Clinical trial NCT02980731
Conditions: Chronic Lymphocytic Leukemia (CLL)
Keywords: Relapsed CLL Refractory CLL 17p deletion TP53 gene B-Cell receptor inhibitor (BCRi) European Organization of Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) Overall response rate (ORR) Duration of overall response (DOR) Complete remission rate (CR + CRi) Progression-free survival (PFS) Overall survival (OS)
Sponsor: AbbVie
Start date: 2016-12-13; Completion date: 2021-12-29
Enrollment: 210 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this open-label, single-arm study was to evaluate the impact of venetoclax on the quality of life of participants including those with with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL; a type of cancer affecting the blood and the bone marrow) with or without the 17p deletion or TP53 mutation, including participants with an unknown status, as well as R/R CLL participants who had been previously treated with B-cell receptor inhibitor (BCRi) therapy. The starting dose of venetoclax was 20 mg once daily. The dose must have been gradually increased over a period of 5 weeks up to the daily dose of 400 mg. Participants may have continued receiving venetoclax for up to 2 years. After the treatment period, participants may have continued on into a 2-year follow-up period.

Detailed description:

Arms: arm 1: Venetoclax was administered orally once daily (QD) for a planned duration of up to 2 years or until disease progression; median time on treatment was 127 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Interventions: intervention 1: Venetoclax
Intervention descriptions: intervention 1: Venetoclax tablets were to be taken orally once daily with a meal and water in the morning at approximately the same time each day. Tablets were to be swallowed whole and not chewed, crushed, or broken prior to swallowing.

Protocol documents:
Prot_000.pdf: 


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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions 
Protocol 
Date
Original
04 May 2016
Amendment 1
11 July 2016
Amendment 2
30 January 2018
The purpose of this amendment is to:
●
Revise Section 1.0 – Title page.
Rationale:  To update new TA/MD name and contact information and back up 
TA/MD name and contact information.
●
Revise Section 1.3 - List of Abbreviations and terms of definitions.
Rationale:  To change 'absolute lymphocyte count' to 'Absolute Lymphocyte 
Count' with initial capital letters to be consistent with the other abbreviations.
Rationale:  To correct 'Bone Marrow' to BM.  It was inadvertently previously 
listed as BIM. 
Rationale:  To correct 'Bcl-2 interacting mediator' to BIM.  It was 
inadvertently previously listed as BM. 
Rationale:  To add 'Bcl-2' (B-Cell Lymphoma 2) to list of abbreviations.  It 
was inadvertently not listed previously.  
Rationale:  To delete Serum Glutamic Pyruvic Transaminase from the list of 
abbreviations since this abbreviation is not mentioned in the protocol.
●
Revise Section 3.0 Introduction - Venetoclax Clinical Data
Rationale:  To update the Venetoclax Clinical Data section to align with the 
most recent version of the Investigator's Brochure.
●
Update Section 5.1, fourth paragraph. 
Rationale:  To add a ± 2 day visit window as of Week 8. 
●
Update Section 5.1, sixth paragraph.
Rationale:  To clarify that Bone Marrow samples will be collected for subjects 
with Complete Response to confirm response.
 


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●
Update Section 5.1, twelfth paragraph. 
Rationale:  To add that in countries where venetoclax is commercially 
available extension of therapy may not be allowed.
●
Revise Section 5.3.1.1 - Study Procedures - Physical Examination (Disease 
Assessment).
Rationale: To remove the requirement to evaluate lymph nodes at physical 
examinations at visits other than Screening and Weeks 24, 36 and 48.
●
Revise Section 5.3.1.1 - Study Procedures - Disease Assessments (2008 
Modified IWCLL NCI-WG Criteria) - first paragraph. 
Rationale:  To clarify that Bone marrow examinations at screening are not 
required but results will be recorded if available. 
●
Revise Section 5.3.1.1 - Study Procedures - Disease Assessments (2008 
Modified IWCLL NCI-WG Criteria) - third paragraph and Section 5.3.2.1
Primary Variables.
Rationale:  To clarify that if the CT is negative a bone marrow biopsy will be 
obtained to confirm clinical response.  If a CT scan is performed and does not 
confirm a clinical response, a bone marrow biopsy should not be obtained.
●
Revise Section 5.3.1.1 - Study Procedures - Disease Assessments (2008 
Modified IWCLL NCI-WG Criteria) - last paragraph.
Rationale:  To add that for patients with only Partial Remission at Week 48, 
an additional CT and a bone marrow examination can be done between 
Week 48 and Week 108 to confirm Complete Response if there is a possibility 
that a patient is in Complete Remission based on laboratory tests and a 
disease assessment physical examination.
●
Revise Section 5.3.1.1 - Study Procedures - 30 Day Safety Visit.
Rationale:  To clarify that If a subject has an ongoing AE or an unresolved 
clinically significant laboratory result 30 days following last dose of study 
drug, the site will attempt to provide follow-up until the AE has resolved to a 
≤Grade 1 or baseline or it is the investigator's judgment that the event is 
unlikely to resolve.  
●
Revise Section 5.3.1.1 - Study procedures - Extended Access Phase- and 
Synopsis - Methodology - Duration of Treatment.
 


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Rationale:  To add a new paragraph on the Extended Access Phase to explain 
that in countries where venetoclax is not commercially available, subjects who 
continue to derive benefit after 2 years of treatment may be able to extend their 
treatment for up to 2 additional years.  AbbVie will work with the investigator 
on a case by case basis to consider the potential continuation of venetoclax 
therapy.  The specific study assessments to be performed during these visits 
are detailed in Appendix E.
●
Revise Section 5.4.1 - Discontinuation of individual subjects.
Rationale:  Clarify that each subject has the right to withdraw from the study 
and/or study drug treatment at any time.  
Rationale:  Update the pregnancy verbiage to be in line with AbbVie's latest 
standard pregnancy language.
●
Revise Section 5.4.1 - Post treatment follow up calls. 
Rationale:  To clarify that subjects will be followed for survival information 
every 6 months even if subjects had an event of progression, they require 
alternate therapy, etc.
●
A window (± 7 days) was added to the post treatment calls. 
●
Revise Section 6.1.8 - Data Monitoring Committee and Synopsis -
Methodology.
Rationale:  To explain that the Data Monitoring Committee (DMC) will 
review the safety data intermittently according to the DMC charter.  Details of 
the DMC review are presented in the DMC charter.  The separate charter has 
been created to provide detailed descriptions of the schedule of analyses and 
the DMC meetings.
●
Revise Section 6.1.9.2 - Dose Modifications Based on Toxicities - Table 7.
Rationale:  To revise the footnote "a." for clinical TLS to explain that Clinical 
TLS was defined as laboratory TLS with clinical consequences such as acute 
renal failure, cardiac arrhythmias, sudden death, and/or seizures.
●
Revise Section 15.0 - Reference list. 
Rationale:  To add a reference for current version of Investigator's Brochure 
and remove the reference for Investigator's Brochure version 8.
●
Revise Appendix D study activities. 
 


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Rationale:  To add that Adverse Event/Concomitant medication assessment is
to be done also at the following visits: within 72 hours of W2 D1, W3 D1, W4 
D1 and W5 D1. 
Rationale: To separate the study activities list for Extended Access Visits from 
the main study activities list Appendix D.  Appendix D is created to capture the 
main study activities and Appendix E is created to capture the Extended 
Access Study Activities.
Rationale:  To be consistent with the changes and updates throughout the 
protocol. 
●
Incorporate additional administrative changes.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix I.
 


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-889
Name of Study Drug:  Venetoclax (ABT-199, 
GDC-0199) 
Phase of Development:  3b
Name of Active Ingredient:  Venetoclax 
Date of Protocol Synopsis:  09 October 2018
Protocol Title:  Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating the Impact of 
Venetoclax on the Quality of Life of Relapsed/Refractory Subjects with Chronic Lymphocytic Leukemia 
(CLL) (VENICE II)
Objectives:
Primary Objective:  The primary objective of this study is to evaluate the impact of venetoclax 
monotherapy on the quality of life of subjects with relapsed or refractory chronic lymphocytic leukemia 
(CLL).  Quality of life will be assessed by the Global Health Status/Quality of Life (GHS/QoL) subscale 
of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 
(EORTC QLQ-C30).
Secondary Objectives:  The secondary objectives are to evaluate the impact of venetoclax monotherapy 
on quality of life based on the European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Chronic Lymphocytic Leukemia Module (EORTC QLQ-CLL16), EuroQoL 5 
Dimension 5 Level Questionnaire (EQ-5D-5L), and the remaining subscales/items from the EORTC 
QLQ-C30; overall response rate (ORR); complete remission rate (CR + CRi); duration of  overall 
response (DOR), time to progression (TTP), duration of progression-free survival (PFS); overall survival 
(OS); and CR rate in BCRi treated subjects. 
The safety and tolerability of venetoclax in subjects with relapsed/refractory CLL will also be evaluated.
Investigators:  Multi-center  
Study Sites:  Approximately 43 sites in Latin America, Eastern Europe, and Asia-Pacific.
Study Population:  Subjects with relapsed/refractory (R/R) CLL with or without the 17p deletion or 
TP53 mutation, including subjects with an unknown status, as well as R/R CLL subjects who have been 
previously treated with B-cell receptor inhibitor (BCRi) therapy.
Number of Subjects to be Enrolled:  Approximately 200 subjects
 


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Methodology:  
This is a Phase 3b, single arm, open-label, multi-center study evaluating the impact of venetoclax on the 
quality of life of subjects with relapsed/refractory CLL.  All screening procedures must be performed 
within 28 days prior to initial study drug administration.  A contrast computed tomography (CT) scan (or 
magnetic resonance imaging [MRI] if a CT with contrast is medically contraindicated) will be accepted 
if previously performed within 35 days prior to study drug administration, otherwise a CT scan (or MRI) 
must be performed within the screening period of 28 days.  The starting dose of venetoclax is 20 mg 
once daily.  The dose must be gradually increased over a 5-week period up to the daily dose of 400 mg.  
For all subjects, study visits will be conducted within 72 hours of dosing and on the first and second day 
of Week 1 and Week 2 during the dose titration phase.  Beginning on Week 3, through Week 5, study 
visits will be conducted within 72 hours of dosing and on Day 1 of each week.  Additional study visits 
on Day 2 of each week should be performed for subjects who continue to be at risk for TLS, based on 
investigator assessment.
Study visits will be reduced to a monthly frequency at Week 8, and at Week 48, they will be reduced to 
every 3 months until the end of study treatment (Week 108).  In countries where venetoclax is not 
commercially available, subjects who continue to derive benefit after 2 years of treatment may be able to 
extend their treatment for up to 2 additional years.  Quality of life assessments will be performed within 
72 hours prior to the first dose of venetoclax, and at Week 4, Week 8, Week 12, Week 24, Week 36, and 
Week 48, then every 12 weeks thereafter until the end of study treatment (Week 108).  A Disease 
Assessment for clinical response by physical exam and hematologic assessments will be performed at 
Week 24, Week 36 and Week 48.  To confirm the response, a CT scan will be performed at Week 48 on 
all subjects.  When confirming a CR or CRi status per 2008 Modified International Workshop for 
Chronic Lymphocytic Leukemia National Cancer Institute Working Group (IWCLL-NCI-WG) criteria a 
bone marrow (BM) biopsy and aspirate should also be performed.  After treatment discontinuation, a 
final visit will be performed.  Subjects will be followed for disease progression (if progression has not 
already occurred) and survival.  Post-treatment follow up calls will be performed every 6 months until 
discontinuation from the study.  Survival information (i.e., the date and cause of death, post-treatment 
cancer therapies, date of progression etc.) will be collected.  This period will continue for 2 years 
following discontinuation of venetoclax.  
The Data Monitoring Committee (DMC) will review safety data intermittently according to the DMC 
charter.  Subsequent reviews may be conducted based on recommendations from the DMC or requests 
from the Sponsor.  Details of the DMC review will be presented in the DMC charter.
 


