995 and 2004 
was 24 per 1000-patient years while the 10-year mortality rate was 41 per 1,000-patient 
years (Abrisqueta et al. 2009).  In Europe, the 5-year relative survival rate of patients 
with CLL and small lymhocyclic lymphoma (SLL) in the period 2000–2002 was 69.1% 
(Marcos-Gragera et al. 2011).  Since the incidence rate increases with age, the 
prevalence and mortality of CLL are likely to increase in the coming decades because of 
the demographic changes associated with an aging population. 
In multiple studies in patients with CLL, achieving disease reduction below reliable limits 
of detection (1 CLL cell/104 leukocytes) using sensitive techniques, such as multicolor 
flow cytometry, allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), 
and next-generation sequencing (NGS), has been shown to be the strongest 
independent predictor of progression-free survival (PFS) and overall survival (OS).  
Thus, minimal residual disease (MRD) negativity rates, independent of the depth of 
clinical response, may predict overall clinical benefit, as previously demonstrated with 
the use of chemo-immunotherapy treatment (Rawstron et al. 2007, 2013, 2015; 
Böttcher et al. 2013; Kovacs et al. 2016; Dimier et al. 2018).  MRD negativity rates have 
similarly shown to be predictable of the outcome regardless of clinical response in 
targeted therapy with a time-limited venetoclax plus rituximab regimen (Kater et al. 2018) 
and are, therefore, considered an established clinically significant endpoint to 
differentiate treatment options. 
1.2 
BACKGROUND ON VENETOCLAX  
Venetoclax (Venclexta; also known as Venclyxto, GDC-0199, or ABT-199) was first 
approved in the United States on 11 April 2016 through an accelerated approval for the 
treatment of patients with CLL with del(17p).  On 8 June 2018, the U.S. Food and Drug 
Administration (FDA) approved the combination therapy venetoclax and rituximab and 
the venetoclax expanded monotherapy.  This approval confirmed the clinical benefit of 
venetoclax in the relapsing/refractory (R/R) CLL population with or without del(17p); 
thus, the initial accelerated approval has been converted to a full approval.  On 
20 November 2018, the European Commission approved venetoclax Type II variation to 
fulfill the Specific Obligation relating to the conditional status of the license, thus 
converting the conditional E.U. marketing authorization into a full E.U. marketing 
authorization.  On 15 May 2019, the FDA approved venetoclax in combination with 
obinutuzumab (Gazyva or Gazyvaro) (VEN  G) in previously untreated patients with 
CLL or SLL based upon the pivotal Study BO25323/CLL14 and supporting 
Study GP28331.  The VEN  G regimen and dose used in the BO25323/CLL14 study is 
the same regimen and dose used in this study.  
Venetoclax is a highly selective, orally bioavailable, small-molecule, B-cell lymphoma 
(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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
24/Protocol CO41685, Version 5 
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, thus, these proteins are 
compelling targets for anti-tumor therapy.  Constitutively elevated expression of the 
anti-apoptotic protein Bcl-2 renders CLL cells resistant to apoptosis, resulting in the 
accumulation of long-lived, clonal lymphocytes that characterize the disease 
(Cimmino et al. 2005, Robertson et al. 1996, Del Gaizo Moore et al. 2007).  In vitro, 
venetoclax demonstrated cell-killing activity against patient derived CLL cells, 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).  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, non-Hodgkin lymphoma (NHL), and AML 
and is highly efficacious when using various doses and combined with other regimens.  
Venetoclax is also active in a model of disseminated acute lymphocytic leukemia (ALL).  
It enhanced the activity of a broad variety of chemotherapeutic agents in other human 
hematological models (Venetoclax Investigators Brochure).  Specifically, venetoclax 
enhances the efficacy of obinutuzumab and rituximab in models of MCL and DLBCL 
(Venetoclax Investigator’s Brochure and Obinutuzumab Investigator’s Brochure).  
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 MM (Touzeau et al. 2014).  
See the Venetoclax 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 co-existing medical conditions.  As a result, a 
cure for patients with CLL necessitates more effective drugs that also have an 
acceptable safety profile.  A chemotherapy-free regimen could meet these expectations. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
25/Protocol CO41685, Version 5 
On 15 May 2019, the U.S. FDA approved the use of venetoclax in combination with 
obinutuzumab in previously untreated patients with CLL or SLL based on the findings 
from the pivotal Study BO25323/CLL14.  This was an open-label, prospective, 
multicenter, randomized, Phase III trial to compare the efficacy and safety of VEN  G 
versus obinutuzumab  chlorambucil (GClb) in previously untreated CLL patients with 
comorbidity.  This study is also under assessment by other competent authorities 
worldwide.  Study BO25323/CLL14 not only demonstrates unprecedented MRD rates 
representing a depth of anti-CLL activity that differentiates treatment with VEN  G, it 
also provides compelling PFS data in the first-line (1L) setting. 
Based on the results of a protocol-specified interim analysis (as of 17 August 2018 
clinical cutoff date [CCOD]), the Independent Data Monitoring Committee (IDMC) 
recommended that Study BO25323/CLL14 had met its primary endpoint of 
investigator-assessed PFS, with a significant and clinically meaningful improvement in 
patients in the VEN  G arm (investigator-assessed PFS:  stratified HR  0.35 [95% CI: 
0.23 to 0.53], Independent Review Committee (IRC)-assessed PFS: stratified HR  0.33 
[95% CI: 0.22, 0.51], p 0.0001) versus patients in the GClb arm.  A consistent trend 
showing that VEN  G was superior to GClb was observed across key secondary efficacy 
endpoints (e.g., complete response [CR] rates, objective response rate [ORR]) and 
across all of the pre-specified subgroups based on baseline characteristics, stratification 
factors, and other key prognostics markers. 
1.3.2 
Safety 
Known risks associated with venetoclax administration include tumor lysis syndrome 
(TLS), hematological effects (including neutropenia/febrile neutropenia), serious and/or 
opportunistic infections, nausea, and diarrhea (Venetoclax Investigator’s Brochure).  
Clinical evaluations of the risks identified from previous preclinical studies (e.g., 
single-cell necrosis, allergic reactions, liver enzyme elevations, and hair color change) 
did not reveal any clinically significant concerns, 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 postdose LVEF data showed no risk of decreased LVEF 
following venetoclax dosing.  Since 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 VEN  G include the following:  
TLS, infusion-related reactions (IRRs) to obinutuzumab, cytopenia (e.g., 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 VEN  G 
can largely be managed (e.g., first dose TLS and IRRs), or are commonly encountered 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
26/Protocol CO41685, Version 5 
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: 
 
In the BO25323/CLL14 study, treatment with obinutuzumab before treatment with 
venetoclax was an effective method to reduce the risk of TLS occurring during the 
venetoclax ramp-up period.  The same regimen and schedule will be followed in this 
protocol.  
 
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 5.1.7.1). 
 
Staggered dosing of venetoclax initiated on Day 22 during the first cycle of 
chemoimmunotherapy (Section 4.3.2.1.1) 
 
Prophylactic medication (Section 5.1.6.1 and Section 5.1.6.2) 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 
(Appendix 1 and Appendix 2) 
 
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 (Section 4.3.2.2, Section 4.5.3, Section 5.1.2.6, Section 5.1.6). 
 
Neutropenia will be closely monitored and may be treated with growth factors, and 
any signs of infection will be treated with appropriate medication (Section 5.1.6). 
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 preexisting infections and past hepatitis are excluded 
from the study to avoid reactivation.  
 
Incidences of prolonged neutropenia are of concern and will be monitored carefully 
(Appendix 1 and Appendix 2). 
 
A list of excluded and cautionary mediations for patients randomized to Arm A is 
provided in view of the possible drugdrug interactions.  
 
1.3.3 
Benefit-Risk Assessment 
Study BO25323/CLL14 provided evidence that the combination of venetoclax and 
obinutuzumab is a very efficacious treatment regimen with an acceptable safety profile in 
the 1L CLL setting.  Safety profiles of both drugs seem to be compatible, especially in 
light of a chemotherapy-free setting.  The head-to-head design of the study, 
precautionary safety measures, and regular monitoring of safety by the Sponsor enabled 
early identification of safety signals in the study and minimized the risk to the patients 
enrolled.  In conclusion, it is considered that the benefit-risk ratio for this study is 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
27/Protocol CO41685, Version 5 
favorable and that a chemotherapy-free fixed treatment therapy would be a very 
important option for patients with CLL in the 1L FIT setting.  FIT is defined by a 
cumulative illness rating scale [CIRS] score  6 and a normal creatinine clearance of 
70 mL/min.   
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of VEN  G compared with fludarabine, 
cyclophosphamide, and rituximab (FCR), and bendamustine and rituximab (BR) in FIT 
patients with previously untreated CLL without del(17p) or TP53 mutations.  Specific 
objectives and corresponding endpoints for the study are outlined in this section. 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of VEN  G 
compared with FCR/BR on the basis of the following endpoint: 
 
MRD response rate, determined as the proportion of patients with MRD-negativity 
(defined as 1 CLL cell in 10,000 leukocytes), measured in peripheral blood (PB) 
using NGS at Month 15. 
 
2.1.2 
Exploratory Efficacy Objective 
The exploratory objectives of this study are as follows: 
 
To investigate the relationship between various baseline markers and clinical 
outcome parameters in both arms of the study 
Baseline markers will include, but are not limited to, CLL fluorescence in situ 
hybridization (FISH) (17p-, 11q-, 13p-, 12q), immunoglobulin heavy chain variable 
region (IgHV) mutation status, p53 mutation status, serum parameters, and other 
CLL disease markers. 
 
2.1.3 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of VEN  G 
compared with FCR/BR on the basis of the following endpoints: 
 
PFS, defined as the time from randomization to the first occurrence of disease 
progression, or death from any cause; disease progression assessed by the 
investigators using the International Workshop on CLL (iwCLL) criteria 
(Hallek et al. 2018) 
 
MRD response rate, in PB at the end of treatment response visit (812 weeks after 
the last dose of FCR/BR [~9 months] vs. 812 weeks after last dose of VEN  G 
[~15 months]) 
 
MRD response rate in BM at the end of treatment response visit (812 weeks after 
the last dose of FCR/BR [approximately 9 months from first dose] vs. 812 weeks 
after last dose of VEN  G [approximately 15 months from first dose])  

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
28/Protocol CO41685, Version 5 
 
ORR, which includes CR, complete remission with incomplete blood count recovery 
(CRi), and partial response (PR) at the Month 15 assessment  
 
CR rate, which includes CR and CRi at the Month 15 assessment 
 
MRD response rate in PB of patients with a CR/CRi at Month 15 
 
MRD response rate in the BM of patients with a CR/CRi at the end of treatment visit 
(812 weeks after the last dose of FCR/BR [~9 months] vs. 812 weeks after the 
last dose of VEN  G [~15 months]) 
 
Duration of objective response (DOR), defined as the time from the first response to 
the time of progressive disease (PD) or death from any cause, whichever comes 
first 
 
Best response achieved (CR, CRi, PR, stable disease [SD], or PD) up to and 
including the assessment at Month 15 
 
Event-free survival (EFS), defined as the time between the date of randomization 
and the date of disease progression/relapse, death, or start of a new anti-leukemic 
therapy 
 
OS, defined as the time from randomization to the date of death from any cause 
 
TLS risk reduction rate in Arm A, defined as the reduction in the proportion of 
participants who were TLS high-risk after 3 doses of obinutuzumab compared to the 
proportion of participants who were TLS high-risk at baseline 
 
Reduction in mandatory hospitalizations during venetoclax ramp-up in Arm A 
patients, defined as the actual number of protocol‑mandated hospitalizations for 
TLS monitoring during venetoclax ramp-up period after 3 doses of obinutuzumab 
compared to the number of protocol‑mandated hospitalizations for TLS monitoring 
during venetoclax ramp-up expected at baseline 
 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is to evaluate the safety of VEN  G compared with 
FCR/BR on the basis of the following endpoints: 
 
Nature, frequency, and severity of adverse events and serious adverse events  
 
Changes in vital signs, physical findings, and clinical laboratory test results during 
and following study treatment 
 
Premature withdrawals 
 
2.3 
BIOMARKER OBJECTIVE  
The exploratory biomarker objectives of this study are as follows: 
 
To evaluate the relationship between efficacy outcomes and potential biomarkers, 
including Bcl-2 expression, for patients treated with VEN  G compared with those 
treated with FCR/BR 
 
To evaluate potential biomarkers, including CLL driver mutations and genomic 
complexity that are prognostic and/or predictive of response and resistance to 
treatment with VEN  G or with FCR/BR 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
29/Protocol CO41685, Version 5 
 
To assess new technologies, such as the circulating tumor DNA (ctDNA) 
assessment, in measuring MRD and monitoring disease clonal evolution  
 
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 VEN  G compared with FCR/BR in patients with previously 
untreated CLL without del(17p) or TP53 mutation as measured by the M.D. 
Anderson Symptom Inventory (MDASI-CLL; see Appendix 5) 
 
To evaluate changes in physical functioning, role functioning, and global health 
status/quality of life (QoL) following treatment with the combination of VEN  G 
compared with FCR/BR in patients with previously untreated CLL without del(17p) 
or TP53 mutation as measured by the European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30; see 
Appendix 6) 
 
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 the combination of VEN  G 
compared with FCR/BR in patients with previously untreated CLL without del(17p) 
or TP53 mutation as measured by the EuroQol 5 Dimension questionnaire 
(EQ-5D-5L; see Appendix 7) 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open-label, international, multicenter, randomized, Phase III study to 
investigate the efficacy and safety of VEN  G compared with FCR/BR in FIT patients 
(FIT defined by a CIRS/score 6 [Appendix 8] and a normal creatinine clearance of 
70 mL/min [Appendix 9]) with previously untreated CLL without del(17p) or 
TP53 mutation requiring treatment.   
Approximately 165 patients will be recruited from approximately 40 centers globally and 
randomly assigned in a 1:1 ratio to receive either VEN  G (Arm A) or FCR/BR (Arm B).  
Randomization will be stratified according to the following factors: 
 
IGHV mutation:  yes or no 
 
Binet stage (3 levels):  A, B, or C 
 
Age:   65 or 65 years 
 
Patients randomized to Arm A (VEN  G) will receive 12 cycles of treatment, each with a 
precise duration of 28 days.  During the first cycle, obinutuzumab will be administered 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
30/Protocol CO41685, Version 5 
intravenously (IV) on Days 1 (and 2), 8, and 15 as well as on Day 1 of Cycles 26.  
Continuous daily administration, with a 5-week ramp-up period, of venetoclax starts on 
Cycle 1, Day 22.  Venetoclax will be administered until the end of Cycle 12.   
Because it is possible that de-bulking from obinutuzumab therapy before starting 
venetoclax dosing already significantly reduces the risk of TLS, TLS prophylactic 
measures will be re-assessed at the time of starting the first dose of venetoclax (see 
Section 5.1.7.1). 
Patients randomized to Arm B (FCR/BR 50:50) (see Figure 1) will receive 6 cycles of 
FCR consisting of a single cycle of a single infusion of rituximab on Day 1 and 
fludarabine and cyclophosphamide infusions on Days 13 of each 28-day cycle or 
bendamustine as infusions on Days 1 and 2 and a single cycle of rituximab on Day 1 of 
each 28-day cycle. 
All patients in Arm B can be considered for treatment with BR, whereas only patients 
 65 years of age will be eligible for FCR.  The choice between FCR or BR in Arm B will 
be at the investigator’s discretion.  
During this study, adverse events will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0) (Appendix 10). 
Figure 1 presents an overview of the study design.  The schedules of activities for Arm A 
and Arm B are provided in Appendix 1 and Appendix 2, respectively. 
Figure 1 Study Scheme 
 
BR  bendamustine and rituximab; C  Cycle; CIRS  cumulative illness rating scale; 
CLL  chronic lymphocytic leukemia; D  Day; FCRfludarabine, cyclophosphamide, and 
rituximab; FIT  defined by a cumulative illness rating scale [CIRS] score  6 and a normal 
creatinine clearance of  70 mL/min; IGHV  immunoglobulin heavy chain variable region; 
PD  progressive disease; PO  orally (by mouth); QD  once daily; TBD  to be determined. 
Note:  Each cycle will consist of 28 days. 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
31/Protocol CO41685, Version 5 
3.1.1 
Minimal Residual Disease Assessments 
The primary endpoint for assessing efficacy will be MRD response rate in PB at 
Month 15 in both arms (~3 months after the last dose of venetoclax in Arm A and 
approximately 9 months after the last cycle of FCR/BR in Arm B).  The primary MRD 
assessment will be conducted in approximately 165 patients enrolled in the study. 
All patients will be assessed for MRD response in PB samples using NGS and will also 
be assessed for MRD response in the BM sample using NGS.  For both, response is 
defined as achieving MRD negativity at a cutoff of 10-4 (1 CLL cell in 
10,000 leukocytes). 
3.1.2 
Disease Response Assessment 
Disease response assessments to determine ORR, response (CR/CRi and PR), SD, and 
PD will be completed according to iwCLL guidelines (Hallek et al. 2018).  
3.1.3 
Timing of Assessments 
3.1.3.1 
MRD Assessments  
All patients will be assessed for MRD in PB at the following timepoints in both arms: 
 
Screening (to be collected prior to randomization before first dose) 
 
Cycle 4, Day 1 interim MRD assessment 
 
End of combination treatment (EOCT) response visit (812 weeks after last dose of 
combination therapy; ~Month 9 in both arms) 
 
Every 3 months after EOCT until 36 months (e.g., 12, 15, 18, 21, 24, 27, 30, 33, and 
36 month visits), then every 6 months until the end of study 
 
A BM sample will be taken 812 weeks after the end of treatment in both arms 
(~15 months in Arm A and ~9 months in Arm B).  A schedule of MRD assessments is 
presented in Figure 2. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
32/Protocol CO41685, Version 5 
Figure 2 Schedule of Minimal Residual Disease Assessments 
 
BM  bone marrow; BR  bendamustine and rituximab; CR  complete response; CRi  complete 
remission with incomplete blood count recovery; FCR  fludarabine, cyclophosphamide, and 
rituximab; MRD  minimal residual disease; mthly  monthly; PB  peripheral blood; PR  partial 
response; pt  patient. 
a A BM aspirate must be taken within 8 weeks from patients who achieve a CR/PR for 
assessment of MRD and confirmation of molecular CR. 
b BM aspirate at completion of treatment assessment (a minimum of 812 weeks after last 
treatment) for patients with CR/CRi and PR).  
  
To minimize the risk of missing MRD sample collections, the Sponsor will inform the 
sites about the importance of MRD sample collection throughout the study.  
Furthermore, the Sponsor will check the collection status of MRD samples weekly.  The 
Sponsor will be notified by the contract research organization (CRO) managing the 
sample collection if a sample is missing, received in poor condition, or cancelled, or 
exceeding the time window for sample processing.  Acceptance of MRD by regulatory 
authorities as a marker of efficacy requires missing and unevaluable assessments of 
MRD to be kept to a minimum.  If a sample is missing or cannot be analyzed, the patient 
might be asked to return to the site for another collection in a timely fashion.  
3.1.3.2 
Tumor and Response Assessments 
All patients will have a baseline tumor assessment and will be assessed for response to 
treatment by the investigator using standard clinical and laboratory examinations and 
computed tomography (CT) scans according to iwCLL guidelines (Hallek et al. 2018) at 
the following timepoints: 
 
Clinical response assessment, only Day 1 of every cycle of combination therapy 
 
In Arm B (FCR/BR), a full response assessment, including CT scan in all patients 
and BM biopsy in responding patients (CR/PR), 12 weeks after the last dose of 
study treatment (no earlier than 8 weeks after the end of study treatment) 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
33/Protocol CO41685, Version 5 
All other follow-up tumor assessments will be clinical assessments conducted within 
 14 days for 3-month and within a month for 6-month assessments of the 
scheduled visits described in Appendix 1.  
 
In Arm A (VEN  G), a full response assessment, including CT assessment in all 
patients and BM biopsy in responding patients (CR/PR) at Month 15 (from cycle 1, 
day 1 [C1D1]), which corresponds to approximately 812 weeks after the last dose 
of drug received in patients that complete the full 12 cycles of venetoclax therapy. 
All other follow-up tumor assessments will be clinical assessments conducted within 
14 days for 3-month and within a month for 6-month assessments of the scheduled 
visits described in Appendix 1. 
 
At each follow-up visit, patients will be assessed for response/progression by physical 
examination and laboratory tests.  If at any time during follow-up when clinical or 
laboratory findings suggest that the response may have improved from SD to PR, or 
from PR to CR, a CT scan may be performed to confirm the response.  
Imaging is not routinely required to determine PD because objective evidence of PD is 
most often documented by measurement of elevated peripheral CLL cells.  However, 
when PD cannot be documented by increasing PB counts, imaging is required to 
document PD as detected by physical examination or suspected based on symptoms. 
Annual follow-up assessments may be conducted by telephone.  Patients who 
discontinue all components of study therapy, either prior to completion of planned 
therapy or prior to disease progression (e.g., for toxicity), will continue to be followed up 
for MRD levels, PD, and OS (regardless of whether they subsequently receive new 
anti-CLL therapy). 
3.1.4 
Summary of Study Procedures 
Written informed consent will be obtained before any study specific procedures are 
undertaken. 
3.1.4.1 
Screening/Baseline Tests  
All screening assessments documented in the schedule of assessments will be 
performed a maximum of 28 days prior to starting study treatment (Appendix 1 and 
Appendix 2) with the exception of a CT scan and optional bone marrow biopsy, which 
are allowed 8 weeks prior to randomization.  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 (e.g., patients with infections requiring IV treatment [Grade 3 or 4] within the 
last 8 weeks prior to enrollment) may be rescreened once their infections resolve (see 
Section 4.1.2).  For patients who fail screening based on creatinine clearance levels, a 
repeat blood test can be performed, or a urine test can be conducted within 24 hours of 
dosing for a more accurate assessment.  If a patient is not randomized within the 28-day 
screening window, the site has to screen fail and can re-screen the patient using an 
interactive voice/web-response system (IxRS).  The patient will get a new 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
34/Protocol CO41685, Version 5 
screening number and all prior assessments that fall outside of the 28-day window from 
randomization will need to be repeated.  This includes biomarker samples.  A patient can 
be re-screened up to 3 times. 
Randomization will be performed by IxRS.  Patients will be assigned to the two treatment 
arms via a 1:1 randomization procedure.  Patients will be stratified by Binet stage, IgHV, 
and age.  Screening tests will be used to assess the Binet stage allowing for stratification 
and completion of the IxRS screening call.  If a patient’s Binet stage progresses between 
screening and randomization, then the Binet stage at the screening timepoint should be 
used for stratification. 
3.1.4.2 
Treatment Period  
3.1.4.2.1 
Treatment Arm A:  Venetoclax and Obinutuzumab 
The doses of venetoclax and obinutuzumab to be administered at each study visit is 
presented in Table 1. 
Table 1 
Treatment Arm A:  VEN  G Doses per Study Visit 
Cycle, Day 
Dose 
Obinutuzumab a 
Cycle 1, Day 1 b 
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, e 
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  

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
35/Protocol CO41685, Version 5 
Table 1 
Treatment Arm A:  VEN  G Doses per Study Visit (cont.) 
TLS  tumor lysis syndrome; VEN  G  venetoclax  obinutuzumab. 
Note:  Cycles will comprise 28 days.  Treatment with obinutuzumab will continue for 6 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 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-mg and 
900-mg infusions of obinutuzumab, please consult Section 4.3.2.2 and the Obinutuzumab 
Investigator’s Brochure regarding drug stability. 
c All patients will be assessed at screening and categorized in a TLS-risk category.  Because of 
possible tumor de-bulking after obinutuzumab therapy, investigators will reassess TLS risk after 
obinutuzumab induction and prior to starting the venetoclax ramp-up (Days 1621) and may 
assign patients to a lower risk group (see Section 5.1.7.1 for more details).   
d 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. 
e Oral tablets. 
  
Guidance on patient management for TLS prophylaxis prior to and following venetoclax 
dosing is provided in Section 5.1.7.1. 
Because it is possible that de-bulking from obinutuzumab therapy before starting 
venetoclax dosing already significantly reduces the risk of TLS, TLS prophylactic 
measures will be re-assessed at the time of starting the first dose of venetoclax (see 
Section 5.1.7.1). 
3.1.4.2.2 
Treatment Arm B:  FCR/BR 
3.1.4.2.3 
Fludarabine, Cyclophosphamide, and Rituximab 
Only patients 65 years of age will be eligible for FCR due to the associated high risk of 
severe neutropenias and infections.  Patients will receive 6 cycles of fludarabine, 
cyclophosphamide, and rituximab each cycle with a duration of 28 days: 
 
Fludarabine IV will be given on Days 13 (Cycles 16) at a dosage of 25 mg/m2  
 
Cyclophosphamide IV will be given on Days 13 (Cycles 16) at a dosage of 
250 mg/m² 
 
Rituximab IV will be given before the administration of chemotherapy at a dosage of 
375 mg/m2 in the first cycle and at a dosage of 500 mg/m2 in Cycles 26 with 
premedication according to the clinical practice of the participating sites (Eichorst et 
al. 2016) 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
36/Protocol CO41685, Version 5 
Bendamustine and Rituximab 
All patients in Arm B, regardless of age, can be considered for treatment with BR.  
Patients will receive 6 cycles of bendamustine and rituximab, each cycle with a duration 
of 28 days: 
 
Bendamustine IV will be given on Days 1 and 2 (Cycles 16) at a dosage of 
90 mg/m2 
 
Rituximab IV will be given before the administration of chemotherapy at a dosage of 
375 mg/m2 in the first cycle and at a dosage of 500 mg/m2 in Cycles 26 with 
premedication according to the clinical practice of the participating sites (Eichorst et 
al. 2016) 
 
3.1.4.3 
Monitoring of Disease Progression during Treatment Period 
All patients should be continually monitored for 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. 
Unless disease progression is confirmed, the patient is withdrawn due to toxicity, the 
patient withdraws consent, or the patient has died, patients should receive up to 6 cycles 
of study treatment of obinutuzumab and 12 cycles of venetoclax in Arm A or 6 cycles of 
FCR/BR in Arm B.  
3.1.4.4 
Post-Treatment Follow-Up Visits  
All patients will be followed until the end of the study (see Section 3.2).  Response will 
be followed at all visits by clinical/laboratory signs and symptoms until progression is 
identified.  A CT scan should be performed 812 weeks after the end of treatment in 
both arms in order to confirm CR and PR if lymphadenopathy was present at baseline.  
In those patients who achieve a CR or CRi, a BM 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 until the 
study is completed.  To capture PRO assessments, post-progression among those 
receiving subsequent therapies, PRO assessments will be conducted 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 1. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
3.2.1 
Duration of Participation 
The total duration of study participation for each individual is expected to be 
approximately 3.5 years after the last patient is enrolled, allowing for completion of the 
maximum duration of planned therapy (in the absence of disease progression) as well as 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
37/Protocol CO41685, Version 5 
at least 2.5 years of follow-up for all patients in order to reach the estimated number of 
events needed for the PFS final analysis. 
Patients are expected to be on study for a minimum of 3.5 years up to a maximum of 
6.2 years, subject to their date of enrollment in relation to the last patient enrolled. 
In addition, the Sponsor may decide to terminate the study at any time. 
3.2.2 
Long-Term Follow Up 
To be able to collect long-term follow-up data until a patient´s death after the end of the 
study, each patient will be informed of the importance of long-term follow-up data and 
asked for his/her consent to the long-term follow-up for OS according to national 
guidelines or in a separate non-interventional or extension study.   
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Dose and Schedule 
3.3.1.1 
Venetoclax 
The approved venetoclax monotherapy dose and regimen for the treatment of patients 
with R/R CLL is 400 mg once daily (QD).  This monotherapy dose was based on the 
experience from the Phase I dose-escalation Study M12-175, which examined 
single-agent venetoclax in patients with R/R 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 (Roberts et al. 2016). 
This experience has demonstrated that starting venetoclax at 20 mg for 1 week followed 
by a gradual ramp up of venetoclax over a 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 400-mg dose was further supported by the results of Study GO28667/MURANO, 
which compared venetoclax  rituximab (VenR) with BR in patients with R/R CLL 
(Seymour et al. 2018). 
The 400-mg QD regimen is also being used in Study BO25323, which is an ongoing, 
open-label, multi-center, international, randomized, Phase III study investigating the 
efficacy and safety of VEN  G compared with GClb in patients with 1L CLL who have 
coexisting medical conditions.   
To date, no evidence of unexpected late toxicities has emerged from continued 
treatment with venetoclax beyond 6 months. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
38/Protocol CO41685, Version 5 
3.3.1.2 
Obinutuzumab 
The recommended dose of obinutuzumab for front-line treatment will be used in this 
study: 
 
Cycle 1:  1000 mg Day 1 (or split dose Day 1 and Day 2), 8, and 15 
(see Section 4.3.2) 
 
Cycles 26:  1000 mg on Day 1 
 
Treatment will be on a 28-day cycle for a total of 6 cycles. 
3.3.1.3 
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. 
As obinutuzumab and venetoclax exhibit different mechanisms of action, there is strong 
scientific rationale to support treatment with a combination of both drugs.  The addition 
of venetoclax to obinutuzumab treatment results in a greatly enhanced anti-cancer 
activity compared with either agent alone, based on in vitro and in vivo results 
(Venetoclax Investigator’s Brochure).  It was, therefore, anticipated that VEN  G would 
show more anti-CLL activity than when each drug is administered alone, resulting in a 
greater, more durable and deeper effect in CLL-disease remission for patients with 1L 
CLL.  In addition, the safety profiles of both drugs seem to be compatible, especially in 
light of a fixed treatment-duration and chemotherapy-free setting.  Thus, VEN  G was 
considered to have the potential to be an attractive combination for patients with 1L CLL. 
3.3.2 
Rationale for Patient Population 
More than 50% of patients with CLL are asymptomatic at diagnosis and require no 
treatment.  Treatment is initiated when a patient’s disease becomes symptomatic or 
progressive as defined by the iwCLL updated guidelines for diagnosis and treatment of 
CLL (Hallek et al. 2018).  Allogeneic stem cell transplant is still the only treatment option 
for CLL patients that is potentially curative; however, the procedure is only appropriate 
for a small number of younger patients and is associated with high morbidity and 
mortality (Gribben 2005).  
The clinical course of CLL is highly variable and can be predicted by clinical staging 
(Rai et al. 1975; Binet et al. 1981) as well as genetic (Dohner et al. 2000), serum, and 
other markers (Smith et al. 2006).  TP53 mutation/deletion is so far the strongest 
prognostic factor predicting non-response to chemotherapy (Zenz et al. 2008).  Patients 
harboring TP53 mutation/deletion should be treated with chemotherapy-free regimens.  