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Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
A subject will be eligible for study participation if he/she meets all of the following criteria:
1.
Age ≥ 18 years.
2.
Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
3.
Subject has relapsed/refractory disease (received at least one prior therapy). 
4.
Diagnosis of CLL that meets published 2008 Modified IWCLL NCI-WG guidelines and:

has an indication for treatment according to the 2008 Modified IWCLL NCI-WG criteria

has clinically measurable disease (lymphocytosis > 5 × 109/L and/or palpable and measurable 
nodes by physical exam and/or organomegaly assessed by physical exam)

subjects with or without the 17p deletion or TP53 mutation are eligible.

subjects who have received prior B-cell receptor inhibitor therapy are also eligible.
5.
Adequate bone marrow function as follows:

hemoglobin ≥ 8.0 g/dL

platelets ≥ 25,000/mm3 without any of the following:
o
transfusion support within 14 days of Screening
o
evidence of mucosal bleeding
o
known history of major bleeding episode within 3 months of Screening
Main Exclusion:  
A subject will not be eligible for study participation if he/she meets any of the following criteria:
1.
Subject has developed Richter's transformation or Prolymphocytic leukemia (PLL)
2.
Subject has previously received venetoclax.
3.
History of active malignancies other than CLL within the past 2 years prior to first dose of 
venetoclax, with the exception of:

adequately treated in situ carcinoma of the cervix uteri

adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin

previous malignancy confined and surgically resected (or treated with other modalities) with 
curative intent.
4.
Active and uncontrolled autoimmune cytopenias (within 2 weeks prior to Screening), including 
autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP), despite low 
dose corticosteroids.
5.
Prior allogeneic stem cell transplant.
 


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Investigational Product:
Venetoclax:  10 mg, 50 mg and 100 mg tablet
Doses:
Venetoclax will be administered orally once daily (QD), continuously.  
The starting dose of venetoclax is 20 mg QD.  After 1 week of 
treatment at 20 mg QD, the dose will be escalated to 50 mg QD 
followed by subsequent increases, each after 1 week, to 100 mg QD, 
200 mg QD and the target dose of 400 mg QD.
Mode of Administration:
Oral
Reference Therapy:
Not applicable.
Doses:
Not applicable.
Mode of Administration:
Not applicable.
Duration of Treatment:  
Subjects may continue receiving venetoclax for up to 2 years provided they continue to tolerate the drug, 
have no evidence of disease progression (based on investigator assessment), do not have unacceptable 
toxicity, and do not meet any of the criteria for subject discontinuation.  After treatment discontinuation, 
subjects will be followed for disease progression (if progression has not already occurred) and survival.  
Post-treatment calls will be performed every 6 months until discontinuation from the study.  Survival 
information (i.e., the date and cause of death, post-treatment cancer therapies, date of progression etc.) 
will be collected.  This period will continue for 2 years following discontinuation of venetoclax.
In countries where venetoclax is not commercially available, subjects who continue to derive benefit 
after 2 years of treatment, may be able to extend their treatment for up to 2 additional years.  AbbVie 
will work with the investigator on a case by case basis to consider the potential continuation of 
venetoclax therapy.
Criteria for Evaluation:
Quality of Life: 
Quality of life will be assessed based on patient-reported outcome (PRO) measures, including the 
EORTC QLQ-C30, EORTC QLQ-CLL16, and EQ-5D-5L.
Efficacy:
Disease response will be assessed by the investigator, based on laboratory results, physical examinations, 
using the 2008 modified IWCLL NCI-WG Criteria for Tumor Response including CT imaging (or MRI 
in the case CT is medically contraindicated) and bone marrow biopsy and aspirate for subjects with CR 
to confirm the response.
All measurable disease must be documented at Screening (baseline) by physical examination, laboratory 
testing, and CT scan (or MRI in the case CT is medically contraindicated).  During the study, clinical 
disease assessments will take place at Week 24, Week 36, and Week 48.  To confirm the response, a CT 
scan will be performed at Week 48.
Safety: 
Adverse event monitoring, vital signs, physical examination, and laboratory assessments will be 
evaluated.
 


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Statistical Methods: 
The study analyses will be descriptive.  All subjects participating in the study who received at least 
one dose of venetoclax will be included in the analyses unless otherwise noted in the separate, statistical 
analysis plan (SAP).
Study Variables:
Quality of Life:
Quality of life will be evaluated by assessing change from baseline (within 72 hours prior to the 
first dose of venetoclax) to Week 48 in the GHS/QoL subscale of the EORTC QLQ-C30 (primary 
endpoint).  Quality of life will be further evaluated by analyzing all multi-item scales and single-item 
scales from the EORTC QLQ-C30, EORTC QLQ-CLL16, and EQ-5D-5L.  Scores will be calculated 
based on the scoring manual for each instrument.
Efficacy Analyses Include:
The following efficacy endpoints will be analyzed:  Complete Remission rate (CR + CRi), Overall 
Response Rate (ORR), Duration of Overall  Response (DOR), Time to Progression (TTP), Duration of 
Progression-Free Survival (PFS) and Overall Survival (OS): 
Complete Remission Rate (CR) and Complete Remission with Incomplete Marrow Recovery (CRi)
Defined as the proportion of subjects who achieved a CR or CRi (all subjects and previously BCRi 
treated subjects)
Overall Response Rate (ORR)
Defined as the proportion of subjects with an overall response (complete remission plus partial 
remission). 
Duration of Overall Response (DOR)
Defined as the number of days from the date of first response (per the 2008 modified IWCLL NCI-WG 
criteria) to the date of disease progression or death.  All disease progression will be included regardless 
whether the event occurred while the subject was taking venetoclax or had previously discontinued 
venetoclax.
Time to Progression (TTP)
Defined as the number of days from the date of first dose of venetoclax to the date of disease 
progression.  All disease progression will be included regardless whether the event occurred while the 
subject was taking venetoclax or had previously discontinued venetoclax.
Duration of Progression-Free Survival (PFS)
Defined as the number of days from the date of first dose of venetoclax to the date of disease progression 
or death, whichever occurs first.  All disease progression will be included regardless whether the event 
occurred while the subject was taking venetoclax or had previously discontinued venetoclax.
Overall Survival (OS)
Defined as number of days from the date of first dose of venetoclax to the date of death.
 


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Statistical Methods (Continued):
Sample Size Estimation:
An improvement in the EORTC QLQ-C30 GHS/QoL subscale of 5 units is considered to be a clinically 
meaningful difference to subjects.  From a prior study of venetoclax monotherapy in 17p del R/R CLL 
subjects (Study M13-982), the standard deviation was approximately 20.5 for the GHS/QoL subscale.  
Using a one-sided alpha of 0.025, 90% power, and a standard deviation of 20.5; 177 subjects are 
required to reject the null hypothesis in favor of the alternative hypothesis that venetoclax improves 
GHS/QoL by at least 5 units.  To account for potential drop-outs at Week 48, a total of 200 subjects to 
be dosed.
Safety:
A safety analysis will be performed for all subjects participating in the study who took at least one dose 
of study drug.  For the study as a whole, adverse events will be evaluated and summarized.  Laboratory 
test results and vital signs will be explored for trends and summarized.
 


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ABT-199
Study Drug Compound, "Venetoclax"
AE
Adverse Event
AIHA
Autoimmune Hemolytic Anemia
ALC
Absolute Lymphocyte Count
ALT
Alanine transaminase
AML
Acute Myeloid Leukemia
ASCO
American Society of Clinical Oncology
AST
Aspartate transaminase
aPTT
Activated Partial Thromboplastin Time
BAK
BCL-2 Antagonist/Killer
BAX
Bcl-2 associated X protein
Bcl
B-Cell Lymphoma
Bcl-2
B-Cell Lymphoma 2
Bcl-w
B-Cell Lymphoma protein W
Bcl-XL
B-Cell lymphoma-extra large
BCR
B-Cell receptor
BCRi
B-Cell receptor inhibitor
BCR PI
B-cell receptor pathway inhibitor
BH
Bcl-2 Homology
β-hCG
Beta-human chorionic gonadotropin
BM
Bone marrow
BIM
Bcl-2 interacting mediator
BUN
Blood Urea Nitrogen
CD
Cluster of differentiation
CLL
Chronic Lymphocytic Leukemia
CI
Confidence interval
cm
Centimeter
CR
Complete Remission
CRi
Complete Remission with Incomplete Marrow Recovery
CT
Computed Tomography
CTLS
Clinical Tumor Lysis Syndrome
 


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CYP3A
Cytochrome P450 3A
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DOR
Duration of Overall Response
eCCr
Estimated creatinine clearance rate using Cockcroft-Gault Formula
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic data capture
EMEA
European Agency for the Evaluation Medicinal Products
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Core Questionnaire
EORTC QLQ-CLL16
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Chronic Lymphocytic Leukemia Module
EQ-5D-5L
EuroQoL 5 Dimension 5 Level Questionnaire
EU
European Union
FL
Follicular Lymphoma
G-CSF
Granulocyte-colony stimulating factor
GCP
Good Clinical Practice
GDC-0199
Venetoclax (ABT-199)
g/dL
Grams per deciliter
GHS
Global Health Status
GM-CSF
Granulocyte macrophage colony-stimulating factor
HBs
Hepatitis B surface
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
High Density Polyethylene
HIV
Human Immunodeficiency Virus
Hr
Hour
HR
Hazard Ratio
HRQoL
Health-related qualify of life
ICH
International Conference on Harmonisation
ICSR
Individual case safety report
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
INR
International Normalized Ratio
 


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IRB
Institutional Review Board
IRT
Interactive Response Technology
ITP
Idiopathic thrombocytopenic purpura
IUD
Intrauterine device
IV
Intravenous
IVIG
Intravenous immunoglobulins
IWCLL NCI-WG
2008 Modified International Workshop on Chronic Lymphocytic Leukemia 
National Cancer Institute-Working Group Guidelines
kg
Kilogram
Ki
Kinetic inhibitor
LDH
Lactate Dehydrogenase
LDi
Longest Diameter
LN
Lymph Node
LTLS
Laboratory Tumor Lysis Syndrome
MedDRA
Medical Dictionary for Regulatory Activities
µL
Microliter
mg
Milligram
MID
Minimum important difference
MiRNA
microRNA
mL
Milliliter
mL/min
Milliliter per minute
mmol
millimolar
MM
Multiple Myeloma
mm
Millimeter
µM
Micromolar
MRI
Magnetic Resonance Imaging
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Event
NHL
Non-Hodgkin's Lymphoma
nM
Nanomolar
nPR
Nodular Partial Remission
ORR
Overall Response Rate
OS
Overall Survival
PB
Peripheral Blood
PD
Progressive Disease
 


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PET
Positron Emission Tomography
PFS
Progression-free Survival
PLL
Prolymphocytic leukemia
PR
Partial Remission
PRO
Patient-reported Outcome
PT
Prothrombin Time
QA
Quality assurance
QC
Quality control
QD
Once Daily
QoL
Quality of Life
RBC
Red Blood Cell
RNA
Ribonucleic Acid
R/R
Relapsed Refractory 
SAE
Serious Adverse Event
SAP
Statistical analysis plan
SD
Stable Disease
SGOT
Serum Glutamic-oxaloacetic Transaminase
SLL
Small Lymphocytic Lymphoma
SPD
Sum of the products of the greatest diameters
STAT
Immediately
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
Therapeutic Area Medical Director
TLS
Tumor Lysis Syndrome
TP53
Tumor protein 53gene
TTP
Time to Progression
ULN
Upper Limit of Normal
US
Ultrasound
VAS
Visual Analog Scale
WBC
White Blood Cell
WOCP
Women of Childbearing Potential
 


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 6
1.3
List of Abbreviations and Definition of Terms...................................... 12
2.0
Table of Contents ................................................................16
3.0
Introduction.........................................................................21
3.1
Differences Statement .......................................................................... 27
3.2
Benefits and Risks................................................................................ 27
4.0
Study Objective ...................................................................28
5.0
Investigational Plan.............................................................29
5.1
Overall Study Design and Plan:  Description ........................................ 29
5.2
Selection of Study Population............................................................... 32
5.2.1
Inclusion Criteria.................................................................................. 32
5.2.2
Exclusion Criteria................................................................................. 34
5.2.3
Prior and Concomitant Therapy............................................................ 37
5.2.4
Contraception Recommendations ......................................................... 40
5.3
Study Assessments/Variables ............................................................... 41
5.3.1
Study Assessments and Flow Chart ...................................................... 41
5.3.1.1
Study Procedures.................................................................................. 42
5.3.2
Study Variables .................................................................................... 55
5.3.2.1
Primary Variable .................................................................................. 55
5.3.2.2
Secondary Variables............................................................................. 55
5.3.2.2.1
Quality of Life Assessments ................................................................. 56
5.3.2.2.2
Disease Assessments ............................................................................ 57
5.3.2.3
Definition of Disease Progression......................................................... 63
5.3.3
Safety Variables ................................................................................... 64
5.4
Removal of Subjects from Therapy or Assessment ............................... 64
5.4.1
Discontinuation of Individual Subjects ................................................. 64
5.4.2
Discontinuation of Entire Study............................................................ 66
5.5
Treatments ........................................................................................... 66
5.5.1
Treatments Administered...................................................................... 66
 


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5.5.2
Identity of Investigational Product........................................................ 67
5.5.2.1
Packaging and Labeling........................................................................ 67
5.5.2.2
Storage and Disposition of Study Drug................................................. 67
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 68
5.5.4
Selection and Timing of Dose for Each Subject.................................... 68
5.5.5
Blinding ............................................................................................... 69
5.5.6
Treatment Compliance ......................................................................... 69
5.5.7
Drug Accountability ............................................................................. 70
5.6
Discussion and Justification of Study Design........................................ 70
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 70
5.6.2
Appropriateness of Measurements........................................................ 71
5.6.3
Suitability of Subject Population .......................................................... 71
5.6.4
Selection of Doses in the Study ............................................................ 71
6.0
Complaints...........................................................................72
6.1
Medical Complaints ............................................................................. 72
6.1.1
Definitions ........................................................................................... 73
6.1.1.1
Adverse Event...................................................................................... 73
6.1.1.2
Serious Adverse Events........................................................................ 74
6.1.1.3
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL.................................................. 75
6.1.1.4
Adverse Events of Special Interest........................................................ 76
6.1.2
Adverse Event Severity ........................................................................ 76
6.1.3
Adverse Events Expected Due to Study-Related Endpoints .................. 77
6.1.3.1
Deaths .................................................................................................. 77
6.1.3.2
Lack of Efficacy or Worsening of Disease............................................ 78
6.1.4
Relationship to Study Drug................................................................... 78
6.1.5
Adverse Event Collection Period.......................................................... 79
6.1.6
Adverse Event Reporting...................................................................... 79
6.1.7
Pregnancy............................................................................................. 81
6.1.8
Data Monitoring Committee................................................................. 81
6.1.9
Toxicity Management........................................................................... 82
6.1.9.1
Prophylaxis and Management of Tumor Lysis Syndrome ..................... 82
6.1.9.2
Dose Modifications Based on Toxicities............................................... 85
 


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6.1.9.3
Management of Neutropenia................................................................. 88
6.1.9.4
Immunization ....................................................................................... 88
6.1.9.5
Management of Hematologic Toxicities Other Than Neutropenia 
or Lymphopenia ................................................................................... 88
6.1.9.6
Management of Non-Hematologic Toxicity.......................................... 89
6.2
Product Complaint................................................................................ 89
6.2.1
Definition............................................................................................. 89
6.2.2
Reporting ............................................................................................. 89
7.0
Protocol Deviations .............................................................90
8.0
Statistical Methods and Determination of Sample 
Size .......................................................................................91
8.1
Statistical and Analytical Plans............................................................. 91
8.1.1
Baseline Characteristics........................................................................ 91
8.1.1.1
Demographics ...................................................................................... 92
8.1.1.2
Medical Histories ................................................................................. 92
8.1.2
Study Endpoints ................................................................................... 92
8.1.2.1
Primary Endpoint ................................................................................. 92
8.1.2.2
Secondary Endpoints............................................................................ 92
8.1.3
Timing of Study Endpoints and Safety Evaluations .............................. 94
8.1.4
Safety................................................................................................... 95
8.1.4.1
Adverse Events..................................................................................... 95
8.1.4.2
Serious Adverse Events........................................................................ 95
8.1.4.3
Deaths .................................................................................................. 95
8.1.4.4
Analyses of Laboratory Data ................................................................ 96
8.2
Determination of Sample Size .............................................................. 96
9.0
Ethics....................................................................................96
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ......................................................................................... 96
9.2
Ethical Conduct of the Study................................................................ 97
9.3
Subject Information and Consent.......................................................... 97
10.0
Source Documents and Case Report Form 
Completion ..........................................................................98
10.1
Source Documents................................................................................ 98
 


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10.2
Case Report Forms ............................................................................... 99
11.0
Data Quality Assurance .................................................... 100
12.0
Use of Information ............................................................ 100
13.0
Completion of the Study ................................................... 101
14.0
Investigator's Agreement.................................................. 102
15.0
Reference List.................................................................... 103
List of Tables
Table 1.
Excluded and Cautionary Medications.................................................. 39
Table 2.
Sample of Permitted Medications ......................................................... 40
Table 3.
ECOG Performance Status ................................................................... 47
Table 4.
Clinical Laboratory Tests (Assessed by Local Laboratory) ................... 48
Table 5.
2008 Modified IWCLL NCI-WG Criteria for Tumor Response ............ 62
Table 6.
Identity of Investigational Product........................................................ 67
Table 7.
Recommended Dose Modifications for Toxicities................................. 86
Table 8.
Dose Modification for Toxicity During Venetoclax Treatment ............. 87
List of Figures
Figure 1.
5-Week Dose-Titration Schedule.......................................................... 30
Figure 2.
5-Week Dose-Titration Schematic ........................................................ 69
Figure 3.
Adverse Event Collection..................................................................... 79
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................109
Appendix B.
List of Protocol Signatories .................................................................111
Appendix C.
Sample List of Excluded and Cautionary Medications .........................112
Appendix D.
Study Activities:  Screening Through Week 5 Day 2 ...........................114
Appendix E.
Schedule of Extended Access Phase* ..................................................119
Appendix F.
Definitions of Laboratory and Clinical Tumor Lysis Syndrome ...........121
 


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Appendix G.
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS)..........123
Appendix H.
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL.................................................128
Appendix I.
Protocol Amendment:  List of Changes ...............................................130
 


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3.0
Introduction
B-Cell Lymphoma-2 (Bcl-2) Family Proteins
The B-cell lymphoma-2 (Bcl-2) family proteins are important regulators of the intrinsic 
apoptosis pathway.  The Bcl-2 oncogene was first identified in follicular lymphoma (FL) 
where the t(14;18) chromosomal translocation results in significant over-expression of the 
protein in B-cells.  The Bcl-2 family of genes encodes a family of closely related proteins 
that possess either pro-apoptotic or anti-apoptotic activity and share up to four Bcl-2 
Homology (BH) domains.1-4  Bcl-2 overexpression is a major contributor to the 
pathogenesis of some types of lymphoid malignancies.  Bcl-2 is also overexpressed in 
acute and chronic leukemias.  Chronic lymphocytic leukemia (CLL) is a genetic disease 
where the microRNAs miR15a and miR16-1 that negatively regulate the transcription of 
Bcl-2 are deleted or down-regulated, resulting in uncontrolled expression of Bcl-2.5,6
Venetoclax (ABT-199) 
Venetoclax (also known as ABT-199) is a novel, orally bioavailable, small molecule 
Bcl-2 family protein inhibitor that binds with high affinity (Kinetic Inhibitor [Ki] 
< 0.010 nM) to antiapoptotic Bcl-2 and with lower affinity to other antiapoptotic Bcl-2 
family proteins like B-cell lymphoma-extra-large (Bcl-XL) and B-cell lymphoma-Walter 
and Eliza Hall Institute (Bcl-w) (> 4,000 fold and > –2,000- to > 20,000-fold lower 
affinity than to Bcl-2, respectively).7  Selective inhibition by venetoclax disrupts Bcl-2 
signaling and rapidly induces multiple hallmarks of apoptotic cell death in Bcl-2-
dependent human tumor cell lines.8  Importantly, venetoclax inhibition of Bcl-2 is 
independent of p53 activity. 
For further details, please see findings from completed and ongoing studies, including 
safety data in the current Venetoclax Investigator's Brochure.8
 


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Venetoclax Clinical Data
Tumor lysis syndrome (TLS) is an important risk, particularly in subjects with 
relapsed/refractory CLL.  As a result of on-target effects, the potential for TLS with 
venetoclax was identified early in the program when the initial 3 subjects with CLL/SLL 
received starting doses of 100 mg or 200 mg and experienced TLS, which was reported as 
an adverse event for each.  Subsequently, 2 fatal events in the setting of TLS and another 
event of clinical TLS in subjects with CLL/SLL occurred in December 2012.  After 
comprehensive review of all safety data available from studies with venetoclax, a revised 
dosing regimen with a dose-titration phase of 5 weeks and enhanced TLS prophylaxis and 
monitoring measures were implemented in all CLL studies.  A subsequent analysis of data 
from subjects with CLL/SLL following the implementation of prophylaxis measures, who 
completed monotherapy indicated a marked reduction in severity and frequency of TLS 
when compared to the previous analysis.  None of the subjects experienced any serious 
(including fatal) or nonserious event of clinical TLS (CTLS) or laboratory TLS (LTLS) or 
had study treatment discontinued because of TLS.  Since May 2014, a more personalized 
approach for prophylaxis and monitoring measures, where subjects with lower tumor 
burden could receive venetoclax on an out-patient basis, has been evaluated with no cases 
of clinical TLS.  Overall, the clinical data strongly support that the risk of TLS with 
venetoclax in CLL/SLL subjects is highest when initiating venetoclax dosing (5-week 
dose titration phase), as well as being greater in subjects with a large tumor burden.
The safety profile in combination studies is consistent with that observed in monotherapy 
studies and with known toxicity profile of combination agents.  Preliminary efficacy data 
indicate that venetoclax, both as monotherapy and in combination with other therapeutic 
agents, continues to show promising efficacy in oncology subject populations.  The 
overall response rate (ORR) in subjects with CLL/SLL was 75.0% to 81.7% (dose 
escalation and safety expansion cohorts, respectively), with a complete remission rate (CR 
+ CRi) of 32.1% in dose escalation and 11.7% in safety expansion cohort for venetoclax 
monotherapy (Study M12-175 as of 10Jun2016).9
Additional safety and efficacy data are described in detail in the Investigator Brochure.8
 


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Chronic Lymphocytic Leukemia (CLL)
CLL is a lymphoproliferative disorder, characterized by progressive accumulation of 
monoclonal, small, mature-appearing CD5+ B cells in peripheral blood, bone marrow, and 
secondary lymphoid organs.  It is the most common form of leukemia in adults in the 
Western World, accounting for approximately 30% of all leukemias.10  CLL primarily 
affects elderly individuals; however, approximately one third of subjects are less than 
60 years of age at diagnosis.11  It is currently estimated that annually approximately 
15,000 people will be diagnosed with CLL in the United States, and that almost 
4,500 individuals will die of the disease.12  In Europe, CLL accounts for approximately 
30% of all leukemias in adults with a reported age standardized incidence rate of 3.79 per 
100,000 individuals (for CLL/SLL) in the years 2000 – 2002.10,13  The approximate 5-year 
survival rate for subjects with CLL is 73%.14  CLL presents with a variable clinical 
course.  Approximately one-third of subjects have indolent disease with prolonged median 
survival that does not require treatment, and die of causes unrelated to disease.  Another 
third have an initial indolent phase that is followed by rapid progression of the disease 
requiring therapy.  The remaining third have aggressive disease and require treatment at 
the time of diagnosis.  Chronic lymphocytic leukemia subjects will often have 
compromised bone marrow reserve due to their underlying disease.  The principal 
complication of CLL is immunodeficiency related to myelosuppression and as a result, 
infection is the major cause of death in subjects with CLL.15
Standard chemotherapeutic options for CLL cause significant immune suppression and 
myelosuppression, are not well-tolerated by the elderly population and have not 
consistently offered survival advantage.  Treatment decisions for subjects with CLL are 
made on the basis of considerations such as age, clinical stage, expected survival, and 
anticipated toxicities.  With the notable exception of allogeneic stem cell transplantation, 
CLL is currently an incurable disease, despite good initial responses to chemo 
immunotherapy.  Nonetheless, globally access to allogeneic stem cell transplant and/or 
clinical trials is limited, and treatment options for relapsed disease tend to have increased 
toxicity and reduced antitumor activity.
 