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
39/Protocol CO41685, Version 5 
The treatment landscape for 1L CLL is evolving.  Deep remissions and clinically 
significant PFS can be achieved in patients without del17p or TP53 mutation with FCR 
(Hallek et al. 2010).  However, due to the high risk of severe neutropenias and infections 
with FCR, BR must also be considered for these patients.  Novel agents, such as 
ibrutinib (a Bruton's tyrosine kinase inhibitor), have resulted in improvements in 
long-term clinical outcomes (Barr et al. 2018; Farooqui et al. 2015, Shanafelt et al. 
2019).  However, the majority of patients remain uncured, only achieve a PR, and do not 
achieve MRD negativity requiring treatment for unlimited time (i.e., until disease 
progression or unacceptable side effects) in order to control the disease, leading to 
potential increase in toxicities.  Therefore, the aim of therapy is to control disease, 
improve symptoms, prolong survival, and maintain QoL while minimizing toxicity with 
regimens that are well tolerated and acceptable to patients. 
3.3.3 
Rationale for Control Group 
For physically fit patients, the combination of FCR is currently considered the standard 
treatment, as a median PFS of 57 months and an OS of 85% 3 years after start of 
treatment with FCR was achieved in the CLL8 trial (Hallek et al. 2010).  However, 90.8% 
of all patients treated with FCR experienced at least one Grade 34 toxicity:  90.0% 
hematological toxicities, 81.7% neutropenias, and 39% infections; the treatment-related 
mortality with FCR was 3.9%.  Experience with bendamustine, an alkylating agent, used 
in routine practice, and results from Phase II trials evaluating the combination of 
bendamustine and rituximab (BR) (Fisher et al. 2011; Fisher et al. 2012) were promising, 
with a lower incidence of CTCAE Grade 34 neutropenias and infections (10.3% and 
6.8% of patients receiving BR as 1L treatment).  The CLL10-trial, therefore, 
prospectively evaluated if the BR regimen was indeed equally effective and less toxic 
compared to the current standard treatment FCR for the 1L treatment of a total of 
564 physically fit patients (Eichhorst et al. 2016).  The final analysis demonstrated a 
higher efficacy of the FCR compared to the BR regimen with regard to CR rate, MRD 
negativity, and PFS, and therefore, FCR remains the standard of care in the 1L 
treatment of physically fit patients (Eichhorst et al. 2016).  However, as FCR is 
associated with a higher risk for severe neutropenias and infections, BR must be kept as 
standard front-line therapy in FIT patients with a high risk of infections (Eichhorst et al. 
2016). 
3.3.4 
Rationale for MRD as the Primary Endpoint 
3.3.4.1 
MRD Negativity Leads to Improved Clinical Outcomes 
For CLL disease, MRD assessment has been increasingly used in clinical studies since 
the development of the iwCLL 2008 guidelines and has been established as an 
independent prognostic factor that correlates with clinical outcomes in both the front-line 
setting and for patients with R/R disease (Böttcher et al. 2012; Kwok et al. 2016).  
Furthermore, MRD has been recognized as an intermediate endpoint for licensure in 
CLL studies by the European Medicines Agency (EMA) (EMA/CHMP/703715/2012 
Rev. 2).  Prospective clinical trials have provided substantial evidence that therapies that 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
40/Protocol CO41685, Version 5 
are able to eradicate MRD usually result in an improved clinical outcome 
(Hallek et al. 2018).  Patients achieving MRD-negative status in PB or BM had a better 
PFS and/or OS outcome irrespective of the treatment they received compared with 
those who could not achieve MRD negativity (chemo-immunotherapy regimens 
[Böttcher et al. 2012; Goede et al. 2014; Santacruz et al. 2014; Eichhorst et al. 2016; 
Kwok et al. 2016]; MAbs [Moreton et al. 2005]; and targeted therapies with VenR [Kater 
et al. 2018]).  The positive association between MRD negativity and PFS in patients with 
previously untreated CLL is further supported by a meta-regression model 
demonstrating a statistically significant relationship between treatment effect on PB MRD 
and treatment effect on PFS at the end-of-induction treatment with 
chemo-immunotherapy in patients with previously untreated CLL (Dimier et al. 2018).  In 
addition, MRD negativity seems to be a stronger predictor of PFS than the clinical 
response assessment.  In a recent meta-analysis in 1L CLL studies, no statistically 
significant difference in PFS was observed between MRD-negative CR and 
MRD-negative PR patients; however, PFS was significantly longer for MRD-negative PR 
than for MRD-positive CR (p  0.048) (Kovacs et al. 2016).  Thus, the recently revised 
iwCLL guidelines highlight the increased value of MRD as an endpoint 
(Hallek et al. 2018). 
3.3.4.2 
High and Promising Rates of MRD Negativity Achieved by 
Venetoclax 
Survival of CLL cells is highly dependent on Bcl-2; therefore, targeting CLL cells with a 
highly potent and selective inhibitor (e.g., venetoclax) can lead to deeper response.  
Studies in venetoclax monotherapy and VenR demonstrated that clinical response was 
more durable in patients who achieved MRD-negative status.  As of 4 April 2017, results 
from Study M13–982, an ongoing, Phase II, open-label study investigating the efficacy of 
venetoclax in patients with R/R CLL with del(17p), the Kaplan-Meier estimate for PFS at 
18 months was 78% (95% CI: 54%, 91%) for the 48 patients achieving PB MRD 
negativity ( 10–4 by multiple-color flow) compared with 51% (95% CI: 32%, 68%) for the 
53 non-MRD-negative patients (Stilgenbauer et al. 2018).  Moreover, as of 
4 March 2016, after a median follow-up of 28 months, results from Study M13-365, an 
ongoing, Phase 1b study evaluating the safety and tolerability of VenR in patients with 
relapsed CLL or SLL showed only 1 of 22 patients (4.5%) who achieved BM MRD 
negativity ( 104 by multi-color flow) by Month 7 had disease progression, whereas 
disease progression was observed in 5 of 15 patients (33.3%) who remained MRD 
positive at this time (Seymour et al. 2017).  Furthermore, with a median follow-up of 
36 months (as of 8 May 2018) in Study GO28667/MURANO, an ongoing, randomized, 
Phase III study comparing a fixed-duration chemotherapy-free regimen of VenR with BR 
in patients with R/R CLL, landmark analysis showed a similar association between PB 
MRD-negativity status at the EOCT and longer PFS in the chemo-free VenR arm 
(HR  0.38 [95% CI: 0.200.72]) and in the control chemoimmunotherapy BR arm 
(HR  0.27 [95% CI: 0.140.52]).  In addition, patients in the VenR arm who achieved an 
investigator-assessed PR and MRD negativity had a PFS outcome similar with that of 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
41/Protocol CO41685, Version 5 
patients who achieved CR with MRD negativity (HR  0.71 [95% CI: 0.242.14]) 
(Kater et al. 2018). 
3.3.4.3 
Venetoclax in Combination with Obinutuzumab Show 
Compelling PFS and MRD Data in 1L CLL 
On 15 May 2019, the FDA approved venetoclax in combination with obinutuzumab in 
previously untreated patients with CLL or SLL based on pivotal Study BO25323/CLL14 
(see Section 1.3.1 for study details).  This study demonstrates unprecedented MRD 
rates representing a depth of anti-CLL activity that differentiates treatment with VEN  G, 
and also provides compelling PFS data in the 1L CLL setting. 
Based on the results of a protocol-specified interim analysis (as of 17 August 2018 
CCOD), the IDMC recommended that Study BO25323/CLL14 had met its primary 
endpoint of investigator-assessed PFS, with a significant and clinically meaningful 
improvement in patients in the VEN  G arm (investigator-assessed PFS:  stratified 
HR  0.35 [95% CI: 0.230.53], IRC-assessed PFS:  stratified HR  0.33 [95% CI: 0.22, 
0.51], p 0.0001) versus patients in the GClb arm.   
In Study BO25323/CLL14, PB and BM MRD responses were assessed using real-time 
quantitative ASO-PCR centrally for all patients at the University of Kiel; the laboratory 
participated in the analytical validation of ASO-PCR.  
PB samples were taken at baseline; at Cycle 4, Day 1 (each cycle  28 days); Cycle 9, 
Day 1 (3 months after the last dose of obinutuzumab [EOCT assessment]), 3 months 
after treatment completion/early termination (end-of-treatment [EOT] assessment), at 
3-month intervals until 24 months after treatment completion, and then at 6-month 
intervals thereafter.  BM aspirate samples for MRD assessment were taken from 
responding patients at 2 landmark timepoints:  Cycle 9, Day 1 (3 months after the last 
dose of obinutuzumab [EOCT assessment]) and 3 months after treatment 
completion/early termination (EOT assessment).  MRD was considered negative if the 
result was 1 CLL cell in 10,000 leukocytes.  All MRD analyses were conducted using 
the intent-to-treat (ITT) population. 
The majority of patients treated with VEN  G achieved PB MRD negativity at the EOCT 
and EOT assessments and continued to maintain MRD-negative status after completion 
of the 1-year fixed duration therapy through follow-up at the time of this CCOD. 
At the EOT assessment (3 months after treatment completion/early termination), MRD 
negativity in PB was observed in 163 patients (75.7%) in the VEN  G arm compared 
with 76 patients (35.2%) in the GClb arm.  The difference between treatment arms 
(40.28%; 95% CI: 31.45, 49.10) was statistically significant in favor of the VEN  G arm 
(p 0.0001).  The rate of MRD test positivity was low in VEN  G at 11.1%.  Of note, the 
missing rates were comparable between the 2 arms:  10.2% in the GClb arm and 8.8% 
in the VEN  G arm. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
42/Protocol CO41685, Version 5 
At the EOCT assessment (Cycle 9, Day 1; 3 months after the last dose of 
obinutuzumab), MRD-negativity in PB was observed in 154 patients (71.3%) in the 
VEN  G arm compared with 83 patients (38.4%) in the GClb arm.  The difference 
between treatment arms (32.87%; 95% CI: 23.76, 41.98) was statistically significant in 
favor of the VEN  G arm (p 0.0001).  The rate of MRD test positivity was lower in 
VEN  G at only 7.9% versus 40.3% in GClb. 
At the EOT assessment (3 months after treatment completion/early termination), 
MRD-negativity in BM in the ITT population was achieved in 123 patients (56.9%) in the 
VEN  G arm compared with the GClb arm with 37 patients (17.1%).  The difference in 
MRD-negative rates was 39.81% (95% CI: 31.27, 48.36) and was statistically higher in 
the VEN  G arm than in the GClb arm (p 0.0001).  The rate of MRD test positivity was 
low in VEN  G at 12.5%.  Of note, the missing rates were again generally comparable 
between the 2 arms. 
At the EOT assessment, patients with CR treated with VEN  G achieved higher 
MRD-negativity rates in both PB and BM than those treated with GClb:  in PB, 87% 
(87/100) patients versus 62% patients (29/47), respectively, and in BM, 69% patients 
(69/100) versus 45% patients (21/47), respectively. 
The high MRD-negative rate in PB observed in the VEN  G arm was maintained through 
follow-up and up to 1 year after completion of treatment (58.3% at follow-up Month 12 
visit, the last visit for which complete data were available prior to the CCOD).  
At follow-up Month 12, the PB MRD-negativity rate had decreased to only 9.3% in the 
GClb arm.  At the time of the CCOD, all patients had been off treatment for at least 
12 months. 
At the EOT assessment, high concordance between PB and BM MRD-negativity status 
in paired samples was observed in the VEN  G arm, 93.5% (of 138 PB MRD-negative 
patients, 129 were also MRD negative in BM), suggesting VEN  G is very effective in 
clearing disease in both PB and BM compartments compared with GClb.  Moreover, 
landmark analysis based on EOT assessment PB or BM MRD status by ASO-PCR 
showed that the majority of patients in the VEN  G arm who achieved MRD negativity 
had a longer duration of PFS compared with a minority of patients who did not 
(PB:  HR  0.12 [0.05, 0.30], p-value 0.0001; BM:  HR  0.12 [0.04, 0.39], 
p-value  0.0004), confirming the association between MRD negativity with PFS similar 
to mentioned literature above.  Furthermore, similar to Study GO28667/MURANO, 
landmark analyses showed that in both arms of the BO25323/CLL14 study, patients who 
achieved a PR with PB MRD-negativity had a PFS outcome similar with that of patients 
who achieved CR with PB MRD-negativity.  The same observations were noted for BM 
MRD status and PFS.  Collectively, the high PB and BM MRD status concordance, the 
similarity of PFS correlation between the PB MRD negativity and the BM MRD 
negativity, and similar PFS outcome of PB MRD negative patients regardless of clinical 
outcome highlight the potential of PB MRD negativity as a surrogate for BM MRD 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
43/Protocol CO41685, Version 5 
negativity.  This provides evidence that the less invasive PB MRD assessment at EOT 
alone is able to appropriately predict PFS outcome in 1L patients with CLL treated with 
VEN  G.   
Overall, Study BO25323/CLL14 showed that a substantially large portion of the patients 
were able to achieve MRD-negativity status with VEN  G regimen and that was 
associated with prolonged PFS benefit.  This association between high MRD levels at 
the end of venetoclax treatment and prolonged PFS benefit is further supported by the 
results observed in all 1L CLL patients and in the subset of FIT patients treated in the 
GP28331 Phase 1b study (Flinn et al. 2019).  As such, similar to what have been 
reported with chemo-immunotherapies in the 1L CLL setting, the totality of evidence 
show that MRD response at the end of treatment is associated with favorable outcomes, 
such as PFS and OS.  The Sponsor anticipates similar or better MRD response and 
longer PFS could be achieved in a Phase III study with a 1L FIT CLL patient population 
treated with a VEN  G regimen.  MRD response at the end of venetoclax treatment as a 
primary endpoint in a Phase III study can ensure timely patient access to more 
efficacious therapies.  Therefore, the Sponsor believes that the use of MRD response 
rate in PB as the primary endpoint in the proposed Phase III study is adequate to 
establish the efficacy of venetoclax in combination with obinutuzumab as a treatment for 
FIT patients with previously untreated CLL. 
3.3.5 
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, is required.  Measurement of relevant RNAs and proteins (including those in the 
Bcl-2 family) in CLL cells will be examined pre-treatment for correlation with outcome. 
Additionally, several prognostic markers have been described that can be used as 
stratification factors for CLL therapies, including del(11q), del(13q14), and trisomy 12, 
IGHV, serum parameters (thymidine kinase, β2 microglobulin) as well as complex 
karyotype or genetic complexity.  There is increasing evidence from prospective clinical 
trials indicating that the 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). 
Recurrent somatic mutations, (i.e., in genes such as NOTCH1, SF3B1, TP53), which 
have recently been identified in CLL in small subsets of patients (~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 CD19-enriched 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
44/Protocol CO41685, Version 5 
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 Bcl-2. 
Biomarkers described here may have both predictive and prognostic value; both arms of 
study will be evaluated and their potential association with disease progression will also 
be explored.  These studies may help identify responsive patient populations and to 
develop better therapies for patients with CLL.  The analyses described in this section 
are exploratory and will be done retrospectively.  
Recently new technological approach, such as ctDNA measurement in plasma, allows 
assessing MRD potentially representing multiple disease compartments (i.e., blood, BM, 
and lymph nodes).  This type of approach may provide a more comprehensive view of a 
patient’s overall molecular response to treatment and may offer additional information on 
disease monitoring and clonal evolution.  Therefore, the exploratory analysis of plasma 
ctDNA measurement will be conducted at relevant timepoints in concordance with MRD 
assessments by NGS. 
Biomarkers described here may have both predictive and prognostic value; both arms of 
study will be evaluated and their potential association with achieving MRD negativity and 
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 conducted retrospectively.   
3.3.6 
Rationale for Chronic Lymphocytic Leukemia Diagnostic 
Laboratory Assessments 
3.3.6.1 
Lymphocyte Count 
The clinical diagnosis of CLL requires an absolute lymphocytosis with a lower threshold 
of at least 5000 mature-appearing lymphocytes/L in the PB.  Lymphocyte counts may 
fluctuate from time of diagnosis to the point at which treatment is required. 
3.3.6.2 
Lymphocyte Immunophenotyping 
Patients must have documented CD20-positive CLL according to the iwCLL criteria 
(Hallek et al. 2018) and the Matutes Scoring system (Matutes et al. 1994; see 
Appendix 11).  CLL cells co-express the T-cell antigen CD5 and B-cell antigen (CD19, 
CD20, and CD23).  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  or .  Variations of the intensity of 
expression of these markers may exist and do not exclude entry in the study. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
45/Protocol CO41685, Version 5 
3.3.7 
Rationale for Not Assessing Pharmacokinetics in 
Study CO41685 
Collection of pharmacokinetic (PK) samples for venetoclax and obinutuzumab in 
Study CO41685 (CRISTALLO) is not planned.  Both the patient population and the 
proposed treatment combination (VEN  G) have been previously evaluated in 
Studies BO25323/CLL14 (N  142 in VEN  G arm, 1L FIT) and GP28331 (N  32 1L; 
N  22 1L FIT, N  45 R/R).  For each of these studies, venetoclax and obinutuzumab 
exposures were consistent with those reported in prior studies and confirmed that there 
were no significant drug-drug interactions (DDI) between venetoclax and obinutuzumab.  
Therefore, no new insights on the PK profile and/or DDI potential of VEN  G is 
anticipated upon further PK evaluation in Study CO41685 (CRISTALLO).   
Venetoclax is primarily metabolized by CYP3A4.  Monoclonal antibodies do not interact 
directly with CYP but may interact with CYP through cytokine modulation.  Treatment 
with obinutuzumab results in transient increases in cytokine levels at time of first infusion 
only.  Therefore, significant effects on CYP proteins and subsequent DDI are considered 
highly unlikely.  Consequently, the risk for obinutuzumab to significantly alter the 
pharmacokinetics of venetoclax is expected to be low. 
Tumor burden affects clearance of obinutuzumab, especially at the beginning of 
treatment.  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, impact the exposure of 
obinutuzumab.   
The drug interaction potential between venetoclax and obinutuzumab was previously 
investigated in the pivotal Study BO25323/CLL14 and the Phase 1b Study GP28331.  
3.3.8 
Rationale for Patient-Reported Outcome (PRO) Assessments  
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 QoL.  There is strong reason to believe that if the anticipated clinical 
benefit is observed between the combination of VEN  G 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 sweats).  PROs will be used to 
comprehensively capture patient reports of disease symptom and functional impact 
changes as well as evaluate treatment-related side effects.  Using PROs to quantify the 
importance of MRD from the patient perspective can further support the primary 
endpoint, while understanding time to disease progression in terms of how patients 
perceive disease symptoms and functional impacts can support assessment of PFS. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
46/Protocol CO41685, Version 5 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
A target of 165 patients will be randomized at a 1:1 ratio to receive either VEN  G 
(Arm A) or FCR/BR (Arm B).   
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Ability to comply with the study protocol, in the investigator's judgment 
 
Aged 18 years or older 
 
Have previously untreated documented CLL according to the iwCLL criteria 
 
CLL requiring treatment according to the iwCLL criteria  
 
CIRS score 6 and creatinine clearance (CrCl) 70 mL/min as calculated by the 
Standard Cockcroft and Gault Formula 
 
Hematology values within the following limits, unless cytopenia is caused by the 
underlying disease (i.e., no evidence of additional BM dysfunction; 
e.g., myelodysplastic syndrome, hypoplastic BM): 
– 
Absolute neutrophil count 1.0  109/L, unless there is BM involvement 
– 
Platelet count 75  109/L and more than 7 days since last transfusion, or 
30  109/L if there is BM involvement 
 
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 
 
Life expectancy 6 months 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception and agreement to refrain from 
donating eggs, as defined below: 
Women must remain abstinent or use contraceptive methods with 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 for 
patients in Arm A, and for at least 6 months after the last dose of bendamustine 
or fludarabine or 12 months after the last dose of rituximab or 
cyclophosphamide for patients in Arm B, whichever is later.  Women must 
refrain from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
47/Protocol CO41685, Version 5 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and 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.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below: 
With a female partner of childbearing potential who is not pregnant, men who 
are not surgically sterile must 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 for patients in 
Arm A, and for at least 6 months after the last dose of bendamustine, 
fludarabine, or cyclophosphamide or 12 months after the last dose of rituximab 
for patients in Arm B, whichever is later.  Men must refrain from donating sperm 
during this same period. 
With a pregnant female partner, men must remain abstinent or use a condom 
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 for patients in 
Arm A, and for at least 6 months after the last dose of bendamustine, 
fludarabine, or cyclophosphamide or 12 months after the last dose of rituximab 
for patients in Arm B, whichever is later, to avoid exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
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 
prolymphocytic leukemia) 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
48/Protocol CO41685, Version 5 
 
Patients with SLL only (a diagnosis of CLL/SLL is permitted) 
 
Known central nervous system involvement 
 
Patients with a history of confirmed progressive multifocal leukoencephalopathy 
(PML) 
 
Detected del(17p) or TP53 mutation (valid test within 6 months from screening is 
required for randomization) 
 
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) 
 
Patients with uncontrolled autoimmune hemolytic anemia or immune 
thrombocytopenia 
 
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 
8 weeks prior to enrollment 
 
Evidence of other clinically significant uncontrolled condition(s) including but not 
limited to active or uncontrolled systemic infection (e.g., viral, bacterial, or fungal) 
 
History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies or known sensitivity or allergy to murine products 
 
Hypersensitivity to fludarabine, bendamustine, cyclophosphamide, rituximab, 
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 
 
Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
hepatitis B surface antigen [HBsAg] serology) 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
49/Protocol CO41685, Version 5 
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 polymerase chain 
reaction (PCR) is negative for HCV RNA. 
 