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Chromosome 17p Deletion and TP53 Gene Mutation in Chronic Lymphocytic 
Leukemia
Chromosome 17p deletion and TP53 gene mutation are among a group of genetic defects 
that occur in subsets of subjects with CLL in addition to defects causing Bcl-2 
dysregulation.  The short arm of chromosome 17 contains the TP53 gene that encodes 
tumor protein p53, a tumor suppressor involved in deoxyribonucleic acid (DNA) repair 
activation, cell cycling regulation, and apoptosis signaling.  Standard cytotoxic 
chemotherapies used in the treatment of CLL (i.e., fludarabine, cyclophosphamide, and 
bendamustine), act by inducing DNA damage and triggering apoptosis.  The p53 tumor 
suppressor is essential for relaying the DNA damage signal to the apoptotic machinery.  
When p53 is functionally inactivated, either through mutation or deletion, these signals 
are not effectively relayed and the efficacy of these agents is diminished.  Chromosome 
17p deletion and TP53 mutation occur over the course of the disease and expand under 
treatment selection pressure as a result of the resistance to chemotherapy and 
chemoimmunotherapy they confer.16-18  Notably, over 80% of subjects with 17p deletion 
also carry a TP53 mutation.17,19
The decreased likelihood of subjects with 17p deletion and/or TP53 mutation responding 
to standard chemotherapy and chemoimmunotherapy regimens is accompanied by a 
greater risk of disease progression and a shorter overall survival (OS).7,16-18,20  In a long-
term follow-up study of the effects of 17p deletion/TP53 mutation in CLL subjects treated 
according to standard practice outside of a clinical study, survival periods measured from 
date of study sampling were 7.6 months or less for subjects with 17p deletion and/or TP53 
mutation compared to 69 months for subjects without TP53 loss or mutations.21
Poorer outcomes in subjects with these aberrations have also been demonstrated in large 
randomized clinical treatment trials.  In the CLL8 trial (n = 817) comparing first-line 
chemoimmunotherapy (fludarabine/cyclophosphamide/rituximab) to chemotherapy alone 
(fludarabine/cyclophosphamide), multivariate analyses of prognostic indicators for 
survival at a median follow-up of 70 months found hazard ratios [HR] of 
2.916 (confidence interval [CI]:  1.779 – 4.781) and 2.715 (CI:  1.602 – 4.602) for 
 


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progression-free survival (PFS) and OS, respectively, for subjects with 17p deletion and 
2.123 (CI:  1.400 – 3.218) and 3.014 (CI:  1.889 – 4.808), respectively, for subjects with 
TP53 mutations indicated.18  Poorer response to first-line treatment and shorter survival in 
subjects with 17p deletion and/or TP53 mutation were also observed in the CLL4 trial of 
777 subjects randomized to chlorambucil or fludarabine with or without 
cyclophosphamide and in subjects with 17p deletion treated in the E2997 trial (n = 278) of 
fludarabine with or without cyclophosphamide.22,23
Relatively improved treatment responses have been shown in 17p deletion/TP53 mutant 
first-line and relapsed subject populations with alemtuzumab, a monoclonal antibody 
specific for B cell surface molecule CD52, in combination with steroids 
(e.g., methylprednisolone, dexamethasone).24,25  In a Phase II study (n = 39) the overall 
response rate, complete response (including with incomplete bone marrow recovery) rate 
(CR/CRi), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, 
respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, 
respectively, in the 17 previously untreated subjects.  Treatment-related death occurred in 
5% of subjects, 67% of subjects experienced Grade 3/4 hematologic and glucocorticoid-
associated toxicity, and 51% experienced Grade 3 infection.24
The tyrosine kinase inhibitors ibrutinib and idelalisib that act downstream of the B cell 
receptor have also been shown to produce relatively improved responses compared to 
standard therapies and have been approved for use in some jurisdictions for the treatment 
of CLL subjects with 17p deletion (ibrutinib, idelalisib) or TP53 mutations (idelalisib 
only).  Ibrutinib inhibits Bruton's tyrosine kinase, an enzyme involved in B-cell receptor 
(BCR) signaling, homing, and adhesion.  A Phase III relapsed or refractory CLL study 
comparing ofatumumab (an anti-CD20 monoclonal antibody) to ibrutinib included 
127 subjects with the 17p deletion.  In this cohort, the median duration of PFS was 
5.8 months in the ofatumumab arm but was not reached in the ibrutinib arm (HR 0.25; 
95% CI:  0.14, 0.45).  The overall response rate was 47.6% with ibrutinib compared with 
4.7% with ofatumumab.  No complete responses were observed.26  Overall, 57% of 
subjects in the ibrutinib arm had at least one ≥ Grade 3 adverse event (AE).  The most 
 


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frequent non-hematologic AEs (> 20% of subjects) with ibrutinib were diarrhea, fatigue, 
pyrexia, and nausea.27  Grade 3/4 AEs reported in ≥ 5% of the 357 subjects with mantle 
cell lymphoma or CLL that received ibrutinib during clinical development were anemia, 
neutropenia, pneumonia and thrombocytopenia.28
Idelalisib targets the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ) involved in 
signal transduction via multiple receptors including the BCR and chemokine receptors 
CXCR4 and CXCR5.  A Phase III study comparing combined idelalisib/rituximab 
treatment with rituximab/placebo in previously treated subjects reported improved PFS in 
the idelalisib arm among the 96 subjects enrolled with 17p deletion or TP53 mutation (HR 
0.12; CI:  0.05, 0.32).  The majority of AEs in the study were Grade 2 and the most 
common in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea.29  The 
overall safety profile determined in Phase I to III studies of idelalisib in hematologic 
malignancies as monotherapy or in combination with an anti-CD20 monoclonal antibody 
is characterized by a very common frequency (≥ 1/10 subjects) of ≥ Grade 3 infections, 
neutropenia, diarrhea/colitis and increased transaminase.30
CLL Subjects Who Have Received Prior B-Cell Receptor Inhibitor (BCRi) Therapy
Ibrutinib and idelalisib cause rapid response with reduction in lymph node size and 
splenic mass accompanied by increased peripheral blood (PB) lymphocytosis likely 
reflecting that microenvironment modulation could prevent these cells from receiving the 
survival signals delivered by the microenvironment.31  In early trials of ibrutinib, 
approximately 10% of the subjects developed progressive disease (PD).  Few of these 
subjects developed resistance after achieving partial response lasting ≥ 6 months.  Distinct 
single nucleotide variations were noted in these subjects.32
In addition, toxicities such as diarrhea, fatigue and pyrexia are common and can affect the 
subjects who receive these drugs.27,29
However, the mechanism of action of venetoclax is independent of the B-cell receptor 
(BCR) pathway.33  Briefly, venetoclax inhibits Bcl-2 allowing the release of BIM, which 
 


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includes oligomerization of pro-apoptotic molecules such as BAK and BAX which 
triggers rapid apoptosis.  The clinical data to date with venetoclax monotherapy shows 
strong activity in refractory CLL indicating that it might be beneficial in a population that 
is refractory to these newer therapeutic agents.
Despite some improvement in disease outcomes in relapsed/refractory CLL subjects, 
including those who have received novel agents, significant toxicities remain a concern, 
complete disease responses are uncommon, and relapse is virtually inevitable.  Subjects 
carrying TP53 aberrations and those who have received prior a BCRi therapy continue to 
represent a significant unmet medical need and current treatment recommendations 
include participation in investigative clinical trials proceeding to allogeneic hematopoietic 
stem cell transplantation in responding subjects eligible for transplant (e.g., younger age 
with no co-morbidities and a suitable donor).16,34
Further details of disease activity observed in clinical studies with venetoclax are 
provided in the Venetoclax Investigator's Brochure.8
3.1
Differences Statement
This is a Phase 3b study to assess the impact on quality of life of venetoclax monotherapy 
as a primary endpoint in relapsed or refractory CLL subjects.  In this study, several PRO 
measures will be utilized to assess quality of life in subjects with relapsed or refractory 
CLL.  This data will add to the quality of life data already collected from 17p deletion 
CLL subjects in Study M13-982.35  In addition, the impact of venetoclax monotherapy on 
quality of life will be assessed in correlation with efficacy data (i.e., overall response rate 
[ORR], duration of overall response [DOR], etc).  This will allow for an assessment of the 
relationship between quality of life and treatment outcomes in this high risk subject 
population.
3.2
Benefits and Risks
There is data from a previous study (Study M13-982) that shows there is substantial 
improvement in quality of life in addition to efficacy with venetoclax monotherapy in 
 


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subjects with relapsed/refractory CLL characterized by 17p deletion.  Venetoclax is 
expected to be as active in subject selected for TP53 mutations as these subject 
populations overlap and the oncogenic effect of both genetic defects occurs via 
p53 abrogation.  In addition, there are limited data in the BCRi failure CLL population for 
subjects that subsequently receive venetoclax and also in subjects without the 
17p deletion.  Current CLL therapies do not reliably produce complete responses and are 
not curative in subjects with p53 aberrations or those refractory to BCRi.  Furthermore, 
drugs more recently approved for these subjects are limited by toxicity.
Clinical safety data indicate that the adverse effects of venetoclax administered with 
appropriate measures are manageable and as expected from a treatment targeting 
hematologic cells including in subjects with 17p, TP53 mutation or subjects who have 
previously received BCRi therapy.
Additional safety and efficacy data can be found in the current Venetoclax Investigator's 
Brochure.8
4.0
Study Objective
The primary objective of this study is to evaluate the impact of venetoclax monotherapy 
on the quality of life of subjects with relapsed or refractory chronic lymphocytic leukemia 
(CLL).  Quality of life will be assessed by the Global Health Status/Quality of Life 
(GHS/QoL) subscale of the European Organization for Research and Treatment of Cancer 
Quality of Life Core Questionnaire (EORTC QLQ-C30).
The secondary objectives are to evaluate the impact of venetoclax monotherapy on quality 
of life based on the European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire Chronic Lymphocytic Leukemia Module (EORTC QLQ-CLL16), 
EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L), and the remaining 
subscales/items from the EORTC QLQ-C30; overall response rate (ORR); complete 
remission rate (CR + CRi); duration of  overall response (DOR), time to progression 
 


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(TTP), duration of progression-free survival (PFS); overall survival (OS); and CR rate in 
BCRi treated subjects. 
The safety and tolerability of venetoclax in subjects with relapsed/refractory CLL will 
also be evaluated.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is an open-label, single arm, Phase 3b, multi-center study evaluating the impact of 
venetoclax monotherapy on the quality of life in relapsed/refractory CLL.
This study is designed to enroll approximately 200 subjects to meet scientific objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.  
All efforts will be made to adhere to these specific enrollment numbers; however, it would 
not be ethical to deny treatment to eligible subjects in screening as they may have 
undergone study related procedures.
Subjects in this study will be enrolled at approximately 43 research sites in Latin America, 
Eastern Europe, and Asia-Pacific.
Subjects will undergo screening procedures within 28 days prior to initial venetoclax 
administration.  For all subjects, a contrast computed tomography (CT) scan (or medically 
indicated alternative such as magnetic resonance imaging [MRI]) will be accepted if 
previously performed within 35 days prior to venetoclax administration.  Otherwise, a CT 
scan (or MRI) must be performed within the screening period of 28 days.  Following the 
4-week Screening period, eligible subjects will initiate venetoclax and attend study visits 
within 72 hours of dosing and on the first and second day of Week 1 and Week 2 during 
the dose titration phase.  Beginning on Week 3, through Week 5, study visits will be 
conducted within 72 hours of dosing and on Day 1 of each week.  Additional study visits 
on Day 2 of each week should be performed for subjects who continue to be at risk for 
TLS, based on investigator assessment.  Study visits will be reduced to a monthly 
 


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frequency at Week 8, and at Week 48, they will be reduced to every 3 months until the 
end of study treatment (Week 108). As of Week 8, the visit window for scheduled visits 
is ± 2 days.  A 30 day Safety Follow-up Visit should be performed approximately 30 days 
(±3 days) following the last dose of venetoclax (to allow for AE collection 30 days 
following last dose of study drug).  If a subject is discontinued from the study with an 
ongoing AE or an unresolved clinically significant laboratory result, the site will attempt 
to provide follow-up until the AE has resolved to a ≤ Grade 1 or baseline or it is the 
investigator's judgment that the event is unlikely to resolve. 
Venetoclax will be administered orally once daily (QD), continuously.  Venetoclax tablets 
should be taken with a meal and water in the morning at approximately the same time 
each day.  To mitigate the risk for TLS, the first 5 weeks of treatment include a dose-
titration phase where venetoclax will be dosed in increments as outlined in Figure 1.  The 
starting dose of venetoclax is 20 mg once daily.  The dose will be gradually increased 
over a period of 5 weeks up to the daily dose of 400 mg.
Figure 1.
5-Week Dose-Titration Schedule
Week
VENETOCLAX 
Daily Dose
1
20 mg
2
50 mg
3
100 mg
4
200 mg
5 and beyond
400 mg
Disease response will be assessed by the investigator based on laboratory results and 
physical examinations using the 2008 Modified International Workshop on CLL National 
Cancer Institute – Working Group (IWCLL NCI-WG) Guidelines for Tumor Response 
with the addition of CT imaging (or MRI).  Quality of Life Assessments will be 
performed within 72 hours prior to the first dose of venetoclax and at Week 4, Week 8, 
Week 12, Week 24, Week 36, and Week 48, then every 12 weeks thereafter until the end 
of study treatment (Week 108).  A Disease Assessment for clinical response by physical 
 