Patients with known infection with 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 
 
Received any of the following agents within 28 days prior to the first dose of study 
treatment: 
– 
Immunotherapy 
– 
Radiotherapy 
– 
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) 
 
Patients who have received the following agents: 
– 
Strong and moderate CYP3A inhibitors within 7 days prior to the initiation of 
study treatment 
– 
Strong and moderate CYP3A inducers within 7 days prior to the initiation of 
study treatment 
– 
Steroid therapy for anti-neoplastic intent with the exception of inhaled steroids 
for asthma, topical steroids, or replacement/stress corticosteroids 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 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
50/Protocol CO41685, Version 5 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Treatment Assignment 
This is a randomized, open-label study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from an IxRS. 
Patients will be randomly assigned to one of two treatment arms:  Arm A (VEN  G) or 
Arm B (FCR/BR).  Randomization will occur in a 1:1 ratio using a block-stratified 
randomization method to ensure a balanced assignment to each treatment arm.  
Randomization will be stratified according to the following criteria: 
 
IGHV mutation:  yes or no 
 
Binet stage (3 levels):  A, B, or C 
 
Age:  65 or 65 
 
In Arm B, the investigator at each site will determine whether the FCR or BR regimen will 
be used for the individual patient, based on their local practice.  All patients in Arm B can 
be considered for treatment with BR, whereas only patients 65 years of age will be 
eligible for FCR. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are venetoclax, 
obinutuzumab, fludarabine, cyclophosphamide, bendamustine, and rituximab.  
Appendix 18 identifies all IMPs and auxiliary medicinal products for this study.  
Where regulations require, all IMPs will be provided by the Sponsor.  For the 
U.S. region, sites will locally source (to be fully reimbursed by the sponsor) the following 
IMPs:  fludarabine, cyclophosphamide, bendamustine, and rituximab.  Generic 
formulation, with the exception of IMPs provided by the Sponsor, are permitted for locally 
sourced IMPs. 
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 Venetoclax 
Investigator’s Brochure. 
4.3.1.2 
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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
51/Protocol CO41685, Version 5 
2.5% overfill.  For information on the formulation, packaging, and handling of 
obinutuzumab, see the local prescribing information. 
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 
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. 
4.3.1.3 
Fludarabine 
For information on the formulation and handling of fludarabine, see the local prescribing 
information for fludarabine.  For sites in the United States, fludarabine will be packaged 
as indicated in the local prescribing information.  For sites not in the United States, 
fludarabine will be repackaged and relabeled by the Sponsor before distribution to sites. 
4.3.1.4 
Cyclophosphamide 
For information on the formulation and handling of cyclophosphamide, see the local 
prescribing information for cyclophosphamide.  For sites in the United States, 
cyclophosphamide will be packaged as indicated in the local prescribing information.  
For sites not in the United States, cyclophosphamide will be repackaged and relabeled 
by the Sponsor before distribution to sites. 
4.3.1.5 
Rituximab 
Rituximab is manufactured by Genentech, Inc., as the licensed product Rituxan in the 
United States and Canada.  For the rest of the world, rituximab is manufactured by 
F. HoffmannLa Roche Ltd. (Roche) as the licensed product MabThera.  It is a sterile, 
clear, colorless, preservative-free liquid concentrate for IV administration.  Rituximab is 
supplied at a concentration of 500-mg (50-mL) single-use vials.  The product is 
formulated for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium 
citrate dihydrate, and 0.7 mg/mL polysorbate 80, after reconstitution with sterile water for 
injection.  The pH is adjusted to 6.5.  Vials are for single use.  Each vial and carton will 
be labeled (i.e., either single-panel or booklet) per individual country requirements.  The 
label must remain affixed to the supplies. 
Rituximab vials must be stored at 2C8C (36F46F).  Rituximab vials should be 
stored in the outer carton in order to protect them from light.  Rituximab solution for 
infusion may be stored at 2C8C (36F46F) for 24 hours and has been shown to be 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
52/Protocol CO41685, Version 5 
stable for an additional 12 hours at room temperature.  However, since rituximab does 
not contain a preservative, diluted solutions should be stored refrigerated (2C8C).  
No incompatibilities between rituximab and polyvinylchloride or polyethylene bags have 
been observed. 
For further details, see the local prescribing information for Rituxan/MabThera. 
4.3.1.6 
Bendamustine 
Bendamustine HCl is marketed by Cephalon as the licensed product Treanda for the 
United States and is marketed in Europe by Mundipharma International Corporation Ltd, 
under the name Levact.  In Australia it is marketed by Jansenn as the licensed product 
Ribomustin.  Bendamustine will be supplied in individual cartons containing single-use 
vials of 100 mg bendamustine HCl as lyophilized powder.  Each vial and carton will be 
labeled (i.e., either single-panel or booklet) per individual country requirements.  The 
label must remain affixed to the supplies.   
Bendamustine should be stored at 15C25C (59F77F).  It is to be retained in the 
original carton until time of use to protect from light.  Bendamustine should be prepared 
for administration as close as possible to the time of administration.  Once diluted with 
sodium chloride or dextrose/sodium chloride, the final admixture is stable for 24 hours if 
Treanda is used and for 2 days if Levact is used and when stored refrigerated 
(2C8C or 36F47F) or for 3 hours when stored at room temperature (15C30C or 
59F86F) and room light.  Administration of bendamustine must be completed within 
this period. 
For further details, see the local prescribing information for Treanda/Levact. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
4.3.2.1 
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 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.  Venetoclax must be stored according to 
labeled storage conditions.  There is to be no break between cycles. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
53/Protocol CO41685, Version 5 
4.3.2.1.1 
Venetoclax Ramp-Up Period 
To mitigate potential serious complications of TLS, patients will require close clinical and 
laboratory monitoring during the venetoclax ramp-up period.  See Section 5.1.7.1 for 
details of the TLS prophylaxis and monitoring guidelines. 
All patients randomized to Arm A will start venetoclax treatment on Cycle 1, Day 22.  
They will start by receiving 20 mg of venetoclax daily for at least 7 days.  Patients who 
demonstrate evidence of electrolyte abnormalities suggestive of TLS during the 24 hours 
following the initial 20-mg dose will receive appropriate treatment to resolution prior to 
receiving their next daily dose of venetoclax.  See Appendix 12 for recommendations for 
initial management of electrolyte imbalances and prevention of TLS. 
Venetoclax dose increases will then occur weekly, starting with 50 mg/day for 1 week 
followed by 100 mg/day for 1 week, 200 mg/day for 1 week, and the final dose of 
400 mg/day for 1 week.  All patients should receive any intended dose for at least 7 days 
before increasing to the next higher dose.  The duration of the venetoclax ramp-up 
period will be 5 weeks as shown in Figure 3.  Patients will then continue taking 
venetoclax 400 mg daily as directed by the investigator. 
Figure 3 Venetoclax Dosing Scheme during the Ramp-Up Period 
 
D  day. 
  
Any dose modification of venetoclax should be noted on the venetoclax administration 
eCRF.  Cases of overdose, medication error, drug abuse, or drug misuse, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.  
Guidelines for venetoclax dosage modification and treatment interruption or 
discontinuation for patients who experience adverse events are provided in 
Section 5.1.6. 
4.3.2.2 
Obinutuzumab 
4.3.2.2.1 
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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
54/Protocol CO41685, Version 5 
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-mg and 900-mg infusions of 
obinutuzumab, see Section 4.3.2.2, Table 2, 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. 
For storage conditions of the infusion bags see Section 4.3.1.2. 
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 anti-hypertensive 
treatment should be considered for 12 hours prior to the obinutuzumab infusions, 
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 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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
55/Protocol CO41685, Version 5 
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.  
4.3.2.2.2 
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.  
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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
56/Protocol CO41685, Version 5 
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. 
4.3.2.2.3 
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 (nodal mass 10 cm) 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 12). 
 
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.  
 
4.3.2.2.4 
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 (Table 2).  If a hypersensitivity or IRR develops, the infusion should be 
temporarily interrupted or slowed down, and concomitant medication may be 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
57/Protocol CO41685, Version 5 
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). 

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
58/Protocol CO41685, Version 5 
Table 2 
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 4.3.4 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 100 mg without dose modification and local label permits, the 
Investigator may continue to administer the remaining 900 mg 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 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 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 tolerated, as defined above, instructions for the first 
infusion rate will be used. 
IRR  infusion-related reaction. 

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
59/Protocol CO41685, Version 5 
Any change in the infusion rate or interruption in the administration of obinutuzumab 
should be noted on the obinutuzumab administration eCRF.  Cases of overdose, 
medication error, drug abuse, or drug misuse, along with any associated adverse 
events, should be reported as described in Section 5.3.5.12. 
Guidelines for obinutuzumab treatment interruption or discontinuation for patients who 
experience adverse events are provided in Section 5.1.6. 
4.3.2.3 
Fludarabine, Cyclophosphamide plus Rituximab 
4.3.2.3.1 
Rituximab 
Rituximab will be administered as an IV infusion before the administration of FC.  
Rituximab will be administered to patients at 375 mg/m2 IV on Cycle 1, Day 1 followed by 
500 mg/m2 on Day 1 of Cycles 26 (total of 6 infusions of rituximab).   
The patient’s body surface area (BSA) calculated at screening should be used to 
calculate the dose of rituximab throughout the study unless the patient’s weight 
increases or decreases by 10% from screening (Appendix 13).  In obese patients, there 
is no cap on BSA, and actual body weight, not adjusted weight, is recommended.  
Nonetheless, empiric dose adjustment is permitted in obese patients (obesity defined as 
body mass index 30 as measured in kilograms divided meters squared). 
During the treatment period, rituximab must be administered to patients in a clinical 
(inpatient or outpatient) setting.  Rituxan should be administered only by a healthcare 
professional with appropriate medical support to manage severe infusion reactions that 
can be fatal if they occur. 
Rituximab should be administered as a slow IV infusion through a dedicated line.  
IV infusion pumps (such as the Braun Infusomat Space) should be used to control the 
infusion rate of rituximab.  Administration sets with polyvinyl chloride, polyurethane, or 
polyethylene as a product contact surface and IV bags with polyolefin, polypropylene, 
polyvinyl chloride, or polyethylene as a product contact surface are compatible and can 
be used.  Do not use an additional in-line filter because of potential adsorption.  See 
Table 3 for instructions regarding first and subsequent infusions of rituximab. 
After the end of each dose of rituximab, patients should be observed for 1 hour.  If no 
adverse events occur after 1 hour, the IV line may be removed, or the central venous 
catheter may be de-accessed. 
Rituximab should not be administered as an IV push or bolus.  IRRs may occur. 
Premedication consisting of acetaminophen, diphenhydramine (or other suitable 
antihistamine), and a single dose of hydrocortisone (up to 100 mg or an equivalent dose 
of methylprednisolone) may also be administered beginning with the first infusion.  
Premedication may attenuate IRRs.  Because transient hypotension may occur during 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
60/Protocol CO41685, Version 5 
rituximab infusion, consideration should be given to withholding antihypertensive 
medications for 12 hours prior to rituximab infusion. 
Table 3 
Administration of First and Subsequent Infusions of Rituximab 
First Infusion (Cycle 1, Day 1) 
Subsequent Infusions 
Begin infusion at an initial rate of 50 mg/hr. 
If no infusion-related or hypersensitivity 
reaction occurs, increase the infusion rate in 
50-mg/hr increments every 30 minutes, to a 
maximum of 400 mg/hr. 
If an infusion reaction develops, stop or slow 
the infusion.  Administer infusion-reaction 
medications and supportive care in accordance 
with institutional guidelines.  If the reaction 
resolves, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate being 
used at the time that the reaction occurred). 
If the patient experienced an infusion-related or 
hypersensitivity reaction during the prior 
infusion, begin infusion at an initial rate of 
50 mg/hr and follow instructions for the first 
infusion. 
If the patient tolerated the prior infusion well 
(defined as an absence of Grade 2 reactions 
during a final infusion rate of 100 mg/hr), 
begin the infusion at a rate of 100 mg/hr. 
If no infusion reaction occurs, increase the 
infusion rate in 100-mg/hr increments every 
30 minutes, to a maximum of 400 mg/hr. 
If an infusion reaction develops, stop or slow 
the infusion.  Administer infusion-reaction 
medications and supportive care in accordance 
with institutional guidelines.  If the reaction 
resolves, resume the infusion at a 50% 
reduction in rate (i.e., 50% of rate being used 
at the time that the reaction occurred). 
Note:  A fast infusion is not allowed. 
  
Any change in the infusion rate or interruption in the administration of rituximab should 
be noted on the rituximab administration eCRF.  Cases of accidental overdose, 
medication error, drug abuse, or drug misuse, along with any associated adverse 
events, should be reported as described in Section 5.3.5.12. 
Guidelines for rituximab treatment interruption or discontinuation for patients who 
experience adverse events are provided in Section 5.1.6. 
4.3.2.3.2 
Fludarabine 
Fludarabine will be administered in a dosage of 25 mg/m² over 1530 minutes IV on 
Days 1, 2, and 3 of each cycle.   
Any dose modification of fludarabine should be noted on the fludarabine administration 
eCRF.  
4.3.2.3.3 
Cyclophosphamide 
Cyclophosphamide will be administered in a dosage of 250 mg/m² over 1530 minutes IV 
on Days 1, 2, and 3 of each cycle. 
Fludarabine and cyclophosphamide can be administered immediately one after the 
other.  The dose of fludarabine and/or cyclophosphamide may be capped for patients 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
61/Protocol CO41685, Version 5 
with a BSA above a certain level (2.0 or higher) according to local practice and the 
investigator’s clinical judgement.  The dose of rituximab should not be capped. 
Any dose modification of cyclophosphamide should be noted on the cyclophosphamide 
administration eCRF.  
4.3.2.3.4 
Bendamustine  
Patients will receive bendamustine 90 mg/m2 administered IV on 2 consecutive days of 
each 28-day cycle for 6 cycles, in combination with rituximab administered intravenously 
on Day 1 of each 28-day cycle for 6 cycles (see Section 4.3.2.3.1 for details of rituximab 
dosage and administration). 
BSA will be calculated at screening and on Cycle 1, Day 1.  The BSA calculated at 
screening should be used to calculate the dose of bendamustine throughout the study 
unless the patient’s weight increases or decreases by 10% from screening.  In obese 
patients, there is no BSA cap and actual body weight, not adjusted weight, is 
recommended.  Nonetheless, empiric dose adjustment is permitted in obese patients 
(obesity defined as body mass index 30 kg/m2). 
Bendamustine will be administered over 30 to 60 minutes on Days 1 and 2 of each 
28-day cycle for a total of 6 cycles.  On days when rituximab and bendamustine are to 
be administered, rituximab will be administered before bendamustine.   
Premedication with anti-emetics may be administered as per institutional guidelines (see 
Section 4.4.1).  Granulocyte colony-stimulating factor (G-CSF) may be administered as 
primary prophylaxis in each cycle of therapy, per the American Society of Clinical 
Oncology (ASCO) guidelines or each site’s institutional standards. 
Any dose modification of bendamustine should be noted on the bendamustine 
administration eCRF.   
Guidelines for bendamustine dosage modification and treatment interruption or 
discontinuation for patients who experience adverse events are provided in 
Section 5.1.6.2.2. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (venetoclax, obinutuzumab, fludarabine, 
cyclophosphamide, rituximab, and bendamustine) will be provided by the Sponsor where 
required by local regulations.  The study site will acknowledge receipt of IMPs supplied 
by the Sponsor, using the IxRS, to 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 be returned to the Sponsor (if supplied by the Sponsor) 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
62/Protocol CO41685, Version 5 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied 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 
4.3.4.1 
Non-Investigational Medicinal Products for this Study 
The non-investigational medicinal products (NIMPs) for this study are rasburicase, 
acetaminophen, paracetamol, prednisolone, dexamethasone, methylprednisolone, 
diphenhydramine, allopurinol, and ondansetron.   
4.3.4.2 
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. 
4.3.5 
Continued Access to Venetoclax, Obinutuzumab, Fludarabine, 
Cyclophosphamide, Rituximab, and Bendamustine 
The Sponsor will offer continued access to Roche IMPs (venetoclax, obinutuzumab, 
fludarabine, cyclophosphamide, rituximab, and bendamustine) free of charge to eligible 
patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive Roche IMPs (venetoclax, obinutuzumab, fludarabine, 
cyclophosphamide, rituximab, and bendamustine) after completing the study if all of the 
following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
63/Protocol CO41685, Version 5 
A patient will not be eligible to receive Roche IMPs (venetoclax, obinutuzumab, 
fludarabine, cyclophosphamide, rituximab, and bendamustine) after completing the study 
if any of the following conditions are met: 
 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not 
otherwise create a financial hardship for the patient) 
 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for CLL 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
CLL 
 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
4.4.1 
Permitted Therapy 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 30 days 
prior to the screening period and until study drug completion or early discontinuation 
visit.  All such 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.  
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination any time 
prior to, during, or after the study should be recorded on the concomitant medications 
eCRF.  
Necessary supportive measures for optimal medical care will be given throughout 
the study according to institutional standards, including the use of growth factors 
(e.g., erythropoietin) if clinically indicated.  G-CSF may be administered as primary 
prophylaxis in each cycle of therapy, per the ASCO guidelines (Smith et al. 2006) or 
each site’s institutional standards. 
Anti-emetic therapy may be instituted for any patient if clinically indicated.  
Bendamustine has a moderate risk of emesis (Cheson et al. 2010).  It is recommended 
that bendamustine infusions be administered following premedication with a serotonin 
(5-HT3) antagonist (i.e., dolasetron, ondansetron, etc.) or per institutional practice. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
64/Protocol CO41685, Version 5 
4.4.1.1 
Premedication before Rituximab 
Premedication may attenuate IRRs.  The following premedication is required prior to 
rituximab therapy:  
 
Acetaminophen (6501000 mg) at least 30 minutes prior to the start of all infusions 
 
Diphenhydramine (2550 mg) approximately 30 minutes prior to the start of the first 
infusion and mandatory for all subsequent infusions unless previous antibody 
infusions did not result in an IRR greater than NCI CTCAE Grade 1 and there was 
no interruption to the infusion (Appendix 10).  (Another suitable antihistamine is also 
acceptable and must follow the preceding guidelines.) 
 
A single dose of hydrocortisone (up to 100 mg or an equivalent dose of 
methylprednisolone) may also be administered with rituximab if this is the usual practice 
at the site.  
Because transient hypotension may occur during rituximab infusion, consideration 
should be given to withholding antihypertensive medications for 12 hours prior to 
rituximab infusion. 
4.4.1.2 
Concomitant administration with SARS-CoV-2 Vaccine 
In all instances, the SARS-CoV-2 vaccines should be given in accordance with the 
approved/authorized vaccine label and official immunization guidance.  The 
SARS-CoV-2 vaccines (covering mRNA, inactivated virus, and replication deficient viral 
vector vaccines) are not live vaccines and are therefore permitted per protocol.  The 
decision to administer a SARS-CoV-2 vaccine should be made on a per patient basis 
according to an individual’s risk of COVID-19 disease, their general condition, as well as 
the severity and seriousness of the underlying disease/condition for which the patient is 
receiving study treatment together with the prevalence of local SAR-CoV-2 infection 
rates.  
Venetoclax 
Due to the immunosuppressive properties of venetoclax, patients who plan to receive 
any SARS-CoV-2 vaccine should do so prior to treatment initiation, unless a delay in 
administration of venetoclax is clinically unacceptable.  If administration of a 
SARS-CoV2 vaccine is indicated during venetoclax treatment, consider monitoring the 
complete blood count to time with recovery of cytopenias, specifically lymphopenia. 
Obinutuzumab 
Due to the immunosuppressive properties of obinutuzumab, patients who plan to receive 
any SARS-CoV-2 vaccines should do so prior to treatment initiation.  Currently, for 
SARS-CoV-2 vaccines that require two doses, it is recommended that patients should 
aim to complete vaccination (i.e., they should receive the second dose) at least 7 days 
before starting immunosuppressive therapy, in order to maximize vaccine efficacy. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
65/Protocol CO41685, Version 5 
Since it is possible that B-cell recovery could persist for 12–18 months following 
treatment with obinutuzumab, there is no strong rationale for withholding or delaying 
obinutuzumab therapy to allow immune recovery prior to vaccination. 
Rituximab 
Patients treated with MabThera/Rituxan may receive non-live vaccinations.  However, 
with non-live vaccines response rates may be reduced.  Patients who plan to receive 
any SARS-CoV-2 vaccines should do so prior to treatment initiation.  At this time there is 
no experience with use of MabThera IV/SC in patients receiving vaccines based on RNA 
and DNA technology platforms and those using live viral vectors.  Hence no 
recommendations concerning use of SARS-CoV-2 vaccines based on these 
technologies in patients receiving immunosuppressive therapy, including rituximab, can 
be made.  
Fludarabine, Cyclophosphamide or Bendamustine 
Roche is not the Marketing Authorisation Holder (MAH) for fludarabine, 
cyclophosphamide, or bendamustine.  Therefore, please assess the benefit/risk to the 
patient, follow the recommendation from the respective label and if necessary, consult 
with the respective MAH for fludarabine, cyclophosphamide, or bendamustine.  
4.4.2 
Prohibited and Cautionary 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 28 days following the patient’s last dose of study 
drug, or until initiation of another anti-cancer therapy, whichever occurs first.  All patients 
who discontinue study treatment for any reason should be followed until progression. 
Use of the following therapies is prohibited during the study and 28 days prior to first 
dose of study drug: 
 
Immunotherapy 
 
Radiotherapy 
 
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) 
Excluded and cautionary medications for patients randomized to Arm A are shown in 
Table 4, and venetoclax dose reductions for strong and moderate CYP3A inhibitors are 
listed in Table 5.  For lists of examples prohibited and cautionary medications, please 
see Appendix 3. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
66/Protocol CO41685, Version 5 
These above lists are not comprehensive, and the investigator should consult the 
applicable prescribing information for any concomitant medication when determining the 
drug-drug interaction potential.   
Table 4 
Excluded and Cautionary Medications for Patients Randomized 
to Arm A (Venetoclax  Obinutuzumab) 
Excluded 
Any live, attenuated vaccine including live, attenuated influenza vaccine (e.g., FluMist®): 
 
Prohibited during treatment and within 28 days following the last dose of venetoclax. 
Anti‑cancer 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. 
Excluded during the venetoclax ramp-up period and cautionary thereafter:  
Strong and moderate CYP3A inhibitors: 
 
Excluded 7 days prior to and 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 or refer to appropriate product label.  
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 7 days prior to and 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 (seek the guidance of the Medical Monitor; additional INR monitoring may also be 
required) 
 
Weak CYP3A inducers 
 
Weak CYP3A inhibitors 
 
P-gp substrates 
 
BCRP substrates 
 
OATP1B1/1B3 substrates 
 
P-gp inhibitors 
 
BCRP inhibitors 
 
OATP1B1/B3 inhibitors 
Note:  For examples of these medications see Appendix 5. 
  

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
67/Protocol CO41685, Version 5 
Table 5 
Venetoclax Dose Reductions for Strong and Moderate CYP3A 
Inhibitors 
Venetoclax Assigned Dose 
(mg) 
Venetoclax Reduced Dose (mg) 
Strong CYP3A Inhibitors 
Moderate CYP3A Inhibitors 
50 
10 
20 
100 
20 
50 
200 
50 
100 
300 
70 
150 
400 
100 
(70 for posaconazole in U.S. 
and countries with 
USPI-based approval 
200 
U.S.  United States; USPI  United States Prescribing Information. 
  
If clinically indicated, anti-herpes and anti-pneumocystis prophylaxis should be 
considered.  Although there is a potential for DDI, there are likely to be limited potential 
clinical effects; therefore, trimethoprim-sulfamethoxazole can be considered for 
pneumocystis prophylaxis, with close clinical monitoring. 
4.4.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended 14 days prior to, during the 
study, and for 28 days after the last dose of study treatment because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.   
4.4.3 
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, throughout venetoclax administration 
and for 28 days after last dose of study treatment.   
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 
 
4.4.4 
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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
68/Protocol CO41685, Version 5 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.   
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms 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 enrollment.  The investigator will maintain a detailed record of 
all patients screened to document eligibility or record reasons for screening failure, as 
applicable. 
4.5.2 
Procedures for Enrollment of Eligible Patients 
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. 
After initial written informed consent has been obtained, all screening procedures and 
assessments have been completed, and eligibility has been established for a patient, the 
study site will obtain the patient's identification number and treatment assignment from 
an IxRS. 
A Subject Enrollment and Identification Code List must be maintained by 
the investigator.  
4.5.3 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures and prior SARS-CoV-2 infection), 
reproductive status, smoking history, and use of alcohol and drugs of abuse, will be 
recorded at baseline.   

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
69/Protocol CO41685, Version 5 
Prior SARS-CoV-2 vaccination, regardless of when it was administered, shall be 
reported at baseline.  All other medications (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the 
patient within 7 days prior to initiation of study treatment will be recorded.  At the time of 
each follow-up physical examination, an interval medical history should be obtained and 
any changes in medications and allergies should be recorded.  Any concomitant 
medications that are related to adverse events that occur up to 28 days post-last 
treatment, or related to adverse events and serious adverse events that are required per 
protocol to be reported indefinitely (e.g., drug-related serious adverse events, second 
primary malignancies, and SARS-CoV-2 infections) should be recorded. 
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. 
4.5.5 
Performance Status 
Performance status (PS) will be measured using the Eastern Cooperative Oncology 
Group (ECOG) Performance Status Scale (see Appendix 14).  It is recommended, 
where possible, that a patient’s PS be assessed by the same person throughout the 
study. 
4.5.6 
Clinical Staging 
During screening, 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 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 femoral arteries (involvement of both groins is counted 
as one area) 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
70/Protocol CO41685, Version 5 
 
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 at least 1 of the following criteria for 
active disease requiring treatment according to the iwCLL: 
 
Evidence of progressive marrow failure as manifested by the development 
or worsening of anemia and/or thrombocytopenia. Cutoff levels of Hb 10 g/dL or 
platelet counts 100  109/L are generally regarded as indication for treatment.  
However, in some patients, platelet counts 100  109/L may remain stable over a 
long period; this situation does not automatically require therapeutic intervention.  
 
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 
 
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 by linear regression extrapolation of absolute lymphocyte count obtained at 
intervals of 2 weeks over an observation period of 23 months; patients with initial 
blood lymphocyte counts of 30  109/L may require a longer observation period to 
determine LDT. Factors contributing to lymphocytosis or lymphadenopathy other 
than CLL (e.g., infections, steroid administration) should be excluded. 
 
Autoimmune complications including anemia and/or thrombocytopenia poorly 
responsive to corticosteroids.  
 
Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine). 
 
Disease-related symptoms as defined by any of the following: 
– 
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 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
71/Protocol CO41685, Version 5 
Hypogammaglobinemia, monoclonal paraproteinemia, or oligoclonal paraproteinemia 
does not by itself constitute a basis for initiating therapy.  However, it is recommended to 
assess the change in these protein abnormalities, if patients are treated.  Also, patients 
with CLL may present with a markedly elevated leukocyte count; however, leukostasis 
rarely occurs in patients with CLL.  Therefore, the absolute lymphocyte count should not 
be used as the sole indicator for treatment. 
4.5.8 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.  
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. 
4.5.9 
MRD Response Criteria 
4.5.9.1 
MRD Evaluation 
For the evaluation of MRD as the primary endpoint of this study, MRD response rate will 
be determined as the proportion of patients with MRD-negativity measured in the PB at 
Month 15 using NGS using a cutoff of 10-4.  MRD was considered negative if the result 
was 1 CLL cell in 10,000 leukocytes.   
For the evaluation of MRD as part of the secondary endpoints, assessment of MRD in 
BM is also required in patients with CR or PR and will be used to determine MRD 
response rate in BM at end of treatment response visit (812 weeks after last dose of 
FCR/BR (~9 months) vs. 812 weeks after last dose of VEN  G (~15 months).  
Additionally, MRD response rates in the PB at completion of combination treatment 
assessment (Cycle 9, Day 1 or 812 weeks after last IV infusion) will also be 
determined.  MRD response rate in PB in patients with a CR/CRi at Month 15 will also 
be evaluated.   
4.5.9.2 
Additional Exploratory Assessments of MRD Response 
For the evaluation of MRD as part of the exploratory endpoints, MRD response rate in 
PB using a cutoff of 10-4 will be evaluated at each MRD assessment timepoint.  
Furthermore, MRD response rate will be evaluated at each timepoint by NGS using 
additional cutoffs (10-5 and 10-6) within the limit of sensitivity of this methodology. 
4.5.10 
Tumor and Response Evaluations  
Baseline tumor assessments must be assessed a maximum of 4 weeks before 
randomization.  Given that response is a secondary endpoint of the trial and PD will be 
followed by physical examination, CT scans (e.g., thorax, neck, abdomen, pelvis) 
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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
72/Protocol CO41685, Version 5 
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.   
In Arm A (VEN  G), a full response assessment of hematological status will also include 
a CT scan and a full physical examination to assess any lymphadenopathy and 
hepato/splenomegaly and BM biopsy in responding patients (CR/PR), will occur 
812 weeks after the last dose of venetoclax at the end of Cycle 12 or 812 weeks after 
the last dose of drug received in the case of early termination.  All other follow-up tumor 
assessments will be clinical assessments conducted within  14 days for the 3-month 
assessments and within a month for the 6-month assessments of the scheduled visits 
described in Appendix 1. 
In Arm B (FCR/BR), a full response assessment of hematological status will also include 
a CT scan and a full physical examination to assess any lymphadenopathy and 
hepato/splenomegaly and BM biopsy in responding patients (CR/PR), will occur 
812 weeks after the last dose of study treatment.  All other follow-up tumor 
assessments will be clinical assessments conducted within 14 days of the 3-month 
assessments and within a month of the 6-month assessments of the scheduled visits 
described in Appendix 1. 
At each follow-up visit, patients will be assessed for response/progression by physical 
examination and laboratory tests.  If at any time during follow-up when clinical or 
laboratory findings suggest that the response may have improved from SD to PR or PR 
to CR, a scan may be performed to confirm the response.  
Imaging is not routinely required to determine PD because objective evidence of PD is 
most often documented by measurement of elevated peripheral CLL cells.  However, 
when PD cannot be documented by increasing PB counts, imaging is required to 
document PD as detected by physical examination or suspected based on symptoms. 
Unless disease progression is confirmed, the patient is withdrawn due to toxicity, the 
patient withdraws consent, or the patient has died, patients should receive a maximum 
of 12 cycles of venetoclax, 6 cycles of obinutuzumab (Arm A), or 6 cycles of FCR/BR 
(Arm B).  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 12 weeks after the last 
study treatment (i.e., no earlier than 8 weeks after the end of study treatment).  For 
those patients with a CR and PR confirmed by laboratory and physical examination and 
CT scan, a BM aspirate and biopsy must also be performed.  The BM aspirate sample 
will also be tested for MRD status by NGC. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
73/Protocol CO41685, Version 5 
All other follow-up tumor assessments will be done within  14 days for the 3-month 
assessments and within a month for the 6-month assessments of the scheduled visits 
described in Appendix 1. 
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. 
4.5.11 
Response Criteria 
4.5.11.1 
Complete Response 
To be considered to have a CR, patients are required to meet all of the following criteria, 
which should be sustained for at least 8 weeks: 
 
PB lymphocytes (evaluated by blood and differential count) below 4  109 /L 
(4000/L) 
 
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 and CT scan as determined by 
measurement below the costal margin 
A spleen size of 13 cm 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/L] (without growth factors) 
– 
Platelets 100  109/L [100,000/L] (without platelet transfusion or growth 
factors) 
– 
Hemoglobin 110 g/L [11 g/dL] (without blood transfusions or erythropoietin). 
 