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exam and hematologic assessments will be performed at Screening, Week 24, Week 36 
and Week 48.  To confirm the response, a CT scan (or MRI if CT is medically 
contraindicated) will be performed at Week 48 on all subjects and BM samples will be 
collected for subjects with CR to confirm the response.
When confirming a CR or Cri status per the 2008 IWCLL NCI-WG guidelines, a bone 
marrow biopsy and aspirate should also be performed.
Quality of life will primarily be assessed by using the GHS/QoL subscale of the EORTC 
QLQ-C30.  Secondary objectives will evaluate the quality of life based on the EORTC 
QLQ-CLL16, EQ-5D-5L, and the remaining subscales/items from the EORTC QLQ-C30.
Subjects may continue to receive venetoclax for up to 2 years provided they continue to 
tolerate the drug, have no evidence of disease progression (based on Investigator's 
assessment), do not have unacceptable toxicity, and do not meet any of the criteria for 
discontinuation (Section 5.4.1).  A final visit will be conducted upon treatment 
discontinuation.
After treatment discontinuation, subjects will be followed for disease progression (if 
progression has not already occurred) and survival.  Post-treatment calls will be 
performed every 6 months until discontinuation from the study.  Survival information 
(i.e., the date and cause of death, post-treatment cancer therapies, date of progression, 
etc.) will be collected.  This period will continue for 2 years following discontinuation of 
venetoclax. 
All study procedures will be performed as outlined in Section 5.3.1.1 and Appendix D and 
Appendix E. 
For subjects who continue to derive benefit after 2 years of treatment, AbbVie will work 
with the investigator on a case by case basis to consider the potential continuation of 
venetoclax therapy.  In countries where venetoclax is commercially available, extension 
of therapy may not be allowed.
 


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A safety analysis will be performed for all subjects participating in the study who took at 
least one dose of study drug.  For the study as a whole, serious adverse events and adverse 
events will be evaluated and summarized.  Laboratory test results and vital signs will be 
explored for trends and summarized. 
5.2
Selection of Study Population
Subjects will undergo screening procedures within 28 days prior to initial venetoclax 
administration, with the exception of the CT scan (or MRI if CT is medically 
contraindicated).  A CT scan will be accepted if previously performed within 35 days 
prior to venetoclax administration.  
Adult male and female subjects who meet the inclusion criteria and who do not meet any 
of the exclusion criteria will be eligible for enrollment into the study.
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
Age ≥ 18 years.
2.
Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2. 
3.
Subject has relapsed/refractory disease (received at least one line of prior therapy). 
4.
Diagnosis of CLL that meets published 2008 Modified IWCLL NCI-WG 
guidelines and:
●
has an indication for treatment according to the 2008 Modified IWCLL 
NCI-WG criteria
●
has clinically measurable disease (lymphocytosis > 5 × 109/L and/or palpable 
and measurable nodes by physical exam and/or organomegaly assessed by 
physical exam)
●
subjects with or without the 17p deletion or TP53 mutation are eligible.
●
subjects who have received prior B-cell receptor inhibitor therapy are also 
eligible
 


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5.
Adequate bone marrow function as follows:
●
Hemoglobin ≥ 8.0 g/dL
●
platelets ≥ 25,000/mm3, without any of the following:
○
transfusion support within 14 days of Screening
○
evidence of mucosal bleeding
○
known history of bleeding episode within 3 months of Screening
6.
Adequate coagulation parameters per local laboratory reference range as follows:
●
activated partial thromboplastin time (aPTT) and prothrombin time (PT) 
and/or International Normalized Ratio (INR) not to exceed 1.5 × the upper 
limit of normal (ULN)
7.
Adequate renal function per local laboratory reference range as follows: 
●
calculated creatinine clearance ≥ 50 mL/min using 24-hour creatinine 
clearance or estimated creatinine clearance using the modified Cockcroft-Gault 
equation:
Estimated creatinine =   
clearance (eCCr)
(140 – age) • Weight(kg) • [0.85 if female]
72 • serum* creatinine (mg/dL)
or, if serum* creatinine is in µmol/L:
eCCr =
(140 – Age) • Weight(kg) • [1.23 if male, 1.04 if female]
serum* creatinine (µmol/L)
*
plasma value may be used inplace of serum depending on local laboratory standard testing
8.
Adequate hepatic function per local laboratory reference range as follows:
●
aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 × ULN 
●
bilirubin ≤ 1.5 × ULN.  Subjects with Gilbert's Syndrome may have a bilirubin 
> 1.5 × ULN per correspondence between the Investigator and AbbVie 
Therapeutic Area Medical Director (TA MD). 
9.
If female, subject must be either postmenopausal defined as: 
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause.
 


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●
Age ≤ 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L.
OR
●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
OR
A Women of Childbearing Potential (WOCP) practicing at least one protocol 
specified method of birth control (Refer to Section 5.2.4), starting at Study Day 1 
through at least 30 days after the last dose of study drug.
10.
Females of childbearing potential must have a negative serum pregnancy test result 
at Screening, and a negative urine pregnancy test at Study Day 1.  Females of 
non-childbearing potential (either postmenopausal or permanently surgically sterile 
as define above) at Screening do not require pregnancy testing.
11.
Subject voluntarily signs and dates an informed consent form that has been 
approved by an Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB) prior to the initiation of any screening or study-specific procedures.
Rationale for Inclusion Criteria
1 – 4 
To select the subject population
5 – 8 
For the safety of the subjects
9 – 10 
The impact of venetoclax on pregnancy is unknown
11
In accordance with Harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after the last dose of study drug.
 


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2.
Subject has developed Richter's transformation or Prolymphocytic leukemia (PLL)
3.
Subject has previously received venetoclax.
4.
History of active malignancies other than CLL within the past 2 years prior to 
first dose of venetoclax, with the exception of:
●
adequately treated in situ carcinoma of the cervix uteri
●
adequately treated basal cell carcinoma or localized squamous cell carcinoma 
of the skin
●
previous malignancy confined and surgically resected (or treated with other 
modalities) with curative intent.
5.
Active and uncontrolled autoimmune cytopenias (within 2 weeks prior to 
Screening), including autoimmune hemolytic anemia (AIHA) or idiopathic 
thrombocytopenic purpura (ITP), despite low dose corticosteroids.
6.
Prior allogeneic stem cell transplant.
7.
Treatment with the following within 30 days prior to the first dose of venetoclax:
●
a biologic agent (i.e., monoclonal antibodies) with anti-neoplastic intent
8.
Treatment with any of the following within five half-lives or 14 days (if half-life 
unknown) as applicable prior to the first dose of venetoclax, or clinically 
significant adverse effect(s)/toxicity(s) of the previous therapy have not resolved to 
< National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v4.03 Grade 2:
●
any anti-cancer therapy including chemotherapy or radiotherapy, with the 
exception of b-cell receptor pathway inhibitors (i.e., ibrutinib, idelalisib)
●
investigational therapy, including targeted small molecule agents
9.
Treatment with any of the following within 7 days prior to the first dose of 
venetoclax:
●
Steroid therapy for anti-neoplastic intent.
●
Moderate or strong Cytochrome P450 3A (CYP3A) inducers.  (See 
Appendix C for examples) 
 


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10.
Treatment, administration or consumption of any of the following within 3 days
prior to the first dose of venetoclax.
●
Strong CYP3A inhibitors (See Appendix C for examples)
●
Moderate CYP3A inhibitors (See Appendix C for examples)
●
B-cell receptor pathway inhibitors (i.e., ibrutinib or idelalisib)
●
grapefruit or grapefruit products
●
Seville oranges (including marmalade containing Seville oranges)
●
Star fruit.
11.
Subject is known to be positive for Human Immunodeficiency Virus (HIV) (due to 
potential drug-drug interactions between anti-retroviral medications and 
venetoclax, as well as anticipated venetoclax mechanism based lymphopenia that 
may potentially increase the risk of opportunistic infections).
12.
Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk 
for TLS.
13.
Cardiovascular disability status of New York Heart Association Class ≥ 2.  Class 2 
is defined as cardiac disease in which subjects are comfortable at rest but ordinary 
physical activity, results in fatigue, palpitations, dyspnea or anginal pain.
14.
Evidence of other clinically significant uncontrolled condition(s) including, but not 
limited to:
●
uncontrolled and/or active systemic infection (viral, bacterial or fungal)
●
chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.  
●
febrile neutropenia.
15.
Significant history of renal, pulmonary, neurologic, psychiatric, endocrinologic, 
metabolic, immunologic, cardiovascular or hepatic disease that in the opinion of 
the Investigator would adversely affect the subject's participation in this study.  
16.
Malabsorption syndrome or other condition that precludes enteral route of 
administration.
 


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Rationale for Exclusion Criteria
1
The impact of venetoclax on pregnancy is unknown
2 – 5, 7 
To select the appropriate subject population
6, 8 – 16 
For the safety of the subjects
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of enrollment, 
or receives during the study, must be recorded along with the reason for use, date(s) of 
administration including start and end dates, and dosage information including dose, route 
and frequency.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapy(ies).
Subjects should receive full supportive care during study participation, including 
hematopoietic growth factors, transfusion of blood products, fluid and electrolyte 
replacement, and antibiotics when appropriate.  Subjects who use oral contraceptives, 
hormone-replacement therapy, or other maintenance therapy should continue their use.
Steroid therapy for anti-neoplastic intent will not be allowed either during or within 
7 days prior to the first dose of venetoclax.
Inhaled steroids for the treatment of asthma or COPD, topical steroids, replacement 
corticosteroid therapy for an inherited or acquired deficiency are allowed.
In addition, limited corticosteroid treatment is allowed while on study for significant 
active autoimmune cytopenias, e.g., autoimmune hemolytic anemia (AIHA) or immune 
thrombocytopenia (ITP).  IVIG (intravenous immune globulin) is also allowable. 
 


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For additional guidance regarding medications for management of neutropenia, refer to 
Section 6.1.9.3.
The AbbVie TA MD identified in Section 6.1.5 should be contacted if there are any 
questions regarding concomitant or prior therapy(ies).
General guidelines regarding excluded, cautionary and allowed medications are 
summarized in Table 1 and Table 2 below.
Subjects may not consume grapefruit or grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit within the 3-day period prior to the 
first venetoclax administration and until the last day of treatment is completed due to 
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Table 2.
Sample of Permitted Medications
Drug or Therapy
Comments
Colony stimulating factors e.g., G-CSF, GM-CSF
Permitted; per ASCO guidelines.33  Notify AbbVie 
medical monitor if subject requires use of these 
medications or recombinant human erythropoietin.
Best supportive care and treatment 
e.g., antiemetics, antibiotics, transfusions, 
nutritional support, pain control, etc.
Permitted
Antiherpes and anti-pneumocystis prophylaxis
Permitted; if clinically indicated.
Autoimmune thrombocytopenia and hemolytic 
anemia medications
Permitted; if clinically indicated.
A sample list of excluded medications and cautionary medications that fall into these 
categories is provided in Appendix C.  It is not possible to produce a complete list of 
medications that fall into these categories, so if in question, please refer to the appropriate 
product label.
If the Investigator determines that such a medication is medically necessary, the 
Investigator will notify the AbbVie TA MD and discuss the Investigator's use of these 
medications and the Investigator's plans to medically monitor the study subject.
5.2.4
Contraception Recommendations
While participating in this research study, female subjects should not become pregnant or 
breastfeed a baby. 
If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of both) OR a Women of Childbearing Potential, 
practicing at least one of the following highly effective methods of birth control, on Study 
Day 1 (or earlier) through at least 30 days after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to Study Day 1.  In addition to combined 
hormonal contraception, a barrier method must be used during this study from 
 


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initial study drug administration to 30 days after the last dose of study drug as 
drug-drug interaction with venetoclax upon the hormonal contraception is 
unknown.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1.  In addition to a progestogen-only hormonal contraception, a barrier 
method must be used during this study from initial study drug administration 
to 30 days after the last dose of study drug as drug-drug interaction with 
venetoclax upon the hormonal contraception is unknown.
●
Bilateral tubal occlusion/ligation at least 1 month prior to Study Day 1.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure at least 1 month before 
study participation.
●
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success, and is the sole sexual 
partner of the WOCP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
5.3
Study Assessments/Variables
5.3.1
Study Assessments and Flow Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix D and Appendix E.
Unless otherwise stated, the baseline measurement for any given variable will be defined 
as the last value obtained for the variable prior to the first dose of venetoclax.
 