BM at least normocellular for age, 30% of nucleated cells being lymphocytes; 
lymphoid nodules should be absent 
BM aspirate and biopsy should be performed 8-12 weeks after the last 
treatment when clinical and laboratory results listed above demonstrate that a 
CR/cytopenic CR has been achieved.  If the BM is hypocellular, a repeat 
determination should be made in 4 weeks or when PB counts have recovered.  
However, this time interval should not exceed 6 months.  Patients who are 
otherwise in a complete remission but have BM 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. 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
74/Protocol CO41685, Version 5 
4.5.11.2 
Complete Response and Incomplete Bone Marrow Recovery 
For patients who fulfil the criteria for CR (including BM) 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. 
4.5.11.3 
Partial Response 
To be considered to have a PR, patients must exhibit the following features for at least 
8 weeks: 
 
50% decrease in PB lymphocyte count from the pre-treatment value 
AND either 
 
50% reduction in lymphadenopathy (sum of longest diameter of up to 6 largest 
lymph nodes by physical exam and 50% reduction in the sum of product of the 
diameter of up to 6 of the largest lymph nodes measured by CT scan) 
There can be no increase in any node and no new enlarged lymph node 
(diameter 15 mm).  In small lymph nodes (15 mm in diameter), an increase of 
less than 25% is not considered to be significant. 
OR 
 
50% reduction of liver enlargement, or normalization in size, if enlarged at 
baseline, as assessed by physical examination. 
OR 
 
50% reduction of spleen enlargement, or normalization in size, if enlarged at 
baseline, as assessed by physical examination. When assessed by CT, scan spleen 
size must have regressed by 50% in length beyond normal. 
AND at least one of the following 
 
Neutrophil count 1.5  109/L (1500/L) (without growth factors) or 50% increase of 
pretreatment value 
 
Platelet count 100  109/L (100,000/L) (without platelet transfusion or growth 
factors) or 50% increase of pretreatment value 
 
Hemoglobin concentration 110 g/L (11 g/dL) (without blood transfusions or 
erythropoietin) or 50% increase of pretreatment value 
 
4.5.11.4 
Progressive Disease 
PD that occurs during or after therapy will be characterized by at least one of 
the following, when compared with nadir values:  
 
Increase of 50% in the absolute number of circulating lymphocytes, to at least 
5  109/L.   
Interim cycle absolute lymphocyte counts may not be stable as certain 
therapies may cause lymphocytosis.  In the setting of therapy with such agents, 
an increase in blood lymphocyte count by itself does not uniformly indicate an 
increased tumor burden but may reflect redistribution of leukemia cells from 
lymphoid tissues to the blood.  Therefore, please use caution and clinical 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
75/Protocol CO41685, Version 5 
interpretation when assessing a potential PD in the context of interim cycle 
absolute lymphocyte count. 
 
Appearance of new palpable lymph nodes (15 mm in longest diameter) or any new 
extra nodal lesion (regardless of size) 
Transient increases of lymph node size during treatment with novel inhibitors 
may occur and should not be counted as PD. 
 
Increase of 50% in the longest diameter of any previous site of clinically significant 
lymphadenopathy (i.e., any lesion 15 mm) 
 
An increase in the spleen size by 50% or the de novo appearance of splenomegaly 
In the setting of splenomegaly, the splenic length must increase by 50% of the 
extent of its prior increase beyond baseline (e.g., a 15 cm spleen must increase 
to 16 cm). If no prior splenomegaly was observed at baseline of if splenomegaly 
has resolved with treatment, the spleen must increase by at least 2 cm from 
baseline. 
 
An increase in the liver size of 50% of the extend of enlargement of the liver below 
the intercostal margin defined by palpation, or the de novo appearance of 
hepatomegaly 
Given the impact of numerous medical conditions, liver size by physical 
examination or by CT scan is not a reliable measure of hepatic involvement by 
CLL and should only be counted if hepatomegaly is clearly attributable to 
lymphoid involvement. 
 
Transformation to a more aggressive histology (e.g., Richter 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), OR 
– 
A decrease of platelet counts by 50% or to 100  109/L (100,000/L), OR  
– 
A decrease of neutrophil counts by 50% or to 1  109/L that occurs no earlier 
than 12 weeks after end of therapy defines progression if the marrow biopsy 
demonstrates an infiltrate of clonal CLL cells. 
 
4.5.11.5 
Stable Disease 
Patients who have not achieved a CR or a PR, or who have not exhibited PD, will be 
considered to have SD (which is equivalent to a nonresponse).  
4.5.12 
Other Disease-Specific Assessments 
Details on the required hematology panel necessary to assess response are provided in 
Section 4.5.13. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
76/Protocol CO41685, Version 5 
4.5.12.1 
Bone Marrow 
A BM aspirate and biopsy are generally not requested at study entry.  Nevertheless, CLL 
is a disease of the BM, 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%. 
A BM aspirate and biopsy should be performed at least 12 weeks after the last treatment 
when clinical and laboratory results listed above demonstrate that a CR/CRi has been 
achieved.  If the BM is hypocellular, a repeat determination should be made in 4 weeks 
or when PB 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 BM 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. 
4.5.12.2 
Lymphadenopathy and Hepatomegaly/Splenomegaly 
A full physical examination should be performed to assess the extent of disease 
involvement.  Up to a maximum of the 6 largest palpable lymph nodes, hepatomegaly, 
and splenomegaly should be recorded in the eCRF. 
A CT scan (i.e., thorax, neck, abdomen, pelvis) will be performed at screening.  Up to a 
maximum of the 6 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 
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. 
4.5.12.3 
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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
77/Protocol CO41685, Version 5 
 
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. 
4.5.13 
Laboratory, Biomarker, and Other Biological Samples 
The following laboratory tests will be performed at the study site's local laboratory for 
analysis. 
4.5.13.1 
During Screening Only (Days 28 to 1) 
 
Lymphocyte count and immunophenotyping (this is to be performed centrally, but in 
exceptional circumstances [e.g., sample could not be shipped in time to the central 
laboratory], it can be performed locally) 
 
Assessment of major site involvement using BM 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 a 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. 
 
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 
 
4.5.13.2 
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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
78/Protocol CO41685, Version 5 
quantification assay (lower limit of detection:  approximately 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. 
If a BM 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 BM aspirate or biopsy is 
recommended in patients with an absolute neutrophil count (ANC) 1.5  109/L or 
platelets 75  109/L to demonstrate BM 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 measurements (in peripheral blood and in bone marrow aspirate [when 
applicable]): 
 
MRD by Next Generation Sequencing: 
– 
Approximately 4-mL whole blood will be collected  during screening (prior to 
randomization) and approximately 10 mL whole blood  at repeated timepoints 
during treatment and follow-up (as per the schedule of assessments; see 
Appendix 1 and Appendix 2) 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. 
 
MRD by ASO-PCR 
– 
Approximately10-mL whole blood will be collected during screening (prior to 
randomization) and at repeated timepoints during treatment and follow-up (as 
per the schedule of assessments; see Appendix 1 and Appendix 2).  The 
baseline CLL count required for the ASO-PCR assay will be determined by flow 
cytometry for B-CLL cell count at screening (described below).  The ‘paired’ 
MRD ASO-PCR and B-CLL cell count whole blood sample collections are 
required for a patient to be randomized.  A patient will not be randomized until a 
viable sample has been collected and received at the testing laboratory.  If 
either the MRD ASO-PCR and/or B-CLL cell count sample is found not to be 
viable, a further sample set will be requested (i.e., the MRD ASO-PCR and 
B-CLL cell count whole blood sample) are required to be collected again. 
 
Lymphocyte counts and immunophenotyping for confirmation of diagnosis, IRR 
prediction and safety monitoring: 
 
B-CLL cell count by flow cytometry 
 
Approximately 6-mL whole blood will be collected during screening (prior to 
randomization) and  at subsequent visits during follow up (see Appendix 1 and 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
79/Protocol CO41685, Version 5 
Appendix 2) for the quantification of CLL cells (namely CD5, CD19, CD20, CD23, 
CD79b, kappa, lambda) 
 
Lymphocyte subset counts by flow cytometry 
 
Approximately 5-mL whole blood will be collected during screening (prior to 
randomization) and at subsequent visits during follow up (see Appendix 1 and 
Appendix 2) for B cells (CD19+) and T cell subsets (CD3+, CD4+, CD8+) and NK 
cells (CD16+, CD56+) 
 
Additional immunophenotyping samples may be collected if required for safety 
reasons at the discretion of the physician 
 
Serum parameters (2 microglobulin): 
 
Approximately 10-mL whole blood (approximately 5-mL serum) will be taken at 
baseline for the testing of serum parameters (including, but not limited to, 
2 microglobulin) 
CLL prognostic factors, genetic and expression analysis:  
 
Approximately 20 mL whole blood will be taken during screening (prior to 
randomization) and at other applicable visits  
Analysis will include but is not limited to: 
o Cytogenetic aberrations by FISH (13q, 11q, 17p, trisomy [12]), TP53 mutations, 
and somatic hypermutation by analysis of IGHV mutational status.   
o 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) 
o Genomic complexity by aCGH 
o RNA expression to understand mechanism of action and resistance of 
Venetoclax treatments (including but not limited to BCL2 family, genes regulating 
apoptosis, and disease relevant markers) 
o DNA 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) 
 
The analysis will include ctDNA measurement in plasma 
 
Approximately 10-mL whole blood will be collected during screening (prior to 
randomization), at Month 15 and at time of progression (early termination, if 
applicable) (see Appendix 1 and Appendix 2) 
 
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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
80/Protocol CO41685, Version 5 
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 approximately100 mL (7 tablespoons).  Total blood 
loss during the study is approximately 1.3 L (86 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 4.5.17). 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.17), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exception: 
 
Blood, plasma, and serum samples and any derivatives thereof (e.g., PBMCs, DNA, 
RNA, proteins, and peptides) collected for biomarker research will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed.  
However, the storage period will be in accordance with the Institutional Review 
Board/Ethics Committee (IRB/EC) -approved Informed Consent Form and 
applicable laws (e.g., health authority requirements).  
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.14 
Electrocardiograms 
Single ECG recordings will be obtained as outlined in the Schedule of Assessments 
(Appendix 1 and Appendix 2) 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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
81/Protocol CO41685, Version 5 
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 postdose 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 5.1.6).  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). 
4.5.15 
Patient-Reported Outcome (PRO) Assessments and Health 
Economic Assessments  
PRO data will be elicited from the patients in this study to more fully characterize the 
clinical profile of the combination of VEN  G compared with FCR/BR in patients with 
previously with previously untreated CLL without del(17p) or TP53 mutation.  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. 
4.5.15.1 
MDASI-CLL 
The MD Anderson Symptom Inventory for Chronic Lymphocytic Leukemia (MDASI-CLL) 
(see Appendix 5) 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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
82/Protocol CO41685, Version 5 
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 additional disease-specific 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). 
4.5.15.2 
EORTC QLQ-C30 
The European Organization for the Treatment and Research of Cancer Quality of Life 
(EORTC QLQ-C30) (see Appendix 6) is a validated and reliable self-report measure 
(Aaronson et al. 1993; Fayers et al. 1999; Fitzsimmons et al. 1999) consisting of 
30 questions incorporated into five functional scales (physical, role, cognitive, emotional, 
and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), 
and a global health status/global quality-of-life scale.  The remaining single items 
(dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the 
additional symptoms experienced by patients with cancer and the perceived financial 
burden of treatment.  The EORTC QLQ-C30 assessment will be conducted during Day 1 
of each treatment cycle.  The EORTC QLQC30 will be administered at all follow-up visits 
until NLT. 
4.5.15.3 
EQ-5D-5L 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses (EuroQol 
Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013) (see Appendix 7).  
This questionnaire is a generic, preference-based health utility measure with two 
components:  a five-item health state profile that assesses mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression, as well as a visual analogue scale 
(VAS) that measures health state.  The EQ-5D-5L is designed to capture the patient's 
current health status.  Published weighting systems allow for creation of a single 
composite score of the patient's health status.   
The EQ-5D-5L will be utilized in this study to estimate quality adjusted life years (QALY) 
for economic modeling.  The EQ-5D-5L also contains a visual analog scale (VAS) to 
assess the patient’s overall health.  The EQ-5D-5L 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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
83/Protocol CO41685, Version 5 
4.5.16 
Data Collection Methods for Clinical Outcome Assessments 
PRO instruments will be self-administered at the clinic at specified timepoints during the 
study (see schedule of activities in Appendix 1 and Appendix 2).  At the clinic, 
instruments will be administered before the patient receives any information on disease 
status, prior to the performance of non-PRO assessments, and prior to the 
administration of study treatment, unless otherwise specified. 
PRO instruments, translated into the local language as appropriate, will be completed 
through use of an electronic device provided by the Sponsor.  The device will be 
preprogrammed to enable the appropriate instruments to be administered in the correct 
order at each specified timepoint.  The electronic device and instructions for completing 
the instruments electronically will be provided by the site staff.  The data will be 
transmitted to a centralized database maintained by the electronic device vendor.  The 
data will be available for access by appropriate study personnel. 
A web-based platform will be used as back-up to collect PRO data in the event of 
electronic device malfunction or unavailability.   
During clinic visits, PRO instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments. 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 20 minutes at each specified visit. 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
4.5.17 
Optional Samples for Research Biosample Repository 
4.5.17.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
84/Protocol CO41685, Version 5 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.17.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.17) 
will not be applicable at that site. 
4.5.17.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to venetoclax and apoptosis, 
diseases, or drug safety: 
 
Leftover blood, BM aspirate, serum, plasma, PBMC, and any derivatives thereof 
(e.g., DNA, RNA, proteins, peptides)  
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
85/Protocol CO41685, Version 5 
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.17.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples 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. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.17.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent 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 RBR samples.  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 and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
86/Protocol CO41685, Version 5 
4.5.17.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address: 
global.rcr-withdrawal@roche.com  
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.17.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient (including high-grade toxicities when continuing treatment is 
deemed detrimental) 
 
Pregnancy 
 
Patient non-compliance 
 
Disease progression 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
87/Protocol CO41685, Version 5 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
Patients will return to the clinic for a treatment completion or treatment discontinuation 
visit 28 ( 7) days after the final dose of study drug (see Appendix 1, Appendix 2, and 
Appendix 3 for additional details). 
After disease progression, information on survival follow-up and new anti-cancer therapy 
will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every year until death or study completion (unless the patient withdraws 
consent or the Sponsor terminates the study).   
4.6.2 
Patient Discontinuation from the Study 
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 patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 
4.6.3 
Study 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 
 
Patient enrollment is unsatisfactory 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
88/Protocol CO41685, Version 5 
 
Insufficient management of TLS 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
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 Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Venetoclax is currently approved in various countries/regions including the United States 
(US), the European Union (EU), Canada, Switzerland, and Australia for the treatment of 
adult patients with R/R CLL either as monotherapy or in combination with rituximab.  In 
2019, venetoclax was also approved by the FDA for the treatment of previously 
untreated CLL or SLL patients in combination with obinutuzumab (see Venetoclax US 
Prescribing Information 2019). 
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 Investigator’s Brochure).  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 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 Section 5.1.6. 
5.1.1.1 
Tumor Lysis Syndrome 
In patients with CLL, TLS is a rare, but potentially life-threatening event.  TLS is 
characterized by cytolysis leading to hyperkalemia, hyperphosphatemia, hyperuricemia 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
89/Protocol CO41685, Version 5 
and/or hypocalcemia, as defined by the Howard criteria (Appendix 15).  Analyses of 
patients treated with venetoclax monotherapy have reported TLS frequencies of up to 
5%.  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.  
In the BO25323/CLL14 study, in which elderly, unfit patients were randomized to receive 
12 cycles of VEN  G or GClb, impaired renal function was reported for most patients at 
study entry.  Therefore, patients in Study BO25323/CLL14 were particularly at risk of 
TLS.  However, TLS was a very rare finding in this study.  The incidence of adverse 
events of TLS was 2.3% in the GClb arm compared with 1.4% in the VEN  G arm.  In 
the VEN  G arm, all events occurred prior to initiation of venetoclax treatment and were 
associated with obinutuzumab treatment.  There were no adverse events of clinical TLS 
consistent with Howard criteria reported; however, 1 event in each arm was reported 
where clinical manifestations were described (both did not meet laboratory Howard 
criteria).  All events were managed per standard of care and resolved. 
There were additional laboratory abnormalities identified from blood test reports, 
consistent with Howard criteria, but that were not reported as adverse events of TLS by 
the investigator.  Medical review by the Sponsor revealed that some of these events 
were associated with pre-dose laboratory abnormalities and were not considered 
medically significant.  There was no venetoclax dose adjustment identified, or other 
treatment given as a result of these laboratory abnormalities.   
TLS is an important identified risk for venetoclax, and requires ongoing prophylactic 
measures and blood test monitoring to manage and reduce the risks associated with 
TLS, as per current prescribing information.  In this study rigorous TLS monitoring and 
prophylaxis will be instituted (Section 5.1.7.1; see Appendix 12 for TLS prophylaxis, 
monitoring plan, and management recommendations).  All patients in Arm A will be 
re-evaluated by laboratory assessment and can be re-categorized in a lower TLS-risk 
group during the venetoclax ramp-up period, as described in Section 5.1.7.1.  
5.1.1.2 
Serious Infections 
Serious infection is an important identified risk for venetoclax and obinutuzumab and will 
be closely monitored by routine surveillance.  The current prescribing information 
provides treating physicians with appropriate guidance on how to mitigate and manage 
this risk.  Most common infections reported with venetoclax include pneumonia, sepsis, 
upper respiratory tract infections, and urinary tract infections.  Fatalities resulting from 
pneumonia and sepsis have been reported in patients receiving venetoclax.  
In Study BO25323/CLL14, the frequency of Grade 3 infections was similar in the GClb 
arm compared with the VEN  G arm (16.4% vs. 19.3%, respectively).  Pneumonia was 
the most frequently reported Grade 3 event (4.2% of patients in both treatment arms).  

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
90/Protocol CO41685, Version 5 
Grade 3 sepsis was reported in 3.3% of patients in the VEN  G arm compared with 
0.9% in the GClb arm. 
Grade 34 infections were comparable across treatment groups (15.0% in the GClb arm 
vs. 17.5% in the VEN  G arm), and comparable across treatment periods (combination, 
single-agent and post-treatment periods).   
The overall frequency of serious infections was numerically higher in the VEN  G arm 
compared with the GClb arm (18.9% vs. 14.0%, respectively).  Pneumonia was the most 
frequently reported SAE (4.7% in the VEN  G arm vs. 4.2% in the GClb arm).  The 
largest difference between treatment groups by individual PT was for sepsis (2.8% in the 
VEN  G arm vs. 0.9% in the GClb arm).  
Infections are well-known to increase morbidity and mortality in patients with CLL 
(Hilal et al. 2018).  This is primarily due to disease-related (inherent immune dysfunction 
caused by the disease process, affecting both humoral and cell-mediated immunity, and 
complement activity) and therapy-related elements (most anti-CLL treatments are 
responsible for causing lymphopenia, either B-cell or T-cell, and/or neutropenia to some 
degree).   
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.  Refer to Section 5.1.6.1 for 
management of infections. 
5.1.1.3 
Neutropenia and Cytopenias 
5.1.1.3.1 
Neutropenia 
Neutropenia is an important identified risk for venetoclax.  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 BM reserves, multiple prior therapies, disease infiltrating the BM, and the use of 
growth factor prior to entering the studies. 
Clinical data from the oncology studies suggest that adverse events of neutropenia are 
observed among patients who receive venetoclax as a single agent or in combination 
with other therapeutic agents, with slightly higher frequency observed in some 
combination studies.  Serious adverse events of neutropenia or neutropenia that lead to 
discontinuations are few across the entire venetoclax oncology program.  Neutropenia 
management guidelines are provided in Section 5.1.6.1.  Granulocyte colony-stimulating 
factors are permitted for supportive measures per local practice guidelines.  

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
91/Protocol CO41685, Version 5 
5.1.1.3.2 
Cytopenias 
Thrombocytopenia and anemia have been reported with venetoclax in the 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.   
In this study, blood counts will be monitored closely throughout treatment (see the 
Schedule of Activities in Appendix 1.  Growth factors are permitted according to local 
practice, and patients will be monitored and treated promptly in case of infections.  Dose 
interruptions or reductions will be allowed on the basis of toxicity.  Refer to 
Section 5.1.6.1 for management of cytopenias. 
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. 
5.1.1.5 
Effects on Fertility and Reproductive Toxicity 
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.  
Two human pregnancies have been reported in the clinical program with venetoclax so 
far, including one pregnancy of a partner; in both cases, a live infant with no neonatal 
complication, congenital anomalies, or birth defects was delivered.  In nonclinical 
embryo-fetal development studies, venetoclax had the potential to cause embryo-fetal 
developmental toxicities.  Consequently, venetoclax should not be administered to 
pregnant women, and must be discontinued if a patient becomes pregnant. 
Long-term effects of venetoclax on either male or female reproductive potential are 
unknown.  Male and female patients should agree to remain abstinent or use 
contraceptive methods as described in Section 4.1.1. 
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, Table 4, and Appendix 4.)  Venetoclax does 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
92/Protocol CO41685, Version 5 
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. 
5.1.1.7 
Treatment-Emergent Malignancies 
(Second Primary Malignancies) 
Events of second primary malignancies (including non-melanoma skin cancers) have 
been reported across the venetoclax hematologic oncology program.  However, no 
causal association with venetoclax administration has been confirmed, and no pattern 
has been observed.  The overall observed incidence rate of malignancy in the 
venetoclax clinical trial programs was comparable to that reported in the general 
population.  Second primary malignancies will be closely monitored in this study. 
5.1.1.8 
Toxicity in Patients with Severe Hepatic Impairment 
Mean venetoclax AUC exposures in patients with severe hepatic impairment were 
approximately 2.3- to 2.7-fold higher as compared with participants with normal hepatic 
function.  On the basis of these results, a dose adjustment in patients with severe 
hepatic impairment is recommended. 
5.1.1.9 
Food Effect 
Administration of venetoclax with a low-fat meal increased venetoclax exposure by 
approximately 3.4-fold, and administration with a high-fat meal increased venetoclax 
exposure by 5.1- to 5.3-fold compared with fasting conditions.  Based on these results, 
venetoclax should be administered with a meal (see Section 4.3.2.1), to ensure 
adequate and consistent bioavailability of venetoclax. 
5.1.2 
Risks Associated with Obinutuzumab 
Important risks associated or potentially associated with obinutuzumab are IRRs and 
hypersensitivity reactions, TLS, thrombocytopenia (including acute thrombocytopenia), 
neutropenia (including prolonged and late-onset neutropenia), prolonged B‑cell 
depletion, infections (including PML and HBV reactivation), worsening of pre-existing 
cardiac conditions, impaired immunization response, immunogenicity, gastrointestinal 
(GI) 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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
93/Protocol CO41685, Version 5 
5.1.2.1 
Infusion-Related Reactions and Hypersensitivity 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). 
 