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5.3.1.1
Study Procedures
All study procedures outlined in Appendix D and Appendix E are discussed in detail in 
this section, with the exception of adverse event (AE) information (discussed in 
Section 6.0).  All study data will be recorded on electronic case report forms (eCRFs) with 
the exception of the patient reported outcomes, which will be recorded on paper and 
considered source documents.
Informed Consent
Subjects must voluntarily sign and date an informed consent form approved by an 
IEC/IRB, prior to the initiation of any screening or study-specific procedures, or before 
any prohibited medications are withheld from the subject in order to participate in the 
study.  Details about how informed consent will be obtained and documented are provided 
in Section 9.3.
Screening
Procedures performed at Screening will serve as baseline, unless repeated on Week 1 
Day 1 prior to dosing; in which case the latter will serve as baseline.  Any abnormal 
laboratory or vital sign assessment between screening and prior to administration of study 
drug will be recorded in the subject's medical history and will also serve as the subject's 
baseline.  The schedule of study visit procedures is based on subject study drug 
administration.  Scheduled study visits and/or procedures will need to be altered if there is 
an interruption in study drug administration.  If study drug administration is interrupted 
for more than 3 days (i.e., adverse event), the site will contact the AbbVie study team or 
AbbVie TA MD to adjust the subject's visit schedule, procedures and/or dosing on a case 
by case basis.
Subjects who signed informed consent, have had at least one study procedure conducted, 
and are determined to be a screen failure, will not proceed in study.
 


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Re-Screening Procedures
Subjects that initially screen fail for the study may be permitted to re-screen following 
re-consent.  All Screening procedures will need to be repeated.  The subject must meet all 
inclusion and none of the exclusion criteria at the time of re-screening in order to qualify 
for the study.  There is no minimum period of time a subject must wait to re-screen for the 
study.  If the subject had a complete initial screening evaluation including the CT scan 
and the re-screen visit is more than 35 days since the initial screening assessment, a CT 
scan should be repeated.  As appropriate, sites are encouraged to contact the AbbVie TA 
MD to confirm if subjects should or should not be re-screened
Detection of 17p Deletion or TP53 Mutation
Subjects may have 17p deletion and/or TP53 mutation as assessed by local laboratory (in 
bone marrow or peripheral blood) to be considered as having this deletion/mutation.  
However, the 17p deletion or TP53 mutation is not a protocol required test for subjects to 
be enrolled in this study.  If a subject does have the 17p deletion or TP53 mutation, a 
recent test is desirable but any previous positive test is acceptable.
Medical and Oncology History
A complete medical history, including history of tobacco, nicotine-containing products 
and alcohol use, will be taken from each subject during the Screening visit, including: 
●
documentation of any clinically significant medical condition
●
a detailed oncology history including:
○
histology
○
cytogenetics
○
date of CLL diagnosis
○
stage
○
any surgical procedures
○
treatments administered (including dates, type of modality, response to 
treatment and reason for treatment discontinuation)  
 


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On Week 1 Day 1, any additional medical history observed after signing of the informed 
consent but prior to initial venetoclax administration and not considered related to study 
required procedures will be recorded in the subject's medical history. 
At each visit, including the Final Visit, the subject's medical history will be reviewed and 
any changes from baseline will be recorded on the adverse event eCRF.
Pregnancy Testing
●
WOCP must have a negative serum pregnancy test result at Screening and a 
negative urine pregnancy test at Study Day 1.
●
Screening – quantitative beta-human chorionic gonadotropin (β-hCG) serum 
pregnancy test.
●
Week 1 Day 1:  Urine test, if it has been > 7 days since obtaining the 
Screening serum pregnancy test results.
●
During the study a urine pregnancy test can be performed at the discretion of 
the Investigator or per local guidelines.
●
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in inclusion Criterion 9) at Screening do not 
require pregnancy testing.
Adverse Event and Concomitant Medication Assessment
On Week 1 Day 1, any protocol-related events observed from the time of signing of the 
informed consent but prior to initial venetoclax administration will be recorded as a 
serious or non-serious adverse event, if considered by the Investigator to be causally 
related to the study-required procedures (Figure 3). 
At each visit, including the Final Visit and the Post-Treatment Follow Up, the subject's 
medical history will be reviewed and any changes from baseline will be recorded on the 
adverse event eCRF.
If a subject reports taking any over-the-counter or prescription medications, vitamins 
and/or herbal supplements or if administration of any medication becomes necessary 
 


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beginning with Screening through the end of the study, the name of the medication, 
dosage information including dose, route and frequency, date(s) of administration 
including start and end dates, and reason for use must be recorded on the appropriate 
eCRF.  
Vital Signs
Vital signs include body temperature (oral or tympanic), weight, blood pressure and pulse.  
On days when venetoclax is administered in the clinic, blood pressure and pulse rate will 
be measured after the subject has been sitting for at least 5 minutes.
NOTE:  Starting with visit Week 8 Day 1, vital signs may be performed within 72 hours 
before or after the scheduled visit.
Physical Examination
At Screening, the subject should have a complete physical examination, including height 
and weight (height only performed during Screening).  A complete physical examination 
should include the evaluation of head, eyes, ears, nose and throat (HEENT); 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal and 
neurological systems. 
A symptom directed physical examination may be performed at all other visits (other 
than screening) and should be limited to systems of primary relevance:  cardiovascular, 
respiratory, and those associated with symptoms.
Physical Examination (Disease Assessment)
Physical examinations performed as a part of Disease Assessments (Screening, Weeks 24, 
36, 48) are to include the evaluation of the presence and degree of enlarged lymph nodes 
in two dimension (cervical, supraclavicular, axillary, inguinal and femoral nodes), 
hepatomegaly, and splenomegaly.  These lymph node evaluations should be noted on all 
physical examinations irrespective of being present or absent.  Refer to Disease 
 


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Assessments (2008 Modified IWCLL NCI-WG Criteria) for additional information 
pertaining to methods of measurement.
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination.  New or worsened abnormalities should be recorded as AEs if appropriate. 
If signs or symptoms suggestive of Richter's Syndrome are observed during physical 
examination, further assessments (i.e., nodes, Positron Emission Tomography (PET) scan) 
should be considered to exclude or confirm the transformation.
Please refer to Appendix D and Appendix E for timing of all physical examinations.
NOTE:  Starting with Week 8 Day 1, all Physical examinations may be performed within 
72 hours before or after the scheduled visit.
Tumor Lysis Syndrome (TLS) Risk Assessment
At Screening, all study subjects will be assessed for risk of developing TLS.  The risk of 
TLS is a continuum based on multiple factors, including tumor burden and comorbidities.  
Subjects with high tumor burden (e.g., any lymph node with a diameter ≥ 5 cm or high 
absolute lymphocyte count (ALC) [ALC ≥ 25 × 109/L]) are at greater risk of TLS.  
Reduced renal function (estimated creatinine clearance [eCrCl] < 80 mL/min) further 
increases the risk.  The risk may decrease as tumor burden decreases with venetoclax 
treatment.
Tumor burden assessments, including radiographic evaluation (e.g., CT scans) as well as 
chemistry/hematology assessments (refer to Table 4, Clinical Laboratory Tests) will be 
performed in all subjects prior to initiating venetoclax treatment.
Appropriate venetoclax dosing and management of subjects throughout their study 
treatment is guided by their individual risk for developing TLS.  Risk-based TLS 
prophylaxis and management measures are described in Section 6.1.9.1.
 


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Eastern Cooperative Oncology Group (ECOG) Performance Status
For all subjects, the ECOG performance status47 will be performed as outlined in 
Appendix D and Appendix E.
It is recommended, where possible, that a subject's performance status will be assessed by 
the same person throughout the study.  ECOG performance status will be assessed as 
follows:
Table 3.
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, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair.
NOTE:  Starting at Week 24 Day 1, ECOG performance status may be performed within 
72 hours before or after the scheduled visit.
Coagulation Panel
Prothrombin time (PT) and/or International Normalized Ratio (INR) and/or activated 
partial thromboplastin time (aPTT) will be collected and will be analyzed by the local 
laboratory during Screening only.
Hematology and Chemistry
Hematology and chemistry will be analyzed by the local laboratory.  Required tests are 
listed in Table 4. 
 


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Table 4.
Clinical Laboratory Tests (Assessed by Local Laboratory)
Hematology
Chemistry
Coagulationa
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Lymphocytes
Platelet count (estimate not 
acceptable)
Reticulocyte count
Blood Urea Nitrogen (BUN)*
Creatinine 
Total bilirubin
Alanine Aminotransferase 
(ALT)
Aspartate Aminotransferase 
(AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acidb
Glucose
Albumin
Lactate dehydrogenase (LDH)
Prothrombin time (PT)
AND/OR
International Normalized Ratio 
(INR)
And/or
Activated partial thromboplastin 
time (aPTT)
*
Urea may be reported instead of BUN.
a.
Performed at Screening and as clinically indicated.
b. 
For samples from subjects treated with rasburicase:  rasburicase causes enzymatic degradation of the uric acid in 
blood/plasma/serum samples left at room temperature, potentially resulting in spuriously low plasma uric acid 
assay readings.  The following special sample handling procedure must be followed to avoid ex vivo uric acid 
degradation.  Uric acid must be analyzed in plasma.  Blood must be collected into pre-chilled 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 pre-cooled centrifuge (4°C).  Finally, the plasma must be 
maintained in an ice water bath and analyzed for uric acid within four hours of collection.
PRE-DOSE LABS:
Prior to the Initial Dose of Venetoclax, for all Subjects:
●
During the Screening Period:  For all subjects, the chemistry/hematology panel 
(see Table 4, Clinical Laboratory Tests) is required.
○
Pre-existing abnormalities should be corrected 
●
Within 72 hours of Week 1/Day 1:  If the screening labs were done more than 
72 hours before the planned first dose, the chemistry/hematology panel should 
be repeated.  These results should be reviewed prior to dosing.
 


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○
Labs should be assessed and pre-existing abnormalities should be 
corrected.
●
On the day of Week 1/Day 1:  Before dosing, the chemistry/hematology panel 
should be drawn.  The results of the labs drawn on Week 1/Day 1 need to be 
reviewed prior to dosing IF an additional lab draw within 72 hours of the 
initial dose at Week 1/Day 1 was not drawn AND reviewed.  Only one set of 
labs is required prior to dosing as long as it is reviewed and corrected.
Prior to Each Subsequent Dose Increase, for all Subjects:
●
Within 72 hours of each subsequent dose increase:  The chemistry/hematology 
panel should be repeated.  The results should be reviewed prior to dose 
increasing.
●
Prior to dosing, on the day of each subsequent dose increase:  Before dosing, 
the chemistry/hematology panel should be drawn.  The results of the labs 
drawn on Day 1 of each dose increase need to be reviewed prior to dosing IF
an additional lab draw within 72 hours of the dose increase was not drawn 
AND reviewed.  
POST-DOSE LABS:
For all subjects, the chemisty/hematology panel (refer to Table 4, Clinical Laboratory 
Tests) should be monitored at 6 to 8 hours and at 24 hours* after the first dose of 
venetoclax (20 mg) and after the first dose increase (50 mg).  Electrolyte abnormalities 
should be corrected promptly.  The next venetoclax doses (the Day 2 20 mg venetoclax 
dose and the Day 2 50 mg venetoclax dose) should not be administered until the 24-hour* 
lab results have been evaluated.  Electrolyte abnormalities should be corrected promptly. 
For subjects who continue to be at risk of TLS, the same lab monitoring schedule 
(i.e., 6 to 8 hour and 24-hr post dose) should be followed at the subsequent dose increases.
*All 24 hour post-dose laboratory assessments may be taken within a 2 hour window, if 
necessary.
 


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This monitoring is also recommended during the re-initiation of the therapy after a dose 
interruption. 
Additional monitoring may be required based on the risk assessment by the Investigator 
and as directed by the AbbVie TA MD. 
Local laboratories will be utilized to process and provide results for clinical laboratory 
tests allowing for immediate subject medical management.  The principal investigator or 
sub-investigator will review, initial, and date all laboratory results used for subject 
treatment management after receipt from the local laboratory.  Local laboratory values 
will be entered by the site directly onto the appropriate eCRF and laboratory normal 
ranges for the laboratory that is used will be provided to the AbbVie Clinical Team.
A laboratory test value that requires a subject to be discontinued from the study, requires a 
subject to receive treatment, meets protocol specific criteria (see Section 6.7 regarding 
toxicity management), or if the Investigator considers clinically significant will be 
recorded as an adverse event.
NOTE:  Starting with Week 8/Day 1, clinical laboratory tests may be collected within 
72 hours prior to the scheduled visit.
Quality of Life Assessments
Quality of life will be assessed using the EORTC QLQ-C30, the EORTC QLQ-CLL16, 
and EQ-5D-5L. 
Quality of life will be assessed within 72 hours prior to the first dose of venetoclax, 
Week 4, Week 8, Week 12, Week 24, Week 36, and Week 48 then every 12 weeks 
thereafter until the end of treatment (Week 108).  The quality of life questionnaires should 
be administered and completed prior to any other study procedures being performed at 
these visits.  Refer to Section 5.3.2.  Study Variables, for further information.
Analyses of these endpoints are described in Section 8.0.
 


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Disease Assessments (2008 Modified IWCLL NCI-WG Criteria)
All measurable disease must be documented at Screening (baseline), prior to the first dose 
of venetoclax, for all subjects based on the analysis of clinical laboratory tests 
(hematology), disease assessment physical examination, contrast-enhanced CT scan of 
involved neck, chest, abdomen and pelvis (or MRI, if CT scan with contrast is medically 
contraindicated).  Bone marrow examinations at screening are not required but results will 
be recorded if available. 
For all subjects, clinical response will be assessed by the Investigator at Week 24, 
Week 36 and Week 48.  Disease response will be based on the analysis of clinical 
laboratory tests and a disease assessment physical examination.  To confirm the response, 
a contrast-enhanced CT scan (or MRI, if CT scan with contrast is medically 
contraindicated) will be performed at Week 48 for all subjects.  Subjects will be evaluated 
using the 2008 Modified IWCLL NCI-WG criteria for Tumor Response with the addition 
of CT imaging (or MRI).
For determination of CR, the CT scan and bone marrow are required to be negative, per 
the IWCLL NCI-WG criteria.  It is recommended that the CT scan is performed first; if it 
does confirm a clinical response, then a bone marrow biopsy will be obtained.  If a CT 
scan is performed and does not confirm a clinical response, a bone marrow biopsy should 
not be obtained.
If a subject exhibits clinical signs of possible disease progression (i.e., increased or 
de novo enlargement of liver, spleen or lymph nodes on physical examination) without an 
increase in lymphocytes meeting the progression of disease criteria, then additional 
assessments including contrast-enhanced CT scan and/or bone marrow can be performed 
to confirm or rule out disease progression
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.
 


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For any subject who has not experienced progressive disease (PD) at the time of 
permanent discontinuation of venetoclax, follow up phone calls will continue until death, 
discontinuation from the study or upon study completion.
Response criteria definitions are outlined in 2008 Modified IWCLL-WG Criteria for 
Tumor Response.  See Table 5.
NOTE:  Disease assessments may be performed approximately 7 days prior to the 
scheduled visit.
For patients with Partial Remission at Week 48 an additional CT scan and a bone marrow 
examination can be done between Week 48 and Week 108 to confirm CR if there is a 
possibility that a patient achieved Complete Remission based on laboratory tests and a 
disease assessment physical examination.
Computed Tomography Scans (or Magnetic Resonance Imaging)
A CT scan with contrast will be accepted if previously performed within 35 days prior to 
the first dose of venetoclax.  Otherwise, a CT scan must be performed within the 
Screening window (28 days) for all subjects.  A CT scan will be performed for all subjects 
at Week 48 to confirm disease response.  Contrast-enhanced CT scans including neck, 
chest, abdomen, and pelvis will be performed to assess response to treatment.  A contrast-
enhanced MRI of the neck, chest, abdomen and pelvis with a non-contrast CT scan of the 
chest may be used for subjects in whom a contrast CT is medically contraindicated 
(i.e., subjects with a severe allergy to CT contrast agents or subjects with impaired renal 
clearance).  Whichever method is used at Screening should be consistently used 
throughout the duration of the study.
Any CT scan (or MRI) performed as standard of care throughout the study should be 
captured on the eCRF.
NOTE:  CT scans (or MRI) may be performed 7 days prior to the scheduled visit.
 


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Bone Marrow Aspirate and Biopsy
At baseline, a bone marrow aspirate and biopsy are not required; however results should 
be recorded if available.  If the subject achieves a CR by clinical criteria and confirmatory 
CT scan, a bone marrow aspirate and biopsy will be performed to confirm the CR.  If a 
CT scan is performed and does not confirm a CR, a bone marrow biopsy should not be 
obtained.
Bone marrow aspirates and biopsies performed as standard of care throughout the study 
should also be captured on an eCRF.
Final Visit
Upon treatment discontinuation (Section 5.4.1), the reason(s) for discontinuation will be 
recorded in the eCRFs and a Final Visit will be performed.  The Final Visit procedures as 
listed in Appendix D and Appendix E should be performed as soon as possible after study 
drug discontinuation.
At the Final Visit all used/unused study drug are to be returned to the site and drug 
accountability performed.
30-Day Safety Visit
A 30 day Safety Follow-up Visit should be performed approximately 30 days (± 3 days) 
following the last dose of venetoclax (to allow for AE collection 30 days following last 
dose of study drug).  Refer to Appendix D and Appendix E for procedures to be 
performed.  
If a subject has an ongoing AE or an unresolved clinically significant laboratory result 
30 days following last dose of study drug, the site will attempt to provide follow-up until 
the AE has resolved to a ≤ Grade 1 or baseline or it is the investigator's judgment that the 
event is unlikely to resolve.
 


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Additionally, CT or MRI scans are not required, however if collected by the site as 
standard of care, the data should be recorded in EDC.
Post-Treatment and Survival Assessments 
After treatment discontinuation, subjects will be followed for disease progression (if 
progression has not already occurred) and survival.  Post-treatment calls will be 
performed every 6 months until discontinuation from the study.  Survival information 
(i.e., the date and cause of death, post-treatment cancer therapies, date of progression etc.) 
will be collected.  This period will continue for 2 years following discontinuation of 
venetoclax.
Extended Access Phase
In countries where venetoclax is not commercially available, subjects who continue to 
derive benefit after 2 years of treatment may be able to extend their treatment for up to 
2 additional years.  AbbVie will work with the investigator on a case by case basis to 
consider the potential continuation of venetoclax therapy.  The Extended Access Visits 
will include:
●
Collection of Survival information
●
AE/SAE/Con Med assessment
●
Study drug reconciliation and dispensing
All other procedures should be performed as standard of care.  The specific study 
assessments to be performed during these visits are detailed in Appendix E Study 
Activities.
Assignment of Subject Numbers
Subjects will be assigned unique consecutive subject numbers at screening, as described 
in Section 5.5.3.  The results of all screening evaluations must be within clinically 
acceptable limits, upon review by the investigator before a subject can be administered 
 


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study drug.  Subjects will not be enrolled in the study if laboratory or other screening 
results are unacceptable.
5.3.2
Study Variables
The primary objective of this study is to evaluate the impact of venetoclax monotherapy 
on the quality of life of subjects with relapsed or refractory chronic lymphocytic leukemia 
(CLL).  Quality of life will be assessed by the GHS/QoL subscale of the 
EORTC QLQ-C30.
The secondary objectives are to evaluate the impact of venetoclax monotherapy on quality 
of life based on the EORTC QLQ-CLL16, EQ-5D-5L, and the remaining subscales/items 
from the EORTC QLQ-C30; overall response rate (ORR); complete remission rate (CR + 
CRi); duration of overall response (DOR), time to progression (TTP), duration of 
progression-free survival (PFS); overall survival (OS); and CR rate in BCRi treated 
subjects.
Analyses of these endpoints are described in Section 8.0.
5.3.2.1
Primary Variable
The primary endpoint will be based on the mean change from baseline to Week 48 on the 
GHS/QoL subscale of the EORTC QLQ-C30.  Subjects will complete the EORTC 
QLQ-C30, along with other PRO measures, at baseline (within 72 hours prior to the 
first dose of venetoclax), Week 4, Week 8, Week 12, Week 24, Week 36, and Week 48, 
then every 12 weeks thereafter until the end of treatment (Week 108).  The GHS/QoL 
subscale will be calculated as per the EORTC scoring manual, and summarized (mean, std 
dev, median) at each visit.
5.3.2.2
Secondary Variables
Secondary variables include assessments of quality of life based on the EORTC 
QLQ-CLL16, EQ-5D-5L, and the remaining subscales/items from the EORTC QLQ-C30; 
overall response rate (ORR); complete remission rate (CR + CRi); duration of overall 
 


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response (DOR), time to progression (TTP), duration of progression-free survival (PFS); 
overall survival (OS); and the CR rate in BCRi treated subjects.
5.3.2.2.1
Quality of Life Assessments
EORTC QLQ-C30
Quality of life and symptoms will be assessed with the European Organization for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 
(EORTC-QLQ-C30) version 3.36  The QLQ-C30 is a 30-item subject self-report 
questionnaire composed of both multi-item and single scales, including five functional 
scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, 
nausea and vomiting, and pain), a global health status/quality of life (GHS/QoL) scale, 
and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties).  Subjects rate items on a four-point scale, with 1 as "not at all" and 
4 as "very much."  The EORTC QLQ-C30 was developed and validated for use in a 
cancer subject population, and its reliability and validity is highly consistent across 
different language cultural groups.  A change of 5 – 10 points is considered a small 
change, and the lower bound (5) is being used to define the minimum important difference 
(MID).  A change of 10 – 20 points is considered a moderate change.
EORTC QLQ-CLL16
The EORTC QLQ-CLL16 was designed specifically for subjects with stage 0 to stage 4 
CLL.37  It is comprised of sixteen questions that address five domains of HRQoL 
important in CLL.  There are three multi-item scales assessing Fatigue (2 items), Disease 
and Treatment Effects (7 items), and Infection (5 items), and two single-item scales 
assessing Social Activities and Future Health Worries.  Subjects rate items on a four-point 
scale, with 1 as "not at all" and 4 as "very much."  A negative change in score from 
baseline represents an improvement in symptoms.  A change of 5 – 10 points is 
considered a small change, and the lower bound (5) is being used to define the minimum 
important difference (MID).  A change of 10 – 20 points is considered a moderate 
change.38-40
 


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EQ-5D-5L
The EuroQol EQ-5D-5L is a generic preference instrument that has been validated in 
numerous populations.41,42  The EQ-5D-5L has five dimensions:  mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression.  These dimensions are measured on a 
five-level scale:  no problems, slight problems, moderate problems, severe problems, and 
extreme problems.  The scores for the 5 dimensions are used to compute a single utility 
index score ranging from zero (0.0) to 1 (1.0) representing the general health status of the 
individual.  The EQ-5D-5L also contains a visual analog scale (VAS) to assess the 
subject's overall health.  The MID for the EQ-5D utility index score in cancer subjects is 
0.08, and the MID for EQ-5D VAS is 7.43,44
Each of the five dimensions of the EQ-5D-5L, the VAS and overall utility score will be 
calculated using the EuroQol scoring manual, and summarized (mean, std. dev., median)
at each assessment.  The impact of treatment over time will be assessed by calculating the 
change in score from baseline at each assessment time point. 
5.3.2.2.2
Disease Assessments
For disease assessments, response will be assessed by the investigator based on analysis 
of clinical laboratory tests (hematology laboratory values), disease assessment physical 
examination, CT scan including neck, chest, abdomen, and pelvis (or MRI if CT with 
contrast is medically contraindicated); a bone marrow aspirate and biopsy is not required 
but results will be recorded if available.  Subjects will be evaluated against the 
2008 Modified IWCLL NCI-WG Criteria for Tumor Response46 with the addition of CT 
imaging (or MRI).  A BM assessment is required to confirm CR.
At screening (baseline), all measurable disease must be documented by laboratory testing 
(hematologic status), physical examination, and CT scan.  All baseline evaluations should 
be performed as closely as possible to the beginning of treatment and not more than 
4 weeks before the beginning of the treatment with the exception of the CT scan (or MRI) 
which will be accepted if previously performed within 35 days prior to study drug 
initiation.  During the study, subjects will have a disease assessment at Week 24, Week 36 
 