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic 
reactions; anaphylaxis has been reported in patients treated with obinutuzumab. 
Hypotension may occur during obinutuzumab IV infusions.  Therefore, withholding of 
anti-hypertensive treatments should be considered for 12 hours prior to and throughout 
each obinutuzumab infusion and for the first hour after administration.  Patients at acute 
risk of hypertensive crisis should be evaluated for the benefits and risks of withholding 
their anti-hypertensive medication. 
Guidelines for medical management of IRRs and anaphylaxis are provided in 
Section 5.1.6.1 and Appendix 16. 
Hypersensitivity reactions with immediate (e.g., anaphylaxis) and delayed onset (e.g., 
serum sickness) have been reported in patients treated with obinutuzumab.  
Hypersensitivity reactions typically occur after previous exposure and very rarely with the 
first infusion.  In the case a hypersensitivity reaction is suspected during or after an 
infusion, the infusion should be stopped and treatment permanently discontinued. 
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 12. 
5.1.2.3 
Neutropenia 
Some patients who were treated with obinutuzumab developed NCI CTCAE Grade 34 
neutropenia, including febrile neutropenia.  Neutropenia resolved spontaneously or with 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
94/Protocol CO41685, Version 5 
use of hematopoietic growth factors.  Patients who experience Grade 3 or 4 neutropenia 
should be closely monitored until neutrophil values return to at least Grade 2.  Cases of 
late-onset neutropenia (ANC 1000 cells/L occurring28 days after obinutuzumab 
treatment has been completed or stopped) or prolonged neutropenia (ANC 
1000-cells/L) that does not resolve after 28 days without obinutuzumab treatment 
have also been reported. 
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.  Guidelines for the treatment of neutropenia are provided in 
Section 5.1.6.1.   
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, including acute thrombocytopenia (occurring 
within 24 hours after the infusion), 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 
as compared with patients treated with rituximab  chlorambucil (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. 
Patients receiving concomitant medication that could possibly worsen thrombocytopenia 
related events (e.g., platelet inhibitors and anticoagulants) may be at greater risk of 
bleeding.  When possible, replace prior vitamin K antagonist therapy with low molecular 
weight heparin (LMWH) prior to Cycle 1, Day 1.  Patients should be closely monitored for 
thrombocytopenia, especially during the first cycle.  For patients who experience 
thrombocytopenia, regular laboratory tests should be performed until the event resolves, 
and dose delays should be considered in case of severe or life-threatening 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
95/Protocol CO41685, Version 5 
thrombocytopenia.  Transfusion of blood products (i.e., platelet transfusion) may be 
performed at the discretion of the treating physician, according to institutional practice. 
5.1.2.6 
Coagulation Abnormalities Including Disseminated 
Intravascular Coagulation 
Disseminated intravascular coagulation (DIC) has been reported in patients receiving 
obinutuzumab for the treatment of FL and CLL.  In the majority of cases, the events have 
involved subclinical (asymptomatic) changes in platelets and laboratory coagulation 
parameters following the first infusion, with spontaneous resolution usually occurring by 
Day 8.  In some cases, the events were associated with IRRs and/or TLS.  No specific 
baseline risk factors for DIC have been identified. 
5.1.2.7 
Infections 
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. 
Serious bacterial, fungal, and new or reactivated viral infections can occur during and 
following the completion of obinutuzumab therapy.  Fatal infections have been reported.  
Serious viral infections may include herpes virus infections (including cytomegalovirus, 
John Cunningham virus infection (JCV), PML, and HCV infection).   
The Medical Monitor is available for guidance regarding the eligibility of patients who are 
thought to have passive transfer of HCV or HBV core surface antibodies from IV 
immunoglobulin administration.  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 
Reactivation of hepatitis B in patients with chronic hepatitis (HBsAg positive) with 
evidence of prior hepatitis B exposure, or in patients who are carriers (HBsAg negative 
and HBcAb positive) has been reported with other anti-CD20 antibodies.  The risk is 
increased particularly when anti-CD20 antibodies are administered with 
immunosuppressive therapies, such as steroids or chemotherapy. 
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.  For the management of Hepatitis 
B Virus reactivation, follow the guidance provided in Table 6. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
96/Protocol CO41685, Version 5 
Table 6 
Management of Hepatitis B Virus Reactivation 
Symptom 
Action to be Taken 
HBV DNA level of 
29 IU/mL 
 Hold VEN  G. 
 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 VEN  G 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 VEN  G 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 venetoclax  obinutuzumab. 
HBV DNA level 
detectable but 
29 IU/mL 
 Continue with VEN  G, 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). 
HBV  hepatitis B virus; VEN  Gvenetoclax  obinutuzumab 
  
Progressive Multifocal Leukoencephalopathy 
JCV infection resulting in 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. 
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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
97/Protocol CO41685, Version 5 
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. 
5.1.2.8 
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. 
5.1.2.9 
Gastrointestinal Perforation 
Gastrointestinal perforations, including fatal events, have been reported in patients 
treated with obinutuzumab.  Patients with GI involvement should be monitored for signs 
of GI perforation. 
5.1.2.10 
Worsening of Preexisting Cardiac Conditions 
In patients with underlying cardiac disease and treated with obinutuzumab, adverse 
events such as angina pectoris, acute coronary syndrome, myocardial infarction, heart 
failure, and arrhythmias, including atrial fibrillation and tachyarrhythmia, have been 
observed.  These events may occur as part of an IRR and can be fatal.  Therefore, 
patients with a history of cardiac disease should be monitored closely.  In addition, these 
patients should be hydrated with caution to prevent a potential fluid overload. 
5.1.2.11 
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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
98/Protocol CO41685, Version 5 
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.  However, in 
Study BO25323/CLL14, no increase in TLS or infections were observed.  Given the 
degree of immunodeficiency associated with the underlying disease, all patients will be 
monitored closely for infection and treated aggressively according to institutional 
guidelines.   
5.1.3 
Risks Associated with Rituximab 
The following adverse events are considered to be important risks associated or 
potentially associated with rituximab: IRRs, infections (including PML and HBV 
reactivation), neutropenia (including prolonged), rTLS, impaired immunization response, 
GI perforation, and severe mucocutaneous reactions.  Details for some of these risks are 
provided below; refer to the Rituximab Investigator’s Brochure for full information. 
5.1.3.1 
Infusion-Related Reactions 
Acute IRRs are very common in patients receiving rituximab (occurring in 10% of 
patients) based on clinical trial experience.  However, serious IRRs are uncommonly 
reported (occurring in 1/1,000 and 1/100 patients) and are rarely fatal (occurring in 
1/10,000 and 1/1,000 patients).  Most IRRs occur with the first administration of 
rituximab.  Rituximab-induced IRRs consist of a cluster of symptoms and signs occurring 
during or within 24 hours of a rituximab infusion.  These are related to cytokine release, 
and these acute IRRs overlap with “cytokine release syndrome”.  Anaphylactic and other 
hypersensitivity reactions also occur following rituximab administration, and clinical 
manifestations of these reactions are similar to cytokine release syndrome.  In contrast 
to cytokine release syndrome, true hypersensitivity reactions typically occur within 
minutes of starting the rituximab infusion. 
5.1.3.2 
Infections (Including Serious Infections) 
Serious infections, including fatal bacterial, fungal, and new or reactivated viral 
infections, can occur during and up to 1 year following completion of rituximab-based 
therapy.  New or reactivated viral infections include cytomegalovirus, herpes simplex 
virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C 
viruses. 
5.1.3.3 
Neutropenia 
Neutropenia is very common in patients receiving rituximab (occurring in 10% of 
patients) based on clinical trial experience.  However, delayed onset neutropenia is very 
rare (occurring in 1/10,000 patients), and the incidence of prolonged neutropenia is 
unknown.  Neutropenia may lead to serious or overwhelming infection, especially if 
profound (Grade 3/4), prolonged, associated with breaches in natural mucosal barriers 
(e.g., diarrhea and/or mucositis), and/or other immunological defects (e.g., lymphopenia, 
hypogammaglobulinemia, acquired immunodeficiency syndrome).  Despite an increase 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
99/Protocol CO41685, Version 5 
in incidence of neutropenia and Grade 3/4 neutropenia associated with rituximab, most 
studies have not reported a significant increase in serious neutropenic infections. 
5.1.3.4 
Tumor Lysis Syndrome 
Patients treated with rituximab may be at risk for TLS.  Severe tumor TLS is very rare in 
patients receiving rituximab (occurring in 1/10,000 patients), based on postmarketing 
experience.  Signs and symptoms (e.g., hyperuricemia, hyperkalemia, hypocalcaemia, 
hyperphosphatemia, acute renal failure, and elevated LDH) that are consistent with TLS 
have been reported to occur after the first MabThera/Rituxan IV infusion in patients with 
high numbers of circulating malignant lymphocytes.  A high number of circulating 
malignant cells (25,000/mm3) or high tumor burden confers a greater risk of TLS.  For 
patients with evidence of TLS, rituximab should be discontinued, and the patient should 
be treated as clinically indicated. 
5.1.3.5 
Hepatitis B Reactivation 
Reactivation of hepatitis B ranges from asymptomatic reactivations (detected by 
changes in laboratory parameters only) to fulminant liver failure and death.  Patients with 
chronic hepatitis B (HBsAg positive) viral infection are at risk for reactivation and will be 
excluded from the study.  Patients with evidence of prior hepatitis B exposure or who are 
carriers (defined as HBsAg negative and anti-HBcAb positive) are at a lower risk for 
reactivation.  Patients who demonstrate evidence of reactivation while receiving an 
appropriate anti-viral therapy will be discontinued from study treatment.   
5.1.3.6 
Progressive Multifocal Leukoencephalopathy 
Rare cases of PML have also been reported in patients treated with rituximab alone or in 
combination with other immunosuppressive medications (Goldberg et al. 2002; 
Calabrese et al. 2007; Carson and Bennett 2009).  In a review of 57 patients who 
developed PML after rituximab administration, all patients had received prior therapies 
with alkylating agents, corticosteroids, purine analogs, or drugs to prevent allogeneic 
stem cell or solid-organ graft rejection.  The diagnosis of PML in any patient treated with 
rituximab is rare, but it should be suspected in any patient who develops new-onset 
neurologic manifestations.  The majority of patients with hematologic malignancies 
diagnosed with PML received rituximab in combination with chemotherapy or as part of a 
hematopoietic stem cell transplant.  Most cases of PML were diagnosed within 
12 months of the patients’ last infusion of rituximab. 
5.1.3.7 
Severe Mucocutaneous Reactions 
Severe reactions, including fatal mucocutaneous reactions, can occur in patients 
receiving rituximab.  These reactions include paraneoplastic pemphigus, 
Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic 
epidermal necrolysis (TEN).  The onset of these reactions in patients treated with 
rituximab has varied from 113 weeks following rituximab exposure. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
100/Protocol CO41685, Version 5 
5.1.3.8 
Gastrointestinal Perforation 
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can 
occur in patients receiving rituximab in combination with chemotherapy.  Patients with 
gastrointestinal involvement should be monitored for signs of gastrointestinal perforation. 
5.1.4 
Risks Associated with FCR/BR 
Potential risks relevant for the FCR/BR arm of this trial as well as specific risks for each 
drug alone are briefly described below.  Refer to the prescribing information for 
fludarabine, cyclophosphamide, and bendamustine for risks related to FCR/BR 
chemotherapy.  Risks associated with rituximab are detailed in Section 5.1.3. 
5.1.4.1 
Tumor Lysis Syndrome 
Detailed instructions and premedication are described in Appendix 12. 
Patients with a high tumor burden (i.e., larger lymph nodes and/or high lymphocyte count 
(25109/L) are at increased risk of TLS, especially if treated with fast-acting, effective 
agents as used in this trial.  The overwhelming activity of these agents leading to a rapid 
destruction of CLL cells can cause electrolyte imbalances, such as hyperkalemia, 
hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperuricosuria; thereby leading 
to cardiac arrhythmias, acute uric acid nephropathy/acute renal failure and epileptic 
seizures if not timely and properly managed.   
Patients with TLS should be treated per institutional practice (including correction of 
electrolyte abnormalities, monitoring of renal function and fluid balance, in some cases 
even dialysis as indicated). 
5.1.4.2 
Cytopenias and Infections 
All drugs tested in this trial cause or may cause cytopenias with decreased levels of 
hemoglobin, neutrophil, and platelet count.  However, it needs to be considered that 
patients with CLL commonly have pre-existing myelosuppression due to BM infiltration 
or previous therapy.  These abnormal laboratory values are clinically relevant and should 
be treated at the investigator´s discretion.  Prophylactic measures are strongly 
recommended as described in Section 5.1.6. 
Treatment should not be administered in the presence of an active or severe infection 
including bacterial, viral and fungal infections.  Caution should be exercised when 
considering the application of study drugs in patients with a history of recurring or 
chronic infections or with underlying conditions that may predispose patients to 
infections.  If clinically indicated, anti-infective prophylaxis should be implemented at the 
investigator's discretion.  Signs and/or symptoms of infection should result in prompt 
evaluation and appropriate samples for bacteriological investigation prior to starting 
antibiotic or other treatment.  Serious, bacterial, fungal, and new or reactivated viral 
infections (including cytomegalovirus [CMV], JC virus infection [PML], and HBV/HCV 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
101/Protocol CO41685, Version 5 
infection) can occur during and following the completion of therapy.  Fatal infections 
related to all drugs used in this trial have been reported. 
5.1.4.3 
Worsening of Preexisting Cardiac Conditions 
In CLL patients with underlying cardiac disease, adverse events such as angina 
pectoris, acute coronary syndrome, myocardial infarction, heart failure and arrhythmias, 
including atrial fibrillation and tachyarrhythmia have been observed during treatment with 
cyclophosphamide, and bendamustine.  These events may also occur as part of an IRR 
and can be fatal.  Therefore, patients with a history of cardiac disease should be 
monitored closely.  In addition, these patients should be hydrated with caution in order to 
prevent a potential fluid overload. 
However, as CLL patients are often elderly and sometimes have cardiac comorbidities, 
ECG and cardiac ultrasound for assessment of LVEF is mandatory at screening and 
recommended as clinically indicated afterwards.  In addition, patients with a history of 
cardiac disease should be monitored closely and should be hydrated with caution in 
order to prevent a potential fluid overload. 
5.1.4.4 
Teratogenicity and Mutagenicity 
Fludarabine, cyclophosphamide and bendamustine are known to be teratogenic and 
mutagenic; a pregnancy must be prevented in both, female patients and partners of 
male patients during and at least 6 months after treatment. 
Potential risks with fludarabine 
For detailed information and further guidance on fludarabine please see the prescribing 
information.  Aside from the above-described risks the following side effects are relevant: 
 
Autoimmune diseases 
 
Neurotoxicity 
 
Transfusion-associated graft-versus-host-reaction 
 
Renal insufficiency 
 
Secondary malignancies, especially of the skin 
 
Potential risks with cyclophosphamide 
For detailed information and further guidance on cyclophosphamide please see the 
prescribing information.  Aside from the above described risks, the following side effects 
are relevant: 
 
Impairment of the urinary tract and the kidneys 
 
Pulmonal toxicity 
 
Veno‑occlusive disease (VOD) 
 
Secondary malignancies 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
102/Protocol CO41685, Version 5 
 
5.1.5 Potential Risks with Bendamustine 
For detailed information on bendamustine please see the prescribing information.  Aside 
from the above-described risks allergies and toxic skin reactions are the most common 
and relevant risks. 
Stevens-Johnson-Syndrome/ toxic epidermal necrolysis 
Cases of Stevens-Johnson-Syndrome (SJS)/TEN, some fatal, have been reported in 
patients who were treated with allopurinol and bendamustine with/without rituximab.  
Therefore, allopurinol should be avoided in combination with bendamustine and if the 
concomitant use of allopurinol is indispensable, allopurinol must be stopped 24 hours 
before administration of bendamustine and reinitiated 24 hours after administration of 
the last dose of bendamustine.  If patients experience any skin reactions during 
treatment, they should be monitored closely and in case of any suspicion of evolving to a 
serious mucocutaneous reaction, treatment with any suspected drugs including but not 
limited to bendamustine and allopurinol should be discontinued until complete resolution 
of event. 
5.1.6 
Management of Patients Who Experience Adverse Events 
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 BM 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 24 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 v5.0 will be used.  

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
103/Protocol CO41685, Version 5 
Table 7 
National Cancer Institute Grading Scale for Chronic Lymphocytic 
Leukemia 
Decrease in Platelets or Hemoglobin from 
Pre-Treatment (%) 
Grade 
ANC/L 
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. 
 
5.1.6.1 
Guidelines for Management of Specific Adverse Events in 
ARM A (Venetoclax + Obinutuzumab) 
Guidelines for management of specific adverse events in Arm A are outlined in Table 8.  
Additional guidelines are provided in the subsections below. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
104/Protocol CO41685, Version 5 
Table 8 
Guidelines for Management of Specific Adverse Events for 
Patients Randomized to Arm A  
Event 
Dose Delay or Dose Modification 
Grade 3 or 4 (NCI CTCAE 
v5.0 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. 
 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/L) 
and/or symptomatic 
bleeding 
 Withhold venetoclax (and obinutuzumab if event occurs during 
Cycles 16) for severe thrombocytopenia (platelets 25,000/L) 
or presence of symptomatic bleeding until resolution of bleeding. 
Platelets may be transfused at the discretion of the 
investigator. 
When platelet level rises to 50,000/L 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 (and obinutuzumab if 
event occurs during Cycles 16). 
When platelet level rises to 50, 000/L without transfusional 
support for 5 consecutive days, restart venetoclax at one 
dose level reduction and obinutuzumab. 
 For subsequent episodes of severe thrombocytopenia, withhold 
venetoclax (and obinutuzumab if event occurs during 
Cycles 16). 
When platelet level rises to 50,000 L 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, contact the Medical Monitor 
regarding continuation on the protocol. 
Grade 4 IRR 
 Discontinue obinutuzumab permanently.  Patients may continue 
venetoclax 
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. 
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 12.  

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
105/Protocol CO41685, Version 5 
Table 8 
Guidelines for Management of Specific Adverse Events for 
Patients Randomized to Arm A (cont.)  
Non-hematologic toxicity 
 
Event 
Dose Delay or Dose Modification 
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 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 obinutuzumab. 
 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 v5.0 
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 (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 and 
obinutuzumab. 
Grade 1 non-hematologic 
toxicity 
 No dose reduction or delay. 
Active infection 
 Do not administer obinutuzumab to patients with an active 
infection. 
 After resolution, reinitiate obinutuzumab. 
ANC  absolute neutrophil count; NCI CTCAE  National Cancer Institute Common Terminology 
Criteria for Adverse Events; G-CSF  granulocyte stimulating factor; HBV  hepatitis B virus; 
IRR  infusion-related reaction. 
  
Gradual dose increase of venetoclax following resolution of toxicity leading to a dose 
reduction may be considered if the patient is stable for 2 weeks on the lower dose (see 
Table 9); however, if the toxicity recurs, the patient may continue treatment on the lower 
dose. 
Table 9 
Venetoclax Dose Reduction 
Venetoclax Current Dose Level 
Venetoclax Dose Reduction 
400 mg 
200 mg 
200 mg 
100 mg 
100 mg 
Discontinue venetoclax and obinutuzumab 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
106/Protocol CO41685, Version 5 
There will be no change in the infusion rate or interruptions in the administration of 
obinutuzumab in this study. 
Patients who discontinue obinutuzumab may continue venetoclax.  Patients who 
discontinue venetoclax for toxicity should also discontinue obinutuzumab, although they 
are to continue evaluation per protocol Appendix 3. 
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 and 
Appendix 2.  For patients who interrupt all study treatments for longer than 28 days due 
to reasons other than treatment-related adverse events, resumption of study drug may 
be possible only after consultation with the Medical Monitor.  TLS risk should be 
reassessed to determine if restarting venetoclax at a reduced dose is necessary (for 
example, all or some levels of the dose ramp-up). 
5.1.6.2 
Guidelines for Management of Specific Adverse Events in 
ARM B (FCR/BR) 
5.1.6.2.1 
Rituximab Dosage Modifications 
There will be no change in the infusion rate or interruptions in the administration of 
rituximab in this study.  Patients at high risk for IRRs may, at the investigator’s 
discretion, receive their initial dose of rituximab split over 2 consecutive days (e.g., 
125 mg/m2 on Cycle 1, Day 1 and 250 mg/m2 on Cycle 1, Day 2). 
Rituximab may be temporarily held.  Any NCI CTCAE v5.0 toxicity Grade 3 in severity 
that is deemed related to rituximab treatment will require interruption of study treatment 
until resolution to Grade 1.  
Patients receiving BR who discontinue rituximab for rituximab-related toxicity may 
continue to receive bendamustine as a single agent for the full 6 cycles if deemed to be 
in the best interest of the patient as assessed by the investigator.  Patients who 
discontinue both bendamustine and rituximab are to continue evaluation per protocol as 
described in Section 4.6.1. 
5.1.6.2.2 
Bendamustine Dosage Modifications 
On the first day of each new treatment cycle and before each bendamustine dose, the 
patient will be evaluated for possible toxicities that may have occurred after the previous 
dose(s).  The following dose-reduction rules for bendamustine should be followed (see 
Table 10 and Table 11). 
If toxicities occurred at 70 mg/m2, reduce dose to 50 mg/m2; if toxicity occurred at 
50 mg/m2, discontinue bendamustine.  If the dose of bendamustine is reduced due to 
toxicity, it will not be re-escalated later in the study. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
107/Protocol CO41685, Version 5 
Table 10 Bendamustine Dose Reduction 
Bendamustine Current Dose Level 
Bendamustine Dose Reduction 
90 mg/m2 
70 mg/m2 
70 mg/m2 
50 mg/m2 
50 mg/m2 
Discontinue bendamustine 
If a patient has disease-related splenomegaly or significant bone marrow involvement as the etiology of 
cytopenias at enrollment, treatment may be continued without meeting the hematologic criteria for 
subsequent cycles of induction chemotherapy.  In such cases, the decision to continue dosing of 
bendamustine at the current dose is at the investigator’s discretion. 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
108/Protocol CO41685, Version 5 
Table 11 Dose Modification Guidelines for Bendamustine 
NCI CTCAE Category 
Severity 
Dose Modification 
Hematologic a 
Neutrophil 1000/L 
on Day 1 of 
Cycles 26 
Initiation (Day 1) of Cycles 26 should be 
delayed until the neutrophil count is 
1000/L (or returns to baseline level 
obtained at screening) and the platelet count 
is 75,000/L.a 
If Day 1 is delayed by more than 2 weeks, 
then bendamustine should be resumed at the 
next lower dose level. 
Platelets 75,000/L 
on Day 1 of 
Cycles 26 
Grade 4 neutropenia 
with fever/infection 
Initiation (Day 1) of Cycles 26 should be 
delayed until the neutrophil count is 
1000/L without evidence of fever or 
infection and the platelet count is 
75,000/L.a 
Bendamustine should then be resumed at 
the next lower dose level. 
Grade 4 neutropenia 
lasting 7 days 
Grade 4 platelets for 
7 days or a platelet 
count 10,000/L at 
any time 
Nausea, emesis, or 
diarrhea in the absence 
of maximal prophylaxis 
Grade 3 
Continue treatment, but with institution of 
maximum prophylactic therapy, including a 
5-HT3 antagonist for nausea and emesis, 
and loperamide, or a comparable 
antidiarrheal agent, for diarrhea.  Events of 
Grade 4 toxicity require holding treatment 
until resolution of toxicity to Grade 2 with 
use of maximum prophylaxis. 
Nausea, emesis, or 
diarrhea with maximal 
prophylaxis 
Grade 3 
Hold bendamustine for up to 2 weeks or until 
the toxicity returns to Grade 2, and restart 
at the next lower dose.  If treatment is 
delayed by more than 2 weeks, treatment 
with bendamustine must be discontinued. 
All other toxicities 
related to bendamustine 
Grade 3 
 
5-HT3  5-hydroxytryptamine 3; NCI CTCAE  National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
a If patients have disease-related splenomegaly or significant bone marrow involvement as the etiology of 
cytopenias at enrollment, treatment may be continued without meeting the hematologic criteria for 
subsequent cycles of induction chemotherapy.  In such cases, the decision to continue dosing of 
bendamustine at the current dose is at the investigator’s discretion. 
  
5.1.6.2.3 
Dose Modification for FCR 
Before starting treatment on day 1 of every cycle, the following retreatment criteria must 
be fulfilled: 
 
No active infection 
 
No CTCAE Grade 3/4 adverse events (except hematological adverse events that 
are due to BM involvement of the CLL, these must be recovered to at least baseline 
value)  
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
109/Protocol CO41685, Version 5 
If these criteria are not met treatment must be delayed for up to 14 days.  
Afterwards the patient must continue with a reduced dose of 75% of the normal dose of 
fludarabine and cyclophosphamide. 
The rituximab dose will not be reduced (except for dose reductions of 100% that may 
occur due to side effects) but will be delayed by the same amount.  
If the patient does not meet the retreatment criteria within the 14-day-period again a 
further delay of 14 days (resulting in a total delay of 28 days) is permitted.  
The patient will than continue with a reduced dose of 50% of the normal dose of the 
fludarabine and cyclophosphamide.  Again, the rituximab dose will not be reduced.   
The reduced dosage must be applied in all consecutive treatment cycles.   
If the retreatment criteria are not met after 4 weeks, the study treatment must be 
permanently discontinued.   
If, after the first dose reduction to 75%, retreatment criteria are not met by day 1 of one 
of the following treatment courses, treatment can be delayed again for up to 2 weeks 
with a following reduction to 50% of fludarabine and cyclophosphamide for subsequent 
cycles.  The rituximab dose will not be reduced.  Further delay is not permitted. 
If the retreatment criteria are not met on day 1 of the subsequent cycles after dose 
reduction to 50%, treatment can be delayed again for up to 2 weeks without further dose 
reduction.  If the event does not resolve after two additional weeks, the study treatment 
has to be discontinued. 
Besides the above described circumstances for permanent discontinuation of standard 
chemo-immunotherapy, it must be performed in the following cases: 
 
CTCAE GRADE 4 infections 
 
Treatment related autoimmune disease 
 
Grade 3 non-hematological toxicity related to study treatment 
 
Patients receiving FCR who discontinue rituximab for rituximab-related toxicity may 
continue to receive FC for the full 6 cycles if deemed to be in the best interest of the 
patient as assessed by the investigator.  Patients who discontinue both FC and rituximab 
are to continue evaluation per protocol as described in Section 4.6.1 and Appendix 3. 
5.1.7 
Dose Modifications of Fludarabine and Cyclophosphamide Due 
to Decreased Renal Function 
Both fludarabine and cyclophosphamide are excreted mainly via the kidneys.  If a 
decrease of renal function occurs during therapy (creatinine clearance 70 mL/min) the 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
110/Protocol CO41685, Version 5 
dose of fludarabine and cyclophosphamide has to be adjusted (Table 12).  A dose 
reduction of fludarabine to 80% and of cyclophosphamide to 75% must be instituted 
when the creatinine clearance is within the range from 30 to 70 mL/min.  If creatinine 
clearance falls to 30 mL/min, FC should be discontinued. 
Table 12 Dose Adjustments for Fludarabine and Cyclophosphamide in 
Renal Impairment 
Creatinine Clearance  
(mL/min) 
Fludarabine 
(mg/m2/day) 
Cyclophosphamide 
(mg/m2/day) 
70 
25 
250 
30-70 
20 
187 (75%) 
30 
No further treatment 
No further treatment 
  
5.1.7.1 
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 13).  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 4.5.12.2).  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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
111/Protocol CO41685, Version 5 
Table 13 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; TLStumor lysis syndrome. 
Note:  The TLS Risk Assessment MUST be made based on measurements of nodal disease burden based 
on radiologic assessments (CT scan or MRI, see Section 4.5.12.2) 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.  Because of possible tumor de-bulking after obinutuzumab 
therapy, investigators will reassess TLS risk after obinutuzumab induction for all patients 
in Arm A 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 will have a 
re-evaluation of their TLS risk category based on their most recent ALC after the 
obinutuzumab run in period and before initiating venetoclax on Cycle 1, Day 22.  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 during the venetoclax ramp-up period.  Only patients who are classified as 
high-risk because they have a lymph node with largest diameter 10 cm will have a 
repeat CT scan after obinutuzumab induction and before starting venetoclax on Cycle 1, 
Day 22.  If the patient’s lymph node size decreases to 10 cm, the investigator may 
follow the management guidelines for the TLS medium-risk category for the venetoclax 
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. 
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.  
A summary of TLS prophylaxis for venetoclax and monitoring measures is presented in 
Table 14. 

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
112/Protocol CO41685, Version 5 
Table 14 Summary of Tumor Lysis Syndrome Prophylaxis for Venetoclax and Monitoring Measures 
TLS Risk 
Category 
Day 1 of 
Dose 
Level 
Prophylaxis Medication 
Hosp. 
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. 
For first dose of 20 mg and 50 mg: hematology and 
chemistry samples will be taken predose and 68 and 
24 hours after dosing. For subsequent ramp-up doses: 
hematology and chemistry will be taken predose. 
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.   
The 68-hour chemistry results must be reviewed before the 
patient leaves the outpatient clinic that day. 
The investigator or subinvestigator must review the 24-hour 
laboratory results prior to dosing on the next day.  
TLS 
medium-risk 
20 and 
50 mg 
Oral uric acid reducer (such as 
allopurinol 300 mg/day) 
beginning at least 72 hours prior 
to dose and continued until the 
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. 
For first dose of 20 mg and 50 mg: hematology and 
chemistry samples will be taken predose and 68 and 
24 hours after dosing. For subsequent ramp-up doses: 
hematology and chemistry will be taken predose.  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 

Table 14 Summary of Tumor Lysis Syndrome Prophylaxis for Venetoclax and Monitoring Measures (cont.)  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
113/Protocol CO41685, Version 5 
TLS Risk 
Category 
Day 1 of 
Dose 
Level 
Prophylaxis Medication 
Hosp. 
Hydration a 
Laboratory Assessments b, e 
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. 
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.   
The 68-hour chemistry results must be reviewed before the 
patient leaves the outpatient clinic that day. 
The investigator or subinvestigator must review the 24-hour 
laboratory results prior to dosing on the next day. 
TLS 
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 mol/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 
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 4, 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. 

Table 14 Summary of Tumor Lysis Syndrome Prophylaxis for Venetoclax and Monitoring Measures (cont.)  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
114/Protocol CO41685, Version 5 
TLS Risk 
Category 
Day 1 of 
Dose 
Level 
Prophylaxis Medication 
Hosp. 
Hydration a 
Laboratory Assessments b, e 
Monitor.  Uric acid levels 
following treatment with 
rasburicase must be analyzed 
using specific guidelines 
described in Section 5.1.7.1.1  
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. 
Hematology and chemistry samples will be taken predose, 
6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. 
The investigator or subinvestigator must review the 24-hour 
laboratory results prior to dosing on the next day. 
 
C  cycle; CrCl  creatinine clearance; D  day; IV  intravenous; Hosp  Hospitalization; 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.  
 

Table 14 Summary of Tumor Lysis Syndrome Prophylaxis for Venetoclax and Monitoring Measures (cont.)  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
115/Protocol CO41685, Version 5 
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. 
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50 mL/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 12.  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; 200 mg → 100 mg; 100 mg → 50 mg; 
50 mg → 20 mg). 
 

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
116/Protocol CO41685, Version 5 
5.1.7.1.1 
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.  If possible, 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.  

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
117/Protocol CO41685, Version 5 
Serum chemistry, hematology, and vital signs will be obtained prior to administering 
venetoclax (predose) and 6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.   
The 6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 mg 
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 TLS High Risk section below for details of hospitalization, 
hydration, laboratory, and so forth). 
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 6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.   

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
118/Protocol CO41685, Version 5 
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient 
clinic that day.  Furthermore, the investigator or subinvestigator must review the 24-hour 
laboratory results prior to dosing on the next day.   
Additional laboratory assessments may be performed per investigator discretion. 
TLS High Risk 
High-risk patients will be hospitalized to receive their initial doses of 20 mg 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 mol/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 below.  
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 4, 8, 12, and 24 hours after dosing.  These samples are to 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
119/Protocol CO41685, Version 5 
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 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 postdose 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. 
5.1.7.1.2 
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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
120/Protocol CO41685, Version 5 
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. 
 
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).  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.   
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).  Laboratory samples should be sent and analyzed immediately.   
Pre-dose 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 pre-dose, 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.   

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
121/Protocol CO41685, Version 5 
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 (pre-dose, defined as up to 
4 hours before venetoclax dose) and 6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 6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 6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.   

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
122/Protocol CO41685, Version 5 
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 6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 12, 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, the following apply: 
 
Hospitalized patients should receive TLS prophylaxis as described above for initial 
venetoclax dosing.  Per institutional standards, nephrology (or acute dialysis 
service) can be consulted/contacted on admission 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. 
 
5.1.7.2 
Prophylaxis for Infections 
If clinically indicated, anti-infective prophylaxis for viral, fungal, bacterial, or 
Pneumocystis infections is permitted.  Although there is a potential for DDI, 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 DDI. 
5.1.7.3 
Prophylaxis for Infusion-Related Reactions 
The rate of infusion of obinutuzumab or rituximab may need to be slowed for those 
patients that experience infusion reactions, and medications to treat IRRs (including 
epinephrine for subcutaneous injections, corticosteroids, and diphenhydramine for IV 
injection) and resuscitation equipment should be available for immediate use during 
dosing. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
123/Protocol CO41685, Version 5 
5.1.7.4 
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 or rituximab should be discontinued 
and no additional obinutuzumab or rituximab should be administered.  Patients who 
experience any of these reactions should receive aggressive symptomatic treatment and 
will be discontinued  
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, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting 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 subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 
and Section 5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
124/Protocol CO41685, Version 5 
 
Is 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) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a 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; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the 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 
are as follows: 
 
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 
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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
125/Protocol CO41685, Version 5 
 
TLS of any grade, irrespective of causality 
 
Second primary malignancies  
 
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 Section 5.4Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (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 will be reported until 28 days after the 
final dose of study drug, or until initiation of another anti-cancer therapy, whichever 
occurs first.  Related serious adverse events, all second primary malignancies 
irrespective of causality, and SARS-CoV-2 infection irrespective of causality will be 
reported indefinitely (Section 5.6).   
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of nondirective 
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 (v5.0) will be used for 
assessing adverse event severity.  Table 15 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
126/Protocol CO41685, Version 5 
Table 15 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 
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
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 in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
  
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether 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 (see also 
Table 16): 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of 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 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
127/Protocol CO41685, Version 5 
Table 16 Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon rechallenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
  
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 considered to be IRRs that occur during or within 24 hours after 
obinutuzumab, cyclophosphamide, fludarabine, rituximab, or bendamustine 
administration and are judged to be related to obinutuzumab, cyclophosphamide, 
fludarabine, rituximab, or bendamustine infusion should be captured as a diagnosis 
(e.g., infusion-related reaction) on the Adverse Event eCRF.  If possible, avoid 
ambiguous terms such as "systemic reaction."  Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient experiences 
both a local and systemic reaction to the same dose of study drug, each reaction should 
be recorded separately on the Adverse Event eCRF, with signs and symptoms also 
recorded separately on the dedicated Infusion-Related Reaction 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 event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
128/Protocol CO41685, Version 5 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
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. 
 
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 or grade) 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 severity 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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
129/Protocol CO41685, Version 5 
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: 
 
Is 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 
 
Is clinically significant in the investigator's judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
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 whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
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: 
 
Is 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 
 
Is clinically significant in the investigator's judgment  
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
130/Protocol CO41685, Version 5 
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 only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
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 (as 
defined by Hy's Law).  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 5.3.5.5) 
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 on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the adverse 
event reporting period, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
131/Protocol CO41685, Version 5 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Pre-existing Medical Conditions 
A pre-existing 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. 
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.  In most cases, the expected pattern of progression will be based on iwCLL criteria.  
In rare cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through 
use of objective criteria.  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., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or 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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
132/Protocol CO41685, Version 5 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
 Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm} 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Special situations are not in themselves adverse events but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For venetoclax, obinutuzumab, and rituximab, adverse events 
associated with special situations should be recorded as described below for each 
situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
133/Protocol CO41685, Version 5 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with venetoclax, obinutuzumab, and 
rituximab, regardless of whether they result in an adverse event, should be recorded on 
the Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
134/Protocol CO41685, Version 5 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor.  In addition, 
the Sponsor will make no attempt to reconcile patient reports of treatment-related 
symptoms with investigator reports of adverse events.  Sites are not expected to review 
the PRO data for adverse events. 
5.3.5.14 
Safety Biomarker Data  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
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 (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information 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 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
135/Protocol CO41685, Version 5 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, access to Medical Monitors is available 24 hours 
per day, 7 days per week.  An Emergency Medical Call Center will also be available 24 
hours per day, 7 days per week.  The Emergency Medical Call Center will connect the 
investigator with an Emergency Medical Contact, provide medical translation service if 
necessary, and track all calls.  Contact information, including toll-free numbers for the 
Emergency Medical Call Center, will be distributed to investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
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.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study drug or until initiation of 
another anti-cancer therapy, whichever occurs first.  Related serious adverse events and 
all second primary malignancies irrespective of causality will be reported indefinitely 
(Section 5.6).  
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 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting serious adverse events that occur 28 days after the final dose 
of study treatment are provided in Section 5.6. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
136/Protocol CO41685, Version 5 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 30 days after the final dose of venetoclax (or within 18 months of the final dose of 
obinutuzumab) for patients in Arm A, and within 6 months of the final dose of 
bendamustine, fludarabine or cyclophosphamide (or within 12 months of the final dose of 
rituximab) for patients in Arm B, whichever is later.  A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  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.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.   
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
90 days after the final dose of venetoclax (or within 18 months of the final dose of 
obinutuzumab) for patients in Arm A, and within 6 months of the final dose of 
bendamustine, fludarabine or cyclophosphamide (or within 12 months of the final dose of 
rituximab) for patients in Arm B, whichever is later.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  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.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form with additional 
information on the pregnant partner and the course and outcome of the pregnancy as it 
becomes available.  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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
137/Protocol CO41685, Version 5 
5.4.3.3 
Abortions 
A spontaneous 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; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity 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).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
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. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, 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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
138/Protocol CO41685, Version 5 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the adverse event reporting period (defined as 28 days after the final 
dose of study drug or until initiation of another anti-cancer therapy, whichever occurs 
first), all deaths, regardless of cause, should be reported through use of the Long-Term 
Survival Follow-Up eCRF. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.  Investigators should also report all second primary 
malignancies and SARS-CoV-2 infections irrespective of whether they are believed to be 
related to previous study treatment or not, indefinitely.  A serious, non-drug-related 
adverse event, such as a serious SARS-CoV-2 infection that occurs after the adverse 
event reporting period does not need to be reported to the Sponsor within 24 hours of 
the investigator becoming aware of it.  However, the site should endeavor to add this 
information to the eCRF in a timely manner.  If the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to 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 adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, Ethics Committees 
(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 through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Venetoclax 
Venetoclax Investigator's Brochure  
Obinutuzumab 
Obinutuzumab Investigator's Brochure 
Fludarabine 
Fludarabine UK Summary of Product Characteristics 
Cyclophosphamide 
Cyclophosphamide UK Summary of Product Characteristics 
Rituximab 
Rituximab Investigator’s Brochure 
Bendamustine 
Bendamustine UK Summary of Product Characteristics 
 
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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
139/Protocol CO41685, Version 5 
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 17.  
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. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size for the primary MRD analysis is determined based on the hypothesis to 
be tested to establish clinically relevant statistical superiority in the MRD response rate.  
To detect an improvement in MRD response rate at a two-sided significance level of 
0.05, approximately 165 patients are required at the MRD primary analysis to achieve 
a power of 92% assuming a target improvement in MRD response rate of 30%.  The 
minimum detectable difference of MRD response rate is 14.1%.  
The primary MRD analysis is expected to occur approximately 46 months after the 
first-patient in. 
The calculation of sample size and estimates of the MRD analysis timelines are based 
on the following assumptions, which are based on the completed enrollment: 
 
Patients will be randomized to FCR/BR and VEN   G arms in a 1:1 ratio 
 
Two-sample test for proportions at the two-sided 0.05 level of significance 
 
MRD response rate for FCR/BR arm at Month 15 (52%) 
 
FCR/BR ratio in the control arm is 55/45 
 
90% power to detect difference in MRD response rate of 30% (response rate of 
82% for VEN+G arm) at Month 15 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
140/Protocol CO41685, Version 5 
 
Proportion of patients with non-evaluable MRD including samples which cannot be 
assayed and patients who have died or discontinued the study prior to Month 15 
MRD assessment (15%) 
 
Misclassification rate for MRD status assessed by clonoSEQ NGS assay 
 
The sample size calculation was performed using rpact package in R version 4.0.3. 
6.2 
ANALYSIS TIMING 
A number of factors may affect the timing of the primary efficacy MRD analysis 
specifically the recruitment rate, since the primary efficacy analysis is triggered when the 
last patient has reached the 15‑month MRD assessment the MRD primary analysis will 
occur when approximately 165 patients randomized in the study have reached the 
15‑month MRD assessment at approximately 46 months after the first patient is 
randomized in the study.  At the time of MRD primary analysis, a first interim analysis 
for PFS will be conducted and approximately 25 (57% information fraction) events are 
expected.  In the event the expected number of PFS events are reached before or after 
the time of MRD analysis, interim PFS analysis will be conducted at the time of MRD 
analysis regardless of the achievement of the planned number of events.  In this 
scenario, the information fraction along with the stopping boundaries will be 
re-evaluated on the basis of the number of events reached at that time.   
A second interim analysis for PFS will be conducted when 33 events (75% information 
fraction) will be reached. 
The final PFS analysis will take place when 44 events will have occurred. 
6.3 
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.  Median length of follow-up will be estimated overall 
and by-treatment in all randomized patients using the reverse Kaplan Meier (K-M) 
method. 
6.4 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, and 
baseline ECOG Performance Status, previous and concurrent medical history and 
medications will be summarized by treatment arm in all randomized patients. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
141/Protocol CO41685, Version 5 
6.5 
EFFICACY ANALYSES 
6.5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is MRD response rate (determined as the proportion of 
patients with MRD-negativity defined as 1 CLL cell in 10,000 leukocytes) measured in 
PB using NGS at Month 15.   
The primary objective of the study is to test the following hypothesis: 
 
MRD response rate of VEN  G versus FCR/BR 
(i.e., H0:  VEN  G – FCR/BR  pre-specified difference versus H1: VEN  G – 
FCR/BR ≠ pre-specified difference 
 
MRD response rate of the 2 arms will be compared based on Cochran-Mantel-Haenszel 
(CMH) test stratified by IGHV mutation status, Binet stage and age.  If the null 
hypothesis of no difference in MRD response rate is rejected and the observed MRD 
response rate is favorable for the VEN  G experimental arm, then it is concluded that 
VEN  G significantly increases the chance to respond compared to FCR/BR.  Difference 
in MRD response rate will be estimated and two-sided 95% Anderson-Hauck CI will be 
provided.  Within each arm, 2-sided 95% Clopper-Pearson exact CIs will also be 
presented. 
6.5.1.1 
Target of Estimation for the Primary Efficacy Endpoint 
To provide clarity on the target of estimation, the five attributes in the estimand 
framework are defined below. 
Population:  Defined as all randomized patients, analyzed by randomized treatment 
group.  FIT patients with previously untreated CLL without del(17p) or TP53 mutation 
requiring treatment.  Inclusion and exclusion criteria have been described in details in 
Section 4.1.1 and Section 4.1.2.  
Variable:  MRD response (defined as a patient with MRD-negativity 1 CLL cell in 
10,000 leukocytes) measured in PB using NGS at Month 15.  Patients with missing MRD 
assessment at Month 15 will be considered non-responders. 
Treatment:  Patients will be randomized to either Arm A (venetoclax+obinutuzumab) or 
Arm B (FCR or BR).  During the conduct of the study patients may also receive 
concomitant medications as detailed in Section 4.4. 
Intercurrent event:  The intercurrent events which will be identified in this study are as 
follows.  
 
Exposure to new anti-CLL treatment   
 
Discontinuation of treatment due to any reason (except PD) 
 
Death  
 
Missing/Non-evaluable MRD sample 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
142/Protocol CO41685, Version 5 
 
Discontinuation from the study due to other reasons 
 
In case of missing data due to death, non-evaluable MRD sample, or for any other 
reason, a composite strategy is planned.  This means that a patient with a missing MRD 
value in PB at Month 15 will be considered a non-responder.  In case of exposure to new 
anti-CLL treatment prior to Month 15, the patient will be considered as a non-responder 
regardless of the availability of MRD data at Month 15.  Discontinuation of treatment due 
to any reason (except PD), if a Month 15 MRD result is obtained a treatment-policy 
strategy is planned.  This means that observed MRD value in PB at Month 15 will be 
used ignoring the intercurrent event.  However, supplementary analyses will be 
performed in these cases to determine the robustness of the primary analysis.   
Population-level summary for the variable:  Difference in the proportion of patients 
achieving MRD response in the 2 arms. 
6.5.2 
Secondary Efficacy Endpoints 
The primary MRD analysis will be supported by further secondary endpoints including 
the following: 
 
PFS, defined as the time from randomization to the first occurrence of disease 
progression, or death from any cause; disease progression assessed by the 
investigators using iwCLL criteria (Hallek et al. 2018).  
 
MRD response rate, in PB at end of treatment response visit (812 weeks after last 
dose of FCR/BR (~9 months) vs. 8-12 weeks after last dose of VEN  G 
(~15 months).  
 
MRD response rate in BM at end of treatment response visit (9 months FCR/BR vs. 
15 months VEN  G).  
 
ORR which includes CR, CRi, and PR at Month 15 assessment. 
 
Complete response (CR) rate which includes CR and CRi at Month 15 assessment. 
 
MRD response rate in PB in patients with a CR/CRi at Month 15. 
 
MRD response rate in BM in patients with a CR/CRi at end of treatment visit 
(812 weeks after last dose of FCR/BR (~9 months) vs. 8-12 weeks after last dose 
of VEN  G (~15 months) 
 
DOR, defined as the time from the first response to the time of PD or death from any 
cause, whichever comes first. 
 
Best response achieved (CR, CRi, PR, SD, or PD) up to and including the 
assessment at Month 15. 
 
EFS, defined as the time between date of randomization and the date of disease 
progression/relapse, death, or start of a new anti-leukemic therapy. 
 
OS, defined as the time between the date of randomization and the date of death 
due to any cause.  Patients who are alive (including lost to follow-up) at the time of 
the analysis will be censored at the date when they were last known to be alive. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
143/Protocol CO41685, Version 5 
 
TLS risk reduction rate in Arm A, defined as the reduction in the proportion of 
patients who were TLS high-risk after 3 doses of obinutuzumab compared to the 
proportion of patients who were TLS high-risk at baseline. 
 
Reduction in mandatory hospitalizations during venetoclax ramp-up in Arm A 
patients, defined as the actual number of protocol‑mandated hospitalizations for 
TLS monitoring during venetoclax ramp-up period after 3 doses of obinutuzumab 
compared to the number of protocol‑mandated hospitalizations for TLS monitoring 
during venetoclax ramp-up expected at baseline. 
 
Hypotheses for response endpoints will be evaluated using CMH test and hypotheses 
for time-to-event endpoints will be evaluated using stratified log-rank test. 
The following key secondary endpoints will be formally tested. 
 
PFS 
 
MRD response rate in PB at end of treatment visit 
 
MRD response rate in BM at end of treatment visit  
 
The hierarchical ordering of selected secondary endpoints will be confirmed in the 
Statistical Analysis Plan (SAP). 
6.5.3 
Type-1 Error Control 
Multiple endpoints and multiple decision timepoints have been proposed for this study.  
To establish a valid claim of efficacy it is important to control the overall type-1 error rate 
at a pre-specified level.  In this study we propose hierarchical testing for the three key 
secondary endpoints (i.e., a hypothesis can only be tested if the previous hypothesis is 
rejected).  For each endpoint an overall   0.05 will be used for testing.  Obrien-Fleming 
alpha spending function will be used for PFS to determine the boundary at the time of 
MRD primary analysis (i.e., which corresponds to the time of the first PFS interim 
analysis), at the second PFS interim analysis, and at the final PFS analysis. 
6.5.4 
Supplementary Analyses 
To check the robustness of the primary MRD analysis and underlying assumptions, the 
following supplementary analyses for MRD will be performed on the ITT population: 
 
To assess the impact of intercurrent events (exposure to a new anti-CLL treatment, 
discontinuation of treatment due to adverse event, or due to lack of efficacy) on 
MRD status in PB at Month 15, an analysis of MRD will be performed considering 
patients with intercurrent events as non-responders. 
 
To assess the impact of missing data on primary MRD analysis, for patients who 
discontinued the treatment and Month 15 assessment is missing their last 
non-missing MRD response will be carried forward and used as the response at 
Month 15. 
 
To assess the impact of missing data on primary MRD analysis, for patients who are 
missing the Month 15 assessment but have an available non-missing assessment 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
144/Protocol CO41685, Version 5 
thereafter, the subsequent available MRD response closest to Month 15 will be used 
as the response at Month 15. 
 
To address potential discrepancies between PB and BM results, proportion of 
patients achieving MRD negativity in both PB and BM will be compared at Month 9 
for FCR/BR and Month 15 for VEN  G. 
 
6.6 
SAFETY ANALYSES 
Safety endpoints include adverse events, serious adverse events, and adverse events of 
special interest.  Safety analyses will be based on safety population which is defined as 
all patients who received at least one dose of any study medication. 
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.   
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. 
6.6.1 
Patient-Reported Outcome Analyses 
The secondary PRO endpoints for the study are as follows: 
 
Change in disease and treatment-related symptoms following treatment with the 
combination of VEN  G compared with FCR/BR in patients with previously with 
previously untreated CLL without del(17p) or TP53 mutation as measured by 
MDASI-CLL. 
 
Change in physical functioning, role functioning and health-related quality of life 
(HRQoL) following treatment with the combination of VEN  G compared with 
FCR/BR in patients with previously with previously untreated CLL without del(17p) 
or TP53 mutation as measured by EORTC QLQ-C3.  
 
The analysis of all other scales will be considered exploratory. 
Repeated-measures for mixed-model analyses will be used to compare changes from 
baseline between the arms. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
145/Protocol CO41685, Version 5 
Scoring for the MDASI-CLL and EORTC QLQ-C30 questionnaires (Appendix 5 and 
Appendix 6) 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 PROs will be provided in the SAP. 
6.6.2 
Health Economic Analyses 
Health economics data, as assessed by the EQ-5D-5L, will be evaluated for patients 
with a baseline assessment and at least one post-baseline EQ-5D-5L 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. 
6.7 
EXPLORATORY ANALYSES 
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 analysis): 
 
Subgroup analyses of primary and key secondary endpoints including, but not 
limited to, baseline characteristics, stratification factors, FCR only patients, and BR 
only patients. 
 
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. 
 
Durability of MRD-negativity (at 10-4) over time in PB measured by NGS  
 
Relationship between MRD at EOT assessment and PFS on the basis of PB assessed 
using NGS. 
Exploratory analyses of MRD negativity by timepoint will also be performed with MRD 
negativity defined using a cutoff of 10-4 (less than 1 CLL cell in 10,000 leukocytes) and 
secondly by additional cutoffs (10-5, and 10-6) within the limit of sensitivity of the 
technology. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
146/Protocol CO41685, Version 5 
6.8 
INTERIM ANALYSIS 
6.8.1 
Planned Interim Analysis 
Two planned interim efficacy analyses will be conducted for PFS as detailed in 
Section 7.2 .  The first interim analysis for PFS will be conducted at the time of MRD 
primary analysis and the second interim analysis will be performed at the occurrence of 
33 PFS events.  PFS will be tested at the significance level determined using the 
O’Brien-Fleming error spending function so that the overall two-sided type I error rate for 
each endpoint will be maintained at the 0.05 level.  Detailed decision rules will be 
reported in the SAP. 
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 
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 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. 
PRO data will be collected through the use of an electronic device provided by a vendor 
(see Section 7.3 for details). 
Back up PRO data can be collected on a web‑based system.  The use of this electronic 
back up allows for completion of all questionnaires on a web portal.  This web backup 
is to be used only when the electronic device (tablet) is not functioning as expected.  For 
information on how to activate the web back up, please refer to the eCOA quick 
reference guide provided by the vendor.  

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
147/Protocol CO41685, Version 5 
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 that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
An electronic device will be used to capture PRO data.  The device is designed for entry 
of data in a way that is attributable, secure, and accurate, in compliance with U.S. FDA 
regulations for electronic records (21 CFR Part 11).  The data will be transmitted to a 
centralized database maintained by the electronic device vendor. 
The electronic data will be available for view access only, via a secure web server.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review 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, PROs, 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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
148/Protocol CO41685, Version 5 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification and review, 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. 
7.5 
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. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 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. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
149/Protocol CO41685, Version 5 
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 applicable 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 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trials Directive (2001/20/EC) 
or Clinical Trials Regulation (536/2014) and applicable local, regional, and national 
laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing 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. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  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. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
150/Protocol CO41685, Version 5 
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  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. 
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 (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7). 
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 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
151/Protocol CO41685, Version 5 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
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. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6). 
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 (see definition of end of 
study in Section 3.2). 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
152/Protocol CO41685, Version 5 
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.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan. 
9.4 
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. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
153/Protocol CO41685, Version 5 
Approximately 40 sites globally will participate to enroll approximately 165 patients.  
Enrollment will occur through an IxRS.   
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and/or summaries of clinical study results may be 
available in health authority databases for public access, as required by local regulation, 
and will be made available upon request, provided the requirements of Roche's global 
policy on data sharing have been met.  For more information, refer to the Roche Global 
Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
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 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
154/Protocol CO41685, Version 5 
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. 
9.7 
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). 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
155/Protocol CO41685, Version 5 
10. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85:36576. 
Abrisqueta P, Pereira A, Rozman C, et al.  Improving survival in patients with chronic 
lymphocytic leukemia (1980-2008):  the Hospital Clinic of Barcelona experience.  
Blood. 2009;114(10):204450. 
Barr PM, Robak T, Owen C, et al. Sustained efficacy and detailed clinical follow-up of 
first-line ibrutinib teatment in older patients with chronic lymphocytic leukemia: 
extended Phase 3 results from RESONATE-2. Haematologica 
2018;103(9):150210. 
Binet JL, Leporrier M, Dighiero G, et al. A clinical staging system for chronic lymphocytic 
leukemia: prognostic significance. Cancer 1977;40:85564. 
Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic 
lymphocytic leukemia derived from a multivariate survival analysis. Cancer 
1981;48:198-206. 
Böttcher S, Hallek M, Ritgen M, et al. The role of minimal residual disease 
measurements in the therapy for CLL is it ready for prime time? Hematol Oncol 
Clin N Am 2013;27:26788. 
Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an 
independent predictor of progression-free and overall survival in chronic 
lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 
trial. J Clin Oncol 2012;30:9808. 
Brooks R. EuroQol: the current state of play. Health Policy 1996;37:5372. 
Calabrese LH, Molloy ES, Huang D, Ransohoff RM. Progressive multifocal 
leukoencephalopathy in rheumatic diseases: evolving clinical and pathologic 
patterns of disease. Arthritis Rheum. 2007;56(7):2116-28. 
Carson KR, Bennett CL. Rituximab and progressive multi-focal leukoencephalopathy: 
the jury is deliberating. Leuk Lymphoma. 2009;50(3):323-4. 
Cheson BD, Wendtner CM, Pieper A, Dreyling M, Friedberg J, Hoelzer D, Moreau P, 
Gribben J, Knop S, Montillo M, Rummel M. Optimal use of bendamustine in 
chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: 
treatment recommendations from an international consensus panel. Clinical 
Lymphoma Myeloma and Leukemia. 2010;10(1):21-7. 
Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting 
BCL2. Proc Natl Acad Sci U S A 2005;102:139449. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
156/Protocol CO41685, Version 5 
Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic 
lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining 
sensitivity to BCL2 antagonist ABT-737. J Clin Invest 2007;117:112-121 
Dimier N, Delmar P, Ward C, et al. A model for predicting effect of treatment on 
progression-free survival using MRD as surrogate end point in CLL. 
Blood 2018;131:955-962. 
Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic 
lymphocytic leukemia. N Engl J Med 2000;343:19106. 
Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, 
Busch R, Ritgen M, Bunjes D. TP53, SF3B1, and NOTCH1 mutations and 
outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up 
of the GCLLSG CLL3X trial. Blood. 2013;121(16):3284-8. 
Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine 
and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients 
with advanced chronic lymphocytic leukaemia (CLL10): an international, 
open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 
2016;17(7):928-42. 
EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199208. 
Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or 
refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, 
single-arm trial. Lancet Oncol 2015;16(2):16976. 
Fayers PM, Aaronson NK, Bjordal K, Curran D, Grønvold M. EORTC QLQ-C30 scoring 
manual. Eortc; 1999. 
Fink AM, Böttcher S, Ritgen M, Fischer K, Pflug N, Eichhorst B, et al. Prediction of poor 
outcome in CLL patients following first-line treatment with fludarabine, 
cyclophosphamide and rituximab. Leukemia. 2013;27(9):1949. 
Fesik SW. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev 
Cancer. 2005;5(11):87685. 
Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients 
with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase 
II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 
2011;29:355966. 
Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for 
previously untreated patients with chronic lymphocytic leukemia: a multicenter 
phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin 
Oncol 2012;30:320916. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
157/Protocol CO41685, Version 5 
Fitzsimmons D, Johnson CD, George S, et al. Development of a disease specific quality 
of life (QoL) questionnaire module to supplement the EORTC core cancer QoL 
questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study 
Group on Quality of Life. Eur J Cancer 1999;35:93941.  
Flinn IW, Gribben JG, Dyer MJ, et al. Phase 1b study of venetoclax-obinutuzumab in 
previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood. 
2019;133(26):2765-75. 
Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with 
CLL and coexisting conditions. N Engl J Med 2014;370:110110. 
Goldberg SL, Pecora AL, Alter RS, Kroll MS, Rowley SD, Waintraub SE, Imrit K, Preti 
RA. Unusual viral infections (progressive multifocal leukoencephalopathy and 
cytomegalovirus disease) after high-dose chemotherapy with autologous blood 
stem cell rescue and peritransplantation rituximab. Blood. 2002;99(4):1486-8. 
Gribben JG. Salvage therapy for CLL and the role of stem cell transplantation. 
Hematology Am Soc Hematol Educ Program 2005:292–8. 
Hallek M, Cheson BD, Catovs.ky D, et al. Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 
1996 guidelines. Blood 2008;111:544656. 
Hallek M, Cheson BD, Catovsky D, et al.. iwCLL guidelines for diagnosis, indications for 
treatment, response assessment, and supportive management of CLL. Blood. 
2018;131:274560. 
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and 
cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, 
open-label, Phase 3 trial. Lancet 2010;376:116474. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ5D-5L). Qual-Life Res 2011;20:172736. 
Hilal T, Gea-Banacloche JC, Leis JF. Chronic lymphocytic leukemia and infection risk in 
the era of targeted therapies: linking mechanisms with infections. Blood reviews. 
2018;32(5):387-99. 
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. New England Journal of 
Medicine. 2011;364(19):1844-54. 
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ5D3L across eight patient groups: a multi-country study. Qual 
Life Res 2013;22:171727. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
158/Protocol CO41685, Version 5 
Kater AP, Seymour JF, Hillmen P, et al. Fixed duration of venetoclax-rituximab in 
relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual 
disease and prolongs survival: post-treatment follow-up of the MURANO Phase III 
study. J Clin Oncol. 2018;37(4):269-77. 
Kovacs G, Robrecht S, Fink AM, et al. Minimal residual disease assessment improves 
prediction of outcome in patients with chronic lymphocytic leukemia (CLL) who 
achieve partial response: comprehensive analysis of two phase III studies of the 
German CLL study group. J Clin Oncol 2016;34(31):375865. 
Kwok M, Rawstron A, Varghese A, et al. Minimal residual disease is an independent 
predictor for 10-year progression-free and overall survival in CLL. 
Blood 2016;128:27703. 
Marcos-Gragera R, Allemani C, Tereanu C, et al.  Survival of European patients 
diagnosed with lymphoid neoplasms in 2000-2002:  results of the HAEMACARE 
project.  Haematologica.  2011;96(5):720-8. 
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. 
Mérino D, Bouillet P. The Bcl-2 family in autoimmune and degenerative disorders. 
Apoptosis. 2009 Apr;14:570−83. 
Moreton P, Kennedy B, Lucas G, et al: Eradication of minimal residual disease in B-cell 
chronic lymphocytic leukemia after alemtuzumab therapy is associated with 
prolonged survival. J Clin Oncol 2005;23:2971-9. 
NIH National Cancer Institute. SEER Stats Fact Sheets: Chronic Lymphocytic Leukemia. 
Available from: http://seer.cancer.gov/statfacts/html/clyl.html 
Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. 
Blood 1975;46:21934. 
Rawstron AC, Villamor N, Ritgen N, et al. International standardized approach for flow 
cytometric residual disease monitoring in chronic lymphocytic leukaemia. 
Leukemia 2007;21:95664. 
Rawstron AC, Bottcher S, Letestu R, et al. Improving efficiency and sensitivity: European 
Research Initiative in CLL (ERIC) update on the international harmonised 
approach for flow cytometric residual disease monitoring in CLL. Leukemia 
2013;27(1):1429. 
Rawstron AC, Cohen D, de Tute R, et al. The level of residual CLL at assessment of 
response and in follow-up objectively predicts the outcome of patients following 
FCR-based therapy: 1% residual disease in the marrow 3 months post-treatment 
predicts early relapse and poor survival. XVI International Workshop on Chronic 
Lymphocytic Leukemia. 2015. Abstract 154. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
159/Protocol CO41685, Version 5 
Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed 
Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374:31122. 
Robertson LE, Plunkett W, McConnell K, Keating MJ, McDonnell TJ. Bcl-2 expression in 
chronic lymphocytic leukemia and its correlation with the induction of apoptosis 
and clinical outcome. Leukemia 1996;10:4569 
Santacruz R, Villamor N, Aymerich M, et al. The prognostic impact of minimal residual 
disease in patients with chronic lymphocytic leukemia requiring first-line therapy. 
Haematologica. 2014;99:873-80. 
Schnaiter A, Paschka P, Rossi M, Zenz T, Bühler A, Winkler D, Cazzola M, Döhner K, 
Edelmann J, Mertens D, Kless S. NOTCH1, SF3B1, and TP53 mutations in 
fludarabine-refractory CLL patients treated with alemtuzumab: results from the 
CLL2H trial of the GCLLSG. Blood. 2013;122(7):1266-70. 
Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or Refractory 
chronic lymphocytic leukemia. N Engl J Med. 2018;378:110720. 
Seymour JF, Shuo M, Brander DM, et al. Venetoclax plus rituximab in relapsed or 
refractory chronic lymphocytic leukaemia: a Phase 1b study. Lancet 
2017;18:230-40. 
Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib–Rituximab or Chemoimmunotherapy for 
Chronic Lymphocytic Leukemia. N Engl J Med. 2019;381(5):43243. 
Smith T, Khatcheressian J, Lyman G, et al. 2006 update of recommendations for the use 
of white blood cell growth factors: an evidence-based clinical practice guideline. J 
Clin Oncol 2006;24(19):3187-205. 
Souers AJ, Leverson JD, Boghaert ER et al. ABT-199, a potent and selective Bcl-2 
inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 
2013;19:2028.  
Stilgenbauer S, Eichhorst B, Schetelig J, Hillmen P, Seymour JF, Coutre S, et al.  
Venetoclax for patients with chronic lyhpmocytic leukemia with 17p deletion:  
results from the full population of a Phase II pivotal trial. J Clin Oncol. 
2018;36(19):1973-80. 
Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Döhner K, et al. Gene 
mutations and treatment outcome in chronic lymphocytic leukemia: results from the 
CLL8 trial. Blood. 2014;123(21):3247-54. 
Stilgenbauer S, Zenz T. Understanding and managing ultra-high risk chronic lymphocytic 
leukemia. Hematology Am Soc Hemat Educ Program 2010;4818. 
Touzeau C, Dousset C, Le Gouill S, Sampath D, Leverson JD, Souers AJ, Maiga S, 
Bene MC, Moreau P, Pellat-Deceunynck C, Amiot M. The Bcl-2 specific BH3 
mimetic ABT-199: a promising targeted therapy for t (11; 14) multiple myeloma. 
Leukemia. 2014;28(1):210. 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
160/Protocol CO41685, Version 5 
Vandenberg CJ, Cory S. ABT-199, a new Bcl-2–specific BH3 mimetic, has in vivo 
efficacy against aggressive Myc-driven mouse lymphomas without provoking 
thrombocytopenia. Blood. 2013;121(12):22858. 
Zenz T, Häbe S, Denzel T, Mohr J, Winkler D, Bühler A, et al. Detailed analysis of p53 
pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): 
dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, 
and miR34a in a prospective clinical trial. Blood. 2009;114(13):2589-97. 
Zenz T, Krober A, Scherer K, et al. Monoallelic TP53 inactivation is associated with poor 
prognosis in chronic lymphocytic leukemia: results from a detailed genetic 
characterization with long-term follow-up. Blood 2008;112:3322-9. 
Zenz T, Mertens D, Kuppers R, et al. From pathogenesis to treatment of chronic 
lymphocytic leukemia. Nat Rev Cancer 2010;10(1):3750. 
 

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
161/Protocol CO41685, Version 5 
Appendix 1 
Schedule of Activities for Arm A 
Arm A:  RAMP-UP to 400 mg of Venetoclax 
Arm A (VEN  G) 
Assessments 
Screening 
Cycle 1 
Cycle 2 
Day (VEN dose) 
28 to 
1 
1 a 
2 
3b 
8 
15 1621 
22 
(20 mg) 23 
1 
(50 mg) 
2 
8 
(100 mg) 
9 
15 
(200 mg) 
16 
22 
(400 mg) 23 
Informed consent c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLS laboratory-based risk 
assessment d 
x 
 
 
 
 
 
x e 
 
 
 
 
 
 
 
 
 
 
TLS Monitoring d 
 
x 
x 
(x) 
 
 
 
x 
x 
x f 
x 
x 
x 
x 
x 
x 
x 
General medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CIRS score 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs g 
x 
x 
x 
(x) 
x 
x 
 
x 
x 
x 
 
x 
 
x 
 
x 
 
Weight 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical staging h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphadenopathy (during 
physical examination/ 
Binet staging at screening) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver/spleen (by physical 
examination) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 12 lead 
x 
As clinically indicated 
LVEF 
x 
As clinically indicated 
ECOG Performance Status 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
162/Protocol CO41685, Version 5 
Arm A (VEN  G) 
Assessments 
Screening 
Cycle 1 
Cycle 2 
Day (VEN dose) 
28 to 
1 
1 a 
2 
3b 
8 
15 1621 
22 
(20 mg) 23 
1 
(50 mg) 
2 
8 
(100 mg) 
9 
15 
(200 mg) 
16 
22 
(400 mg) 23 
B-symptoms 
(see Section 4.5.12.3) 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
CT scan assessment i 
x 
 
 
 
 
 
x e 
 
 
 
 
 
 
 
 
 
 
BM biopsy/aspirate j 
(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 
Obinutuzumabk 
 
x 
(x) 
 
x 
x 
 
 
 
x 
 
 
 
 
 
 
 
Venetoclax 
 
 
 
 
 
 
 
Daily, as per dosing chart schedule (20, 50, 100, 200, 400 mg) starting C1D22 
Adverse events c 
x 
x 
x 
(x) 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
(x) 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PRO questionnaires 
(MDASI-CLL, EQ-5D-5L, and 
EORTC-QLQ C30) l 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Local Laboratory m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IGHV n 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulins 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV, HCV, HIV, HTLV1  
(if applicable) o 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coombs test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation (INR OR PT, AND 
aPTT or PTT) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test p 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Urinalysis q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology r 
x 
x 
x 
(x) 
x 
x 
x e 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry s 
x 
x 
x 
(x) 
x 
x 
x e 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
163/Protocol CO41685, Version 5 
Arm A (VEN  G) 
Assessments 
Screening 
Cycle 1 
Cycle 2 
Day (VEN dose) 
28 to 
1 
1 a 
2 
3b 
8 
15 1621 
22 
(20 mg) 23 
1 
(50 mg) 
2 
8 
(100 mg) 
9 
15 
(200 mg) 
16 
22 
(400 mg) 23 
Central Laboratory m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum parameters (2 
microglobulin,) 
 
x a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for CLL 
Prognostic factors (including 
IGHV, 17p, TP53) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for genetic analysis 
(genetic complexity, gene 
mutations and resistance 
markers) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for lymphocyte counts/ 
immunophenotyping (B-CLL 
count, B-cell, T-cell and NK cell 
markers) by flow cytometry 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD in PB by NGS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD in PB by ASO-PCR 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ctDNA sample 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALC  absolute lymphocyte count; ASO-PCR  allele-specific oligonucleotide polymerase chain reaction; BM  bone marrow; C  Cycle; 
CIRS  cumulative illness rating scale; CLL  chronic lymphocytic leukemia; CR  complete remission; CT  computed tomography; D  Day; 
ECOG  Eastern Cooperative Oncology Group; EORTC-QLQ-C30  European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30; EQ-5D-5L  EuroQol 5-Dimension Questionnaire, 5-level version; HBV  hepatitis B virus; HCV  hepatitis C virus; 
HTLV1  human T-cell leukemia virus 1; IRR  infusion-related reaction; IV  intravenous(ly); LVEF  left ventricular ejection fraction; 
MDASI-CLL  MD Anderson Symptom Inventory for Chronic Lymphocytic Leukemia; MRD  minimal residual disease; MRI  magnetic resonance 
imaging; NGS  next-generation sequencing; PB  peripheral blood; PR  partial response; PRO  patient-reported outcome; TLS  tumor lysis 
syndrome; VEN  G  venetoclax (Venclexta or Venclyxto) in combination with obinutuzumab (Gazyva or Gazyvaro). 
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 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
164/Protocol CO41685, Version 5 
[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 postdose 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 a randomization number has been assigned.  
b In patients where the first obinutuzumab dose is administered over Days 1 and 2, the 24‑hour postdose TLS monitoring will also need to occur 
on Day 3 
c 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 of study drug, or until initiation of another anti-cancer therapy, whichever occurs first.  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 event that is believed to be related to prior exposure to study drug or any second primary malignancies, irrespective of whether 
they are believed to be related to previous study treatment or not.  In addition, all deaths, regardless of cause, should be reported.  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. 
d TLS risk assessment and monitoring:  Chemistry and hematology panels must be assessed within 04 hours prior and 24 hours after the first 
obinutuzumab dose.  For TLS low-risk and TLS medium-risk patients: at the first 20 mg and 50 mg dose of venetoclax, hematology and 
chemistry samples are to be taken 0-4 hours predose and 68 and 24 hours after dosing.  For subsequent ramp-up doses hematology and 
chemistry will be taken within 04 hours predose.  For TLS high-risk patients: at the first 20 mg and 50 mg dose of venetoclax, patients will be 
hospitalized, and hematology and chemistry samples will be taken 0-4 hours predose and 4, 8, 12, and 24 hours after dosing.  For subsequent 
ramp-up doses hematology and chemistry will be taken within 0-4 hours predose and 6-8 and 24 hours after doing.  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, if possible, 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. 
e Because of possible tumor de-bulking after obinutuzumab therapy, investigators will reassess TLS risk after obinutuzumab induction for all 
patients in Arm A 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 will have a re-evaluation of 
their TLS risk category based on their most recent ALC after the obinutuzumab run-in period and before initiating venetoclax on Cycle 1, Day 22.  
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 during the venetoclax ramp-up period.  Only patients who are classified as high-risk because they have a lymph 
node with largest diameter 10 cm will have a repeat CT scan after obinutuzumab induction and before starting venetoclax on Cycle 1, Day 22.  

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
165/Protocol CO41685, Version 5 
If the patient’s lymph node size decreases to 10 cm, the investigator may follow the management guidelines for the TLS medium-risk category 
for the venetoclax ramp-up period. 
f For Cycle 2 only, in addition to Day 1, the TLS assessment must be performed on Day 8, Day 15, and Day 22.  
g Vital signs include measurements of respiratory rate, pulse rate and systolic and diastolic blood pressure while the patient is in a seated position, 
and temperature.  For TLS low-risk and TLS medium-risk patients:  At the first 20‑mg and 50‑mg dose of venetoclax, vital signs are to be taken 
04 hours predose, and 68 and 24 hours after dosing.  For subsequent ramp-up doses, vital signs will be taken within 04 hours predose.  For 
TLS high-risk patients:  At the first 20‑mg and 50‑mg dose of venetoclax, vital signs will be taken 04 hours predose and 4, 8, 12, and 24 hours 
after dosing.  For subsequent ramp-up, vital signs will be taken within 04 hours predose and 68 and 24 hours after doing. 
h 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. 
i CT scans are allowed 8 weeks prior to randomization and required as confirmation of CR/PR at 12 weeks after end of treatment.  An MRI is only 
to be conducted if a contrast enhanced CT is not possible.  All patients must have a baseline CT scan (or MRI if CT is not possible) of the neck 
(if indicated), chest, abdomen, and pelvis with IV and oral contrast.  Conventional CT and MRI should be performed with contiguous cuts of 
10 mm or less in slice thickness.  Spiral CT should be performed by use of a 5-mm contiguous reconstruction algorithm; this specification applies 
to the tumors of the chest, abdomen, and pelvis.  If MRIs are used instead of CT scans, MRIs should be used consistently throughout the study. 
j A BM biopsy and aspirate is optional at screening (investigator discretion if clinically indicated) and can be performed 8 weeks prior to 
randomization.  At the end of treatment response visit, a BM biopsy and aspirate is required to confirm response in all responding patients 
(CR/PR). 
k Obinutuzumab may be given over 2 days if the patient is considered high risk for IRR or as per standard of care. 
l 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. 
m For samples drawn on days of study treatment, predose laboratory samples should be drawn within 04 hours before the dose.  If these results 
need to be reviewed prior to dosing and 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 can be reviewed prior to dosing.  
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 safety.  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.  
n IGHV mutational status is required for randomization. Historical results irrespective of when test was performed can be used (tests that have 
occurred prior to the 28day screening window are valid indefinitely and do not need to be repeated).  If IGHV mutational status is unknown at 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
166/Protocol CO41685, Version 5 
screening, then sites will need to perform this locally prior to randomization.  Patients with an undetermined IGHV mutational status cannot be 
randomized and will be considered a screen-fail.  
o Certain patients (occult or prior HBV infection) require monthly DNA testing, although the data is not collected for the study. 
p All women who are not postmenopausal (i.e., 12 months of non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy 
test at screening.  If a 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 (i.e., 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. 
q Urinalysis includes:  dipstick pH, specific gravity, glucose, protein, ketones, blood, and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria). 
r Hematology includes:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 
s Chemistry 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, and LDH. 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
167/Protocol CO41685, Version 5 
Arm A:  Cycle 3-Cycle 12 and Follow-Up Day 28 
Arm A 
(VEN  G) 
Assessment 
C3 
C4 
C5 
C6 
Day 28 after 
Completion/ Early 
Termination of 
Combination 
Therapya 
C7 
C8 
EOCTRV 
812 Weeks 
Post End of 
Combinationb 
C9 
C10 
C11 
C12 
Day 28 after 
Treatment 
Completion/Early 
Termination of Ven 
Monotherapy c 
Vital signs 
(Day 1 of each 
cycle only) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Complete 
physical 
examination 
 
x 
 
 
x 
 
 
x 
 
 
 
 
x 
Lymphadenopa
thy (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 
x 
x 
x 
B-symptoms 
(see 
Section 4.5.12.3) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Obinutuzumab  
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Venetoclax  
Daily dosing 400 mg for 10 cycles 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
168/Protocol CO41685, Version 5 
Arm A 
(VEN  G) 
Assessment 
C3 
C4 
C5 
C6 
Day 28 after 
Completion/ Early 
Termination of 
Combination 
Therapya 
C7 
C8 
EOCTRV 
812 Weeks 
Post End of 
Combinationb 
C9 
C10 
C11 
C12 
Day 28 after 
Treatment 
Completion/Early 
Termination of Ven 
Monotherapy c 
CLL response 
assessment d 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
CT scan 
assessment (or 
MRI if 
performed at 
screening) 
 
 
 
 
 
 
 
(x) e 
 
 
 
 
 
CT scan if PD 
detected 
(lymph nodes 
only) 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PRO 
questionnaires 
(MDASI-CLL, 
EQ-5D-5L, 
EORTC 
QLQ-C30) f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Local Laboratory 
Hematology 
(Day 1) 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
x 
x 
Biochemistry 
(Day 1) 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
x 
x 
Pregnancy 
Test g 
x 
x 
x 
x 
x 
 
x 
 
 
x 
x 
x 
x 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
169/Protocol CO41685, Version 5 
Arm A 
(VEN  G) 
Assessment 
C3 
C4 
C5 
C6 
Day 28 after 
Completion/ Early 
Termination of 
Combination 
Therapya 
C7 
C8 
EOCTRV 
812 Weeks 
Post End of 
Combinationb 
C9 
C10 
C11 
C12 
Day 28 after 
Treatment 
Completion/Early 
Termination of Ven 
Monotherapy c 
BM 
biopsy/aspirate 
 
 
 
 
 
 
 
(x)h 
 
 
 
 
 
Central Laboratory 
MRD in PB by 
NGS 
 
x 
 
 
 
 
 
x 
 
 
 
x 
 
MRD in PB by 
ASO-PCR 
 
 
 
 
 
 
 
x 
 
 
 
 
 
MRD in BM 
 
 
 
 
 
 
 
(x) i 
 
 
 
 
 
ctDNA 
 
 
 
 
(x) j 
 
 
 
 
 
 
 
(x) j 
Blood for 
genetic 
analysis 
(genetic 
complexity, 
gene mutations 
and resistance 
markers) 
 
 
 
 
(x) j 
 
 
 
 
 
 
 
(x) j 
ASO-PCR  allele-specific oligonucleotide polymerase chain reaction; C  Cycle; CLL  chronic lymphocytic leukemia; CT  computed tomography; 
ECOG  Eastern Cooperative Oncology Group; EOCTRV  End of Combination Treatment Response Visit; EORTC-QLQ-C30European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L  EuroQol 5-Dimension Questionnaire, 5-level 
version; LVEF  left ventricular ejection fraction; MDASI-CLL  MD Anderson Symptom Inventory for Chronic Lymphocytic Leukemia; MRD  minimal 
residual disease; NGSnext-generation sequencing; PD  progressive disease; PR  partial response; PRO  patient-reported outcome; 
VEN  G  venetoclax (Venclexta or Venclyxto) in combination with obinutuzumab (Gazyva or Gazyvaro). 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
170/Protocol CO41685, Version 5 
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 This visit is mandatory for all patients.  For patients who discontinue all study drug prior to completing the combination period, the Early 
Treatment Termination Visit occurs 28 days after last dose of study treatment.  For patients that have completed the full 6 cycles of combination 
therapy, this visit should be performed at the same time as C7D1. 
b Patients who discontinue all study drug prior to completing the combination period should have their EOCTRV visit performed 8-12 weeks after 
the last dose of combination therapy.  Patients who discontinue study drug for reasons other than progressive disease prior to completing 
12 cycles of therapy should continue to be followed for disease progression and MRD assessment per the schedule of assessments (follow-up 
period).  For patients who have not discontinued study drugs and have completed the full 6 cycles of combination therapy, the EOCTRV visit 
should be performed 8-12 weeks after the last dose of combination therapy.  This visit may be performed on the same day as other scheduled 
visits (e.g., C8D1 or C9D1) 
c Patients who complete venetoclax monotherapy or 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.  For patients in Arm A, this would be the last day of 
venetoclax administration.  Patients who discontinue study drug prior to completing 12 cycles of therapy should continue to be followed for 
disease progression and MRD assessment per the schedule in schedule of assessments (follow-up period). 
d The CLL response assessment will consist of a physical examination and laboratory tests.  
e CT scan is only required at this visit in patients who discontinue all treatment early during the combination phase.  
f 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.  
g 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. 
h A bone marrow biopsy and aspirate (including for central assessment of MRD) must be taken in patients who discontinue all treatment early 
during the combination phase and achieve a CR/PR 
i A bone marrow aspirate must be taken in patients who discontinue treatment early during the combination phase and achieve a CR/PR for 
central assessment of MRD.  
j ctDNA sample and blood for genetic analysis sample collection is mandatory in patients who have discontinued due to disease progression. 
 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
171/Protocol CO41685, Version 5 
ARM A:  Follow-Up Period 
Arm A (VEN  G) 
Assessments 
 
Follow-Up Visits 
Duration from Last Study Drug Administration until Disease Progression 
Survival 
(All Patients) 
Assessment 
 3 months after Early 
Termination a 
Month 15b 
 6, 9, 12, 15, 18, and 
21 months after Treatment 
Completion/Early 
Termination 
 24 months after Treatment 
Completion/Early Termination then 
every 6 months until end of study 
Every year after 
disease progression 
until end of study 
Complete physical examination 
x 
x 
x 
x 
 
Weight 
x 
x 
x 
x 
 
Vital signs c 
x 
x 
x 
x 
 
ECG 12-lead 
As clinically indicated 
As clinically indicated 
As clinically indicated 
As clinically indicated 
 
LVEF 
As clinically indicated 
As clinically indicated 
As clinically indicated 
As clinically indicated 
 
Physical examination d 
x 
x 
x 
x 
 
Liver/spleen (by physical 
examination) 
x 
x 
x 
x 
 
ECOG Performance Status 
x 
x 
x 
x 
 
B-symptoms (see Section 4.5.12.3) 
x 
x 
x 
x 
 
CT scan assessment (or MRI if 
performed at screening) 
x 
x 
 
 
 
CT scan if PD is detected by 
lymph nodes only 
x 
 
CLL response assessmente 
x 
x 
x 
x 
 
PRO questionnaire (MDASI-CLL, 
EQ-5D-5L, and EORTC-QLQ 
C30) until NLT f 
x 
x 
x 
x 
 
Collection of NLT  
x 
x 
x 
x 
x 
Related serious adverse events 
x 
x 
x 
x 
x 
Concomitant medication 
x 
x 
x 
x 
x 
All second primary malignancies 
x 
x 
x 
x 
x 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
172/Protocol CO41685, Version 5 
Arm A (VEN  G) 
Assessments 
 
Follow-Up Visits 
Duration from Last Study Drug Administration until Disease Progression 
Survival 
(All Patients) 
Assessment 
 3 months after Early 
Termination a 
Month 15b 
 6, 9, 12, 15, 18, and 
21 months after Treatment 
Completion/Early 
Termination 
 24 months after Treatment 
Completion/Early Termination then 
every 6 months until end of study 
Every year after 
disease progression 
until end of study 
Local Laboratory 
Hematology g 
x 
x 
x 
x 
 
Chemistry h 
x 
x 
x 
x 
 
Immunoglobulin (IgA, IgG, IgM) 
x 
x 
x 
x 
 
Urinalysis i 
x 
x 
 
 
 
BM biopsy/aspirate 
(x)j  
x k 
 
 
 
Central Laboratory 
Blood for Lymphocyte counts/ 
Immunophenotyping (B-CLL 
count, B-cell, T-Cell and NK cell 
markers) by flow cytometry 
 
 
x (12 & 18 months only) 
x 
 
MRD in PB by NGS 
x  
x 
x  
x  
 
MRD in PB by ASO-PCR 
 
x 
 
 
 
MRD in BM 
(x)j  
x k 
 
 
 
ctDNA 
 
x 
(x)l 
(x)l 
 
Blood for genetic analysis 
(genetic complexity, gene 
mutations and resistance 
markers) 
 
x 
(x)l 
(x)l 
 
ASO-PCR  allele-specific oligonucleotide polymerase chain reaction; BM  bone marrow; C  Cycle; CLL  chronic lymphocytic leukemia; 
CT  computed tomography; ECOG  Eastern Cooperative Oncology Group; EORTC-QLQ-C30  European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L  EuroQol 5-Dimension Questionnaire, 5-level version; LVEF  left ventricular 
ejection fraction; MDASI-CLL  MD Anderson Symptom Inventory for Chronic Lymphocytic Leukemia; MRD  minimal residual disease; 
MRI  magnetic resonance imaging; NGS  next-generation sequencing; NLT  next line treatment; PD  progressive disease; PRO  patient-reported 
outcome; VEN  G  venetoclax (Venclexta or Venclyxto) in combination with obinutuzumab (Gazyva or Gazyvaro). 

Appendix 1:  Schedule of Activities for Arm A 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
173/Protocol CO41685, Version 5 
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 (12 weeks 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-month and within a month for 6-month assessments of the scheduled visits. 
a Visit should be performed no earlier than 8 weeks and no later than 12 weeks after last dose of study drug.  If the patient is in CR or PR following 
the CT scan a bone marrow biopsy should be performed a minimum of 12 weeks after last dose of study drug.  This visit also correlates to 
8 weeks after the Day 28 after Treatment Completion/Early Termination visit. 
b Month 15 is to be performed 15 months from C1D1 in all patients who have not developed progressive disease. 
c Includes pulse rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
d Physical examination includes evaluation of the head, eyes, ears, nose, and throat; cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems; and assessment for lymphadenopathy.  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 
e The CLL response assessment will consist of a physical examination and laboratory tests.  A CT scan is only required at the first follow-up visit 
(3 months after early termination) or at Month 15. If at any time during follow-up when clinical or laboratory findings suggest that the response 
may have improved from SD to PR, or from PR to CR, a CT scan may be performed to confirm the response. 
f 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. 
g Includes: WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells. 
h 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, and LDH. 
i Includes:  dipstick pH, specific gravity, glucose, protein, ketones, blood, and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria). 
j A bone marrow biopsy and aspirate (including for central assessment of MRD) must be taken in patients who discontinue treatment early during 
the monotherapy phase and achieve a CR/PR. 
k A bone marrow biopsy and aspirate (including for central assessment of MRD) must be taken in patients who achieve a CR/PR. A bone marrow 
biopsy/aspirate is not required in patients who have discontinued and have had a BM biopsy done at their +3 months after early termination visit. 
l ctDNA sample and blood for genetic analysis sample collection is mandatory in patients who have discontinued due to disease progression. 
   

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
174/Protocol CO41685, Version 5 
Appendix 2 
Schedule of Activities for Arm B 
Arm B: Schedule of Assessments 
Arm B (FCR/BR) 
Assessments 
Screening 
Combination (FCR/BR) Therapy 
Observation and Follow-Up 
Cycle 1 
Cycles 23 
Cycle 4 
Cycles
 56 
Day 28 
after 
Treatment 
Completion 
or Early 
Termination 
b 
EOCTR 
Visit / c 
Follow-Up 
Visits d 
Month 
15e 
Survival 
Follow- 
Up  
Visits  
Day 
28 
to 
1 
1 a 
2 
3 
8 
15 
1 
2 
3 
8 
15 
1 
1 
 
 
 
 
 
Informed consent f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLS laboratory-based risk 
assessment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CIRS score 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs g 
x 
x 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
 
Weight 
x 
x 
 
 
 
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
 
Height  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination h 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
x 
 
Clinical staging h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 2:  Schedule of Activities for Arm B 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
175/Protocol CO41685, Version 5 
Arm B (FCR/BR) 
Assessments 
Screening 
Combination (FCR/BR) Therapy 
Observation and Follow-Up 
Cycle 1 
Cycles 23 
Cycle 4 
Cycles
 56 
Day 28 
after 
Treatment 
Completion 
or Early 
Termination 
b 
EOCTR 
Visit / c 
Follow-Up 
Visits d 
Month 
15e 
Survival 
Follow- 
Up  
Visits  
Day 
28 
to 
1 
1 a 
2 
3 
8 
15 
1 
2 
3 
8 
15 
1 
1 
 
 
 
 
 
Lymphadenopathy (during 
physical examination/ 
Binet staging at screening) 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
x 
 
Liver/spleen (by physical 
examination) 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
x 
 
ECG 12 lead 
x 
As clinically indicated 
LVEF 
x 
As clinically indicated 
ECOG Performance Status 
x 
x 
 
 
 
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
 
B-symptoms (see Section 4.5.12.3) 
x 
x 
 
 
 
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
 
CT scan assessment (or MRI if 
performed at screening) i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
CT scan if PD detected (lymph 
nodes only) 
x 
CLL response assessment j  
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
x 
 
BM biopsy/aspirate k  
(x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Fludarabine 
 
Days 1-3 (Cycles 16) 
 
 
 
 
 

Appendix 2:  Schedule of Activities for Arm B 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
176/Protocol CO41685, Version 5 
Arm B (FCR/BR) 
Assessments 
Screening 
Combination (FCR/BR) Therapy 
Observation and Follow-Up 
Cycle 1 
Cycles 23 
Cycle 4 
Cycles
 56 
Day 28 
after 
Treatment 
Completion 
or Early 
Termination 
b 
EOCTR 
Visit / c 
Follow-Up 
Visits d 
Month 
15e 
Survival 
Follow- 
Up  
Visits  
Day 
28 
to 
1 
1 a 
2 
3 
8 
15 
1 
2 
3 
8 
15 
1 
1 
 
 
 
 
 
Cyclophosphamide 
 
Days 1-3 (Cycles 16) 
 
 
 
 
 
Rituximab 
 
x 
(x) 
 
 
 
x 
 
 
 
 
x 
x 
 
 
 
 
 
Bendamustine 
 
Day 1 & 2 (Cycles 16) 
 
 
 
 
 
Adverse events f 
x 
x 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
All second primary malignancies 
x 
x 
x 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
PRO questionnaires 
(MDASI-CLL, EQ-5D-5L, and 
EORTC-QLQ-C30) l 
 
x 
 
 
 
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
 
Collection of NTL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Local Laboratory m 
IGHVn 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulins 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV, HCV, HIV, HTLV1 
(if applicable) o 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coombs test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 2:  Schedule of Activities for Arm B 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
177/Protocol CO41685, Version 5 
Arm B (FCR/BR) 
Assessments 
Screening 
Combination (FCR/BR) Therapy 
Observation and Follow-Up 
Cycle 1 
Cycles 23 
Cycle 4 
Cycles
 56 
Day 28 
after 
Treatment 
Completion 
or Early 
Termination 
b 
EOCTR 
Visit / c 
Follow-Up 
Visits d 
Month 
15e 
Survival 
Follow- 
Up  
Visits  
Day 
28 
to 
1 
1 a 
2 
3 
8 
15 
1 
2 
3 
8 
15 
1 
1 
 
 
 
 
 
Coagulation (INR OR PT, AND 
aPTT or PTT) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test p 
x 
x 
 
 
 
 
x 
 
 
 
 
x 
x 
x 
 
 
 
 
Urinalysis q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology r 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
 
Chemistry s 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
 
Central Laboratory a 
Serum Parameters 
(2 microglobulin, thymidine 
kinase) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for CLL Prognostic 
factors (including IGHV, 17p, 
TP53) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Lymphocyte counts/ 
Immunophenotyping (B-CLL 
count, B-cell, T-Cell and NK cell 
markers) by flow cytometry 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 2:  Schedule of Activities for Arm B 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
178/Protocol CO41685, Version 5 
Arm B (FCR/BR) 
Assessments 
Screening 
Combination (FCR/BR) Therapy 
Observation and Follow-Up 
Cycle 1 
Cycles 23 
Cycle 4 
Cycles
 56 
Day 28 
after 
Treatment 
Completion 
or Early 
Termination 
b 
EOCTR 
Visit / c 
Follow-Up 
Visits d 
Month 
15e 
Survival 
Follow- 
Up  
Visits  
Day 
28 
to 
1 
1 a 
2 
3 
8 
15 
1 
2 
3 
8 
15 
1 
1 
 
 
 
 
 
MRD in PB by NGS 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
x 
x 
 
MRD in PB by ASO-PCR 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
MRD in BM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x t 
 
 
 
ctDNA 
x 
 
 
 
 
 
 
 
 
 
 
 
 
(x)u 
 
(x)u 
x 
 
Blood for genetic analysis 
(genetic complexity, gene 
mutations and resistance 
markers) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
(x)u 
 
(x)u 
x 
 
 
ASO-PCR  allele-specific oligonucleotide polymerase chain reaction; BM  bone marrow; BR  bendamustine and rituximab; C  Cycle; CIRS  cumulative illness 
rating scale; CLL  chronic lymphocytic leukemia, CR  complete response; CT  computed tomography; D  Day; ECOG  Eastern Cooperative Oncology Group; 
EOCTRV  End of Combination Treatment Response Visit; EORTC-QLQ-C30  European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30; eCFR  electronic Case Report Form; EQ-5D-5L  EuroQol 5-Dimension Questionnaire, 5-level version; FCR  fludarabine, 
cyclophosphamide, and rituximab; HBV  hepatitis B virus; HCV  hepatitis C virus; HTLV1  human T-cell leukemia virus 1; LVEF  left ventricular ejection 
fraction; M  Month; MDASI-CLL  MD Anderson Symptom Inventory for Chronic Lymphocytic Leukemia; MRD  minimal residual disease; MRI  magnetic 
resonance imaging; NGS  next-generation sequencing; NTL  next treatment line; PB  peripheral blood; PD  progressive disease; PR  partial response; 
PRO  patient-reported outcome. 

Appendix 2:  Schedule of Activities for Arm B 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
179/Protocol CO41685, Version 5 
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 
(12 weeks 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-month and within a month for 6-month assessments of the scheduled visits. 
a Samples should be taken after a randomization number has been assigned. 
b Patients who discontinue all study drug prior to completing 6 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 6 cycles of therapy should continue to be followed for disease 
progression per the schedule of assessments. 
c Visit should be performed no earlier than 8 weeks and no later than 12 weeks after end of treatment/early termination.  If the patient is in CR or PR following 
the CT scan a BM examination should be performed a minimum of 12 weeks after the end of the treatment.  This visit also correlates to 8 weeks after the 
Day 28 after Treatment Completion/Early Termination visit. 
d Follow-up visits occur every 3 months until 3 years and then every 24 weeks until PD. 
e Month 15 is to be performed 15 months from C1D1 in all patients who have not developed progressive disease. 
f After the 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 of study 
drug, or until initiation of another anti-cancer therapy, whichever occurs first.  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 event that is believed to be related to prior exposure to study drug or any second primary malignancies, irrespective of whether they are 
believed to be related to previous study treatment or not.  In addition, all deaths, regardless of cause, should be reported.  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. 
g Vital signs include measurements of respiratory rate, pulse rate and systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature. 
h 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. 
i CT scans are allowed 8 weeks prior to randomization and required as confirmation of CR/PR 12 weeks after end of treatment.  An MRI is only to be conducted 
if a contrast enhanced CT is not possible.  All patients must have a baseline CT scan (or MRI if CT is not possible) of the neck (if indicated), chest, abdomen, 
and pelvis with IV and oral contrast.  Conventional CT and MRI should be performed with contiguous cuts of 10 mm or less in slice thickness.  Spiral CT 
should be performed by use of a 5-mm contiguous reconstruction algorithm; this specification applies to the tumors of the chest, abdomen, and pelvis.  If MRIs 
are used instead of CT scans, MRIs should be used consistently throughout the study.  
j The CLL response assessment will consist of a physical examination and laboratory tests. 

Appendix 2:  Schedule of Activities for Arm B 
  
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
180/Protocol CO41685, Version 5 
k A BM biopsy and aspirate is optional at screening (investigator discretion if clinically indicated) and can be performed 8 weeks prior to randomization.  At the 
end of treatment response visit, a BM biopsy and aspirate is required to confirm response in all responding patient (CR/PR). 
l 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.  
m For laboratory samples drawn on days of study treatment, predose samples should be drawn within 04 hours before the dose.  If these results need to be 
reviewed prior to dosing and 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 can be reviewed prior to dosing.  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 safety.  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. 
n IGHV mutational status is required for randomization. Historical results irrespective of when test was performed can be used (tests that have occurred prior to 
the 28-day screening window are valid indefinitely and do not need to be repeated).  If IGHV mutational status is unknown at screening, then sites will need to 
perform this locally prior to randomization.  Patients with an undetermined IGHV mutational status cannot be randomized and will be considered a screen-fail.  
o Certain patients, those with occult or prior HBV infection, require monthly DNA testing, although the data is not collected for the study. 
p All women who are not postmenopausal (i.e., 12 months of non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy test at 
screening.  If a 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 (i.e., 
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. 
q Urinalysis includes:  dipstick pH, specific gravity, glucose, protein, ketones, blood, and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria). 
r Hematology includes:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells. 
s Chemistry 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. 
t A BM aspirate must be taken in patients who achieve a CR/PR for central assessment of MRD. 
u ctDNA sample and blood for genetic analysis sample collection is mandatory in patients who have discontinued due to disease progression.   
  

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
181/Protocol CO41685, Version 5 
Appendix 3 
Visits for Arm A Patients Who Discontinue Treatment for 
Reasons Other than Progressive Disease 
 

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
182/Protocol CO41685, Version 5 
Appendix 4 
Sample List of Excluded and Cautionary Medications for 
Patients Randomized to Arm A (Venetoclax  Obinutuzumab) 
Type 
Medication 
Excluded 7 days prior to and 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, crizotinib b, 
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, bicalutamide b, 
cilostazol, cimetidine, cyclosporine b, fluoxetine, fluvoxamine, ginkgo, 
goldenseal, isoniazid, nilotinib b, oral contraceptives, pazopanib b, 
ranitidine, ranolazine, tipranavir/ritonavir, ticagrelor, and zileuton 
P-gp substrates 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, 
everolimus b, fexofenadine, lapatinib b, loperamide, maraviroc, 
nilotinib b, ranolazine, saxagliptin, sirolimus b, sitagliptin, talinolol, 
tolvaptan, and topotecan b 
BCRP substrates 
Methotrexate b, mitoxantrone b, irinotecan b, lapatinib b, rosuvastatin, 
sulfasalazine, and topotecan b 
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 
BCRP inhibitors 
Gefitinib b, cyclosporine b 
OATP1B1/B3 inhibitors 
Gemfibrozil, eltrombopag, cyclosporine b, tipranavir 
Note:  This is not an exhaustive list; refer to the label of the drug under consideration for the most current 
drug-drug intervention information.  For an updated list, see the following link:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling
/ucm080499.htm.  In addition to the medications listed in this table, patients receiving venetoclax should 
not consume grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville 
oranges), or star fruits. 
a 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 anti‑cancer agents; contact Medical Monitor before use. 
 
 

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
183/Protocol CO41685, Version 5 
Appendix 5 
M.D. Anderson Symptom Inventory (MDASI-CLL) 
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study. 
 

Appendix 5:  M.D. Anderson Symptom Inventory (MDASI-CLL) 
  
Venetoclax (GDC-0199) and ObinutuzumabF. Hoffman-La Roche Ltd 
184/Protocol CO41685, Version 5 
 
 

 
Venetoclax (GDC-0199) and ObinutuzumabF. Hoffman-La Roche Ltd 
185/Protocol CO41685, Version 5 
Appendix 6 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) 
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study. 
 

Appendix 6:  European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) 
Venetoclax (GDC-0199) and ObinutuzumabF. Hoffman-La Roche Ltd 
186/Protocol CO41685, Version 5 
 

 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
187/Protocol CO41685, Version 5 
Appendix 7 
EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Questionnaire 
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study. 
 
 

Appendix 7:  EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Questionnaire 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
188/Protocol CO41685, Version 5 
 

Appendix 7:  EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Questionnaire 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
189/Protocol CO41685, Version 5 
 
 

 
Appendix 8 
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). 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
/Protocol CO41685, Version 5 
 
190

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
191/Protocol CO41685, Version 5 
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 patients with diabetes), 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 this 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. 
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. 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
192/Protocol CO41685, Version 5 
 
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) 
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. 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
193/Protocol CO41685, Version 5 
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, endocarditis, myocarditis, pericarditis, 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 
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 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
194/Protocol CO41685, Version 5 
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; 
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 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
195/Protocol CO41685, Version 5 
iron, B12 vitamin or folate deficiency, or to chronic renal failure; total white blood cell 
(WBC) 20004000/mmc; mild thrombocytopenia (50,000150,000/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 (50,000/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 
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. 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
196/Protocol CO41685, Version 5 
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.). 
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 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
197/Protocol CO41685, Version 5 
of gastritis (consider also Helicobacter 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 
 
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 
 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
198/Protocol CO41685, Version 5 
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 
 
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 MM should not be considered. 
35. No problem 
36. Asymptomatic kidney stone; kidney stone passage within the last 10 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 
 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
199/Protocol CO41685, Version 5 
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 
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 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
200/Protocol CO41685, Version 5 
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. 
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. 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
201/Protocol CO41685, Version 5 
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) 
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., hypercalcemia); replacement therapy for adrenal failure; any electrolytes 
disorder requiring hospitalization. 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
202/Protocol CO41685, Version 5 
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 
10 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 10 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 
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). 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
203/Protocol CO41685, Version 5 
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. 
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 
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, and fractioned bilirubin 
 
Thyroid function and serum B12 (when indicated) 
 
Hemoglobin A1c (for diabetic patients) 

Appendix 8:  The Modified Cumulative Illness Rating Scale (CIRS) 
  
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
204/Protocol CO41685, Version 5 
REFERENCES 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: 
DSM-IV. 4th ed. Washington: Amer. Psychiatric Assn., 1994. 
Cummings JL, Mega M, Gray K, et al. The Neuropsychiatric  Inventory: comprehensive 
assessment of psychopathology in dementia. Neurology 1994;44:230814. 
Folstein MF, Folstein SE, McHugh PR. “Mini Mental State”: a practical method for 
grading the cognitive state of patients for the clinician. J Psiychiatr Res 
1975;12:18998. 
Linn BS, Linn MW, Gurel L. Cumulative Illness Rating Scale. J Am Geriatr Soc 
1968;16:6226. 
Miller MD, Paradis CF, Houck PR, et al. 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 guideline for scoring the Cumulative Illness Rating Scale 
for Geriatrics (CIRS-G). Pittsburg, PA: University of Pittsburgh; 1991. 
Mistry R, Gokhman I, Bastani R, et al. 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. 
Parmelee PA, Thuras PD, Katz IR, et al. Validation of the Cumulative Illness Rating 
Scale in a geriatric residential population. J Am Geriatr Soc 1995;43:1307. 
Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric 
depression screening scale: a preliminary report. J Psiychiatr Res 1983;17:3749. 
 
 

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
205/Protocol CO41685, Version 5 
Appendix 9 
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 mol/L: 
CrCl   (140-age  )  (wt)  0.85 (if female), or 1.0 (if male) 
(mL/min) 0.81  serum creatinine 
   (mol/L) 
 age in years, weight (wt) in kilograms 
Reference:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41. 
 

 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
206/Protocol CO41685, Version 5 
Appendix 10  
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 5.0.  
A pdf of the NCI CTCAE v5.0 can be downloaded from the following website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Investigators who do not have access to Internet can contact the Data Center to receive 
a hard copy of this document by mail. 
 

Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
207/Protocol CO41685, Version 5 
Appendix 11  
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 
REFERENCE 
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. 

Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
208/Protocol CO41685, Version 5 
Appendix 12  
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.

For any blood chemistry changes requiring more than 48 hours to resolve, resume
venetoclax at the reduced dose, as detailed in Table 9.

For any events of clinical TLS (defined as laboratory TLS with clinical consequences
such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures),
resume venetoclax at reduced dose following resolution, as detailed in Table 9.

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 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.

Appendix 12:  Recommendations for Initial Management of Electrolyte Imbalances and 
Prevention of Tumor Lysis Syndrome 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
209/Protocol CO41685, Version 5 
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.

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.

Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
210/Protocol CO41685, Version 5 
Appendix 13  
Body Surface Area (BSA) Calculation Using the Mosteller 
Formula 
The following formula is to be used when calculating BSA: 
BSA(m2)([Height (cm)  Weight (kg)]/3600)½ 

Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
211/Protocol CO41685, Version 5 
Appendix 14  
Eastern Cooperative Oncology Group (ECOG) 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 

Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
212/Protocol CO41685, Version 5 
Appendix 15  
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 5.0 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 mol/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 mmol/L
(4.5 mg/dL) 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]). 
Table 2 
Howard Definition of Clinical Tumor Lysis Syndrome 
The presence of laboratory TLS and one or more of the following criteria: 
Creatinine a:  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, laryngospasm or 
bronchospasm), hypotension, or heart failure probably or definitely caused by hypocalcemiab 

Appendix 15: Guidelines for Defining Tumor Lysis Syndrome 
Venetoclax and Obinutuzumab—F. Hoffmann-La Roche Ltd 
213/Protocol CO41685, Version 5 
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.  
Erratum in The tumor lysis syndrome. New Engl J Med 2018;379:1094.

Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
214/Protocol CO41685, Version 5 
Appendix 16  
Anaphylaxis Precautions 
EQUIPMENT NEEDED 

Oxygen

Epinephrine for subcutaneous, intravenous (IV), and/or endotracheal use in
accordance with standard practice

Antihistamines

Corticosteroids

IV infusion solutions, tubing, catheters, and tape
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, the 
following procedures should be performed: 

Stop the study treatment infusion.

Apply a tourniquet proximal to the injection site to slow systemic absorption of study
treatment.  Do not obstruct arterial flow in the limb.

Maintain an adequate airway.

Administer glucocorticoids, antihistamines, epinephrine, or other medications as
required by patient status and directed by the physician in charge.

Continue to observe the patient and document observations.

Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
215/Protocol CO41685, Version 5 
Appendix 17  
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)
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

Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
216/Protocol CO41685, Version 5 
Appendix 18 
Investigational Medicinal Product and 
Auxiliary/Non-Investigational Medicinal Product Designations 
(for Use in European Economic Area and United Kingdom) 
Table 1 
Investigational and Authorized Auxiliary Medicinal Product 
Designations for European Economic Area 
Product Name 
IMP/AxMP Designation 
Marketing Authorization 
Status in EEA 
Used within 
Marketing 
Authorization 
venetoclax 
IMP 
Authorized 
Yes 
obinituzumab 
IMP 
Authorized 
Yes 
fluradabine 
IMP 
Authorized 
Yes 
cyclophosphamide 
IMP 
Authorized 
Yes 
rituximab 
IMP 
Authorized 
Yes 
bendamustine 
IMP 
Authorized 
Yes 
rasburicase 
AxMP (rescue medicine) 
Authorized 
Yes 
acetaminophen 
AxMP (rescue medicine) 
Authorized 
Yes 
paracetamol 
AxMP (rescue medicine) 
Authorized 
Yes 
prednisolone 
AxMP (rescue medicine) 
Authorized 
Yes 
dexamethasone 
AxMP (rescue medicine) 
Authorized 
Yes 
methylprednisolone 
AxMP (rescue medicine) 
Authorized 
Yes 
diphenhydramine 
AxMP (rescue medicine) 
Authorized 
Yes 
allopurinol 
AxMP (rescue medicine) 
Authorized 
Yes 
ondansetron 
AxMP (rescue medicine) 
Authorized 
Yes 
AxMP  auxiliary medicinal product; EEA   European Economic Area; IMP   investigational medicinal product.
Note:  Rasburicase, acetaminophen, prednisolone, dexamethasone, methylprednisolone, diphenhydramine, 
allopurinol, and ondansetron are used as pre-medications to treat anticipated adverse reactions. 

Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
217/Protocol CO41685, Version 5 
Appendix 19 
Abbreviations 
Abbreviation 
Definition 
1L 
first-line 
ALC 
absolute lymphocyte count 
ALL 
acute lymphocytic leukemia 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
ASO-PCR 
allele-specific oligonucleotide polymerase chain reaction 
BCL 
B-cell lymphoma
BM 
bone marrow
BR 
bendamustine and rituximab
BSA 
body surface area
CCOD 
clinical cut-off date
CIRS 
cumulative illness rating scale
CLL 
chronic lymphocytic leukemia
CMH 
Cochran-Mantel-Haenszel
CMV 
cytomegalovirus
CR 
complete remission
CrCl 
creatinine clearance
CRi 
complete remission with incomplete blood count recovery
CRO 
contract research organization
CRR 
complete response rate
CT 
computed tomography
ctDNA 
circulating tumor DNA
DDI 
drug-drug interactions
DIC 
disseminated intravascular coagulation
DLBCL 
diffuse large B-cell lymphoma
DOR 
duration of objective response
ECOG 
Eastern Cooperative Oncology Group
eCRF 
electronic Case Report Form
EDC 
electronic data capture
EFS 
event-free survival
EMA 
European Medicines Agency
EOCT 
end of combination treatment
EORTC 
QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of
Life Questionnaire Core 30
EOT 
end of treatment
EQ-5D-5L 
EuroQol 5-Dimension Questionnaire, 5-level version

Appendix 19:  Abbreviations 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
218/Protocol CO41685, Version 5 
Abbreviation 
Definition 
EU 
European Union 
FCR 
fludarabine, cyclophosphamide, and rituximab 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FIT 
patients with a CIRS score 6 and a normal creatinine clearance of 
70 mL/min 
FL 
follicular lymphoma 
GCIb 
obinutuzumab  chlorambucil 
G-CSF
granulocyte colony-stimulating factor 
GI
gastrointestinal 
HBV
hepatitis B virus 
HBcAb
hepatitis B core antibody  
HBsAb
hepatitis B surface antibody 
HBsAg
hepatitis B surface antigen 
HCV
hepatitis C virus 
HIPAA
Health Insurance Portability and Accountability Act 
HTLV-1
human T-cell leukemia virus 1 
ICH
International Council for Harmonisation 
IDMC
Independent Data Monitoring Committee 
IgHV
immunoglobulin heavy chain variable region 
IND
Investigational New Drug (Application) 
IRB/EC
Institutional Review Board/Ethics Committee 
IRC
Independent Review Committee 
IRR
infusion-related reaction 
ITT
intent-to-treat (population) 
iwCLL
International Workshop on Chronic Lymphocytic Leukemia 
IxRS
interactive voice/web-response system 
JCV
John Cunningham virus 
LDT
lymphocyte doubling time 
LVEF
left ventricular ejection fraction 
mAb
monoclonal antibody 
MAH
Marketing Authorisation Holder 
MCL
mantle cell lymphoma 
MDASI-CLL
MD Anderson Symptom Inventory for Chronic Lymphocytic Leukemia 
MM
multiple myeloma 
MRD
minimal residual disease 
MRI
magnetic resonance imaging 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events 

Appendix 19:  Abbreviations 
Venetoclax and ObinutuzumabF. Hoffman-La Roche Ltd 
219/Protocol CO41685, Version 5 
Abbreviation 
Definition 
NGS 
next-generation sequencing 
NHL 
non-Hodgkin lymphoma 
NIMP 
non-investigational medicinal products 
ORR 
objective response rate 
OS 
overall survival 
PB 
peripheral blood 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response  
PRO 
patient-reported outcome 
PS 
performance status 
QD 
once daily 
QoL 
quality of life 
QTc 
QT interval corrected 
QTcF 
QT interval corrected through use of Fridericia's formula 
RBR 
Research Biosample Repository 
R/R 
relapsed/refractory 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
stable disease 
SEER 
Surveillance, Epidemiology, and End Results (report) 
SJS 
Stevens-Johnson Syndrome 
SLL 
small lymphocytic lymphoma 
TEN 
toxic epidermal necrolysis 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
VEN  G 
venetoclax (Venclexta or Venclyxto) in combination with obinutuzumab 
(Gazyva or Gazyvaro) 
VenR 
venetoclax in combination with rituximab 

Signature Page for Protocol - CO41685 - VENCLEXTA - v5 - Published
System identifier: RIM-CLIN-489606
Approval Task
Company Signatory
07-Jun-2023 20:06:58 GMT+0000