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and Week 48.  To confirm the response, a CT scan will be performed at Week 48 on all 
subjects.  For subjects with CR as response at Week 48, a BM is required to confirm the 
response.
Methods of Measurement
Disease response and progression will be assessed by analysis of peripheral blood, clinical 
examination, radiographic scans and bone marrow aspirate and biopsy.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.
A full disease assessment physical examination should be performed to assess the extent 
of disease involvement.  Physical examinations should include the evaluation of the 
presence and degree of enlarged lymph nodes in two dimension (cervical, supraclavicular, 
axillary, inguinal and femoral nodes), hepatomegaly, and splenomegaly.  These should be 
noted on all examinations irrespective of being present or absent.  All measurements 
should be taken and recorded in metric notation using a ruler or calipers.  Clinical lesions 
will only be considered measurable when they are superficial (e.g., palpable lymph 
nodes).  The diameter, in two planes, of the largest palpable nodes in each of the 
following sites should be measured:  cervical, supraclavicular, axillary, inguinal, and 
femoral.  The presence of hepatomegaly and splenomegaly should be performed.
The 12 largest bi-dimensional lesions should be recorded in the eCRF.
●
Target Lesions:  A maximum of 12 target lesions may be selected (up to 
6 nodal and 6 extra nodal).  Target nodal lesions must be abnormal (> 1.5 cm 
in LDi [Longest Diameter at baseline), clearly measurable and suitable for 
consistent, reproducible measurement in at least two perpendicular 
dimensions.  Target extra nodal lesions must be > 1 cm in two perpendicular 
diameters at baseline.
●
Non-Target Lesions:  Sites will be classified as non-target lesions where 
disease is present but not selected for target lesions.  A maximum of 
10 non-target lesions can be selected.  Non-target nodal lesions must be 
 


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abnormal (> 1.5 cm in LDi at baseline).  Non-target extra nodal lesions must 
be > 1 cm in two perpendicular diameters.  Nodal and extra nodal lesions that 
were not selected as target lesions at baseline can be followed as non-target 
lesions.
Computed tomography (CT) is the preferred method to measure lesions selected for 
response assessment.  CT scans (with contrast) should include neck, chest, abdomen, and 
pelvis scans.  CT scans for response assessment may be limited to areas of prior 
involvement only, if required by local regulatory authorities.  A contrast-enhanced MRI of 
the neck, chest, abdomen and pelvis with a non-contrast CT scan of the chest may be used 
if CT with contrast is medically contraindicated (e.g., severe contrast allergy).  If MRIs 
are used instead of CT scans, MRIs should be used consistently throughout the study.  
Conventional CT and MRI should be performed with cuts of 5 mm or less in slice 
thickness contiguously.  Spiral CT should be performed by use of 5 mm contiguous 
reconstruction algorithm; this specification applies to the regions of the neck, chest, 
abdomen and pelvis at baseline and follow ups.  The 12 largest bi-dimensional lesions 
should be recorded in the eCRF (6 nodal and 6 extra nodal).
For accurate overall response evaluation, ultrasound (US) should not be used to measure 
tumor lesions.
Details on bone marrow biopsy and aspirate are provided in Section 5.3.1.1.  Study 
Procedures.
Tumor Response Criteria
Complete Remission (CR)
CR requires all of the following criteria:
●
Peripheral blood lymphocytes (evaluated by blood and differential count) 
below 4 × 109/L (4000/µL)
●
Absence of lymphadenopathy (nodes > 15 mm in longest diameter or any extra 
nodal disease) by physical examination and CT scan
 


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●
No hepatomegaly or splenomegaly by physical examination (as determined by 
measurement below the relevant costal margin)
●
Absence of disease or constitutional symptoms (B symptoms:  unexplained 
fevers > 38°C or 100.4°F, drenching night sweats, > 10% body mass weight 
loss in the preceding 6 months)
●
Blood counts above the following laboratory values:
○
Neutrophils > 1.5 × 109/L [1500/µL] (without the need for exogenous 
growth factors)
○
Platelets > 100 × 109/L [100,000/µL] (without the need for platelet 
transfusion or exogenous growth factors)
○
Hemoglobin > 110 g/L [11 g/dL] (without the need for blood transfusions 
or exogenous erythropoietin)
●
Bone marrow at least normocellular for age, < 30% of nucleated cells being 
lymphocytes.  Lymphoid nodules should be absent.  Bone marrow aspirate and 
biopsy should be performed after CR/CRi has been achieved.  If the bone 
marrow is hypocellular, a repeat determination should be made in 4 weeks or 
when peripheral blood counts have recovered.  A marrow biopsy should be 
compared to a pre-treatment marrow if available.  Subjects who are otherwise 
in a complete remission, but bone marrow nodules can be identified 
histologically should be considered to be nodular PR (nPR).  
Immunohistochemistry (IHC) should be performed to define whether these 
nodules are composed of primarily T cells or lymphocytes other than CLL 
cells, or CLL cells.
Complete Remission with Incomplete Marrow Recovery (CRi)
Subjects who fulfill the criteria for CR (including bone marrow) but who have persistent 
cytopenia (anemia or thrombocytopenia or neutropenia) apparently unrelated to CLL but 
related to drug toxicity will be considered CRi.  The marrow evaluation described above 
should be performed with scrutiny and not show any clonal infiltrate.
Partial Remission (PR)
To be considered a PR at least 2 of the following must be met:
 


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●
≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment 
baseline value.
●
≥ 50% reduction in lymphadenopathy.
●
≥ 50% reduction in the enlargement of the liver and/or spleen (if abnormal 
prior to therapy).
In addition at least one of the following criteria must be met:
●
Neutrophils > 1,500/µL or ≥ 50% improvement over baseline.
●
Platelets > 100,000/µL or ≥ 50% improvement over baseline.
●
Hemoglobin > 11.0 g/dL or ≥ 50% improvement over baseline without 
transfusions or exogenous growth factors.
 


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Table 5.
2008 Modified IWCLL NCI-WG Criteria for Tumor Response
Parameter
Complete Remission 
(CR) All Criteria 
Must be Meta
Partial Remission 
(PR) at Least 
2 Criteria from 
Group A AND at 
Least 1 Criterion 
from Group B 
Must be Met
Progressive Disease 
(PD) at Least 
1 Criterion from Group 
A OR 1 Criterion from 
Group B Must be Metb
Stable Disease 
(SD) All Criteria 
Must be Met
Group A
Lymphadenopathy
None > 1.5 cm
Decrease ≥ 50%c
Increase ≥ 50%d or any 
new LN > 1.5 cm
Change of –49% 
to +49%e
Blood 
Lymphocytes
< 4000/µL
Decrease ≥ 50% 
from baseline
Increase ≥ 50% over 
baseline (≥ 5000/µL)
Change of –49% 
to +49%
Hepatomegalyf
None
Decrease ≥ 50%
Increase ≥ 50%g
Change of –49% 
to +49%
Splenomegalyf 
None
Decrease ≥ 50%
Increase ≥ 50%g
Change of –49% 
to +49%
Marrow
Normocellular, 
< 30% lymphocytes, 
no B lymphoid 
nodules; hypocellular 
marrow defines CRi
N/A
N/A
N/A
Group B
Platelet Count
> 100,000/µLh
> 100,000/µL or 
increase ≥ 50% 
over baselineh
Decrease of ≥ 50% from 
baseline secondary to 
CLL
Change of –49% 
to +49%
Hemoglobin
> 11.0 g/dLh
> 11.0 g/dL or 
increase ≥ 50% 
over baselineh
Decrease of > 2 g/dL 
from baseline secondary 
to CLL
Increase to 
≤11.0 g/dL over 
baseline, or 
decrease < 2 g/dL
Neutrophils
> 1500/µLh
> 1500/µL or 
increase ≥ 50% 
over baselineh
Decrease ≥ 50% from 
baseline secondary to 
CLL
N/A
New Lesions
None
None
Appearance of new 
palpable lymph nodes 
(> 1.5 cm in longest 
diameter) or any new 
extra nodal lesion 
(regardless of size) or 
transformation to a more 
aggressive histology, 
e.g., Richter Syndromed
None
 


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Table 5.
2008 Modified IWCLL NCI-WG Criteria for Tumor Response 
(Continued)
Parameter
Complete Remission 
(CR) All Criteria 
Must Be Meta
Partial Remission 
(PR) at Least 
2 Criteria from 
Group A AND at 
Least 1 Criterion 
from Group B 
Must Be Met
Progressive Disease 
(PD) at Least 
1 Criterion from 
Group A OR 
1 Criterion from 
Group B Must Be Metb
Stable Disease 
(SD) All Criteria 
Must Be Met
Other Considerations
Non-Target 
Lesions
Nodes must be 
normal size as 
visually estimated; 
extra nodal and other 
assessable disease 
should be absent
No 
change/decreased
Unequivocal progression
No change or 
decrease or 
non-substantial 
increase
Target Extra 
Nodal Disease
Absence of any extra 
nodal disease by 
physical examination 
(palpable, visualized 
extra nodal) and CT 
scan
≥ 50% decrease in 
SPD
≥ 50% increase in the 
longest diameter of any 
extra nodal lesion
Not CR, CRi, PR, 
or PD
CLL = chronic lymphocytic leukemia; LN = lymph nodes; N/A = Not applicable; SPD = sum of the products of 
diameters; CRi = complete remission with incomplete marrow recovery
a.
CR also requires the lack of disease-related constitutional symptoms.
b.
Transformation to a more aggressive histology (e.g., Richter Syndrome) would also qualify as a PD.
c.
Sum of the products of multiple LNs (as evaluated by CT scans).  Note in eCRF if by physical examination only.
d.
Increase in SPD of multiple nodes, or in greatest diameter of any previous site, or appearance of any new 
lymphadenopathy or organomegaly.  Degree of change in LN or lymphocyte counts should be measured from nadir 
(lowest post-treatment) values.
e.
Sum products of up to 6 LNs or LN masses (target lesions), with no increase in an LN or new enlarged LN.  
Increase of < 25% in small LNs (< 2 cm) not significant.  Decreases should be measured compared to baseline 
(pre-treatment) values.
f.
If enlarged before therapy.
g.
An increase in the previously noted enlargement of the liver or spleen by 50% or more or the de novo appearance 
of hepatomegaly or splenomegaly.
h.
Without the need for exogenous growth factors or transfusions.
5.3.2.3
Definition of Disease Progression
Disease progression according to 2008 Modified IWCLL NCI-WG Criteria for Tumor 
Response is characterized by at least one of the following:
 


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●
Appearance of any new lesion, such as enlarged lymph nodes (> 1.5 cm), 
splenomegaly, hepatomegaly, or other organ infiltrates.  An increase by 50% 
or more in greatest determined diameter of any previous site.
●
An increase in the previously noted enlargement of the liver or spleen by 50% 
or more or the de novo appearance of hepatomegaly or splenomegaly.
●
An increase in the number of blood lymphocytes by 50% or more with at least 
5,000 B lymphocytes per microliter.  The increase should be assessed against 
the best response while on study.
●
Transformation to a more aggressive histology (e.g., Richter's Syndrome).  
Whenever possible, this diagnosis should be confirmed by lymph node biopsy.  
For subjects experiencing disease progression due to Richter's Syndrome while 
on study, supplemental data may be collected.
●
Occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) 
attributable to CLL.
5.3.3
Safety Variables
The following safety evaluations will be performed during the study:  serious adverse 
event and adverse event monitoring including AEs of special interest (Section 6.1.1.4), 
vital signs, physical examination, and laboratory assessments.  Certain types of events 
require immediate reporting to the Sponsor, as outlined in Section 6.1.6.  Safety will be 
monitored on an ongoing basis and summarized periodically in aggregate safety reports 
and end of study.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study and/or study drug treatment at any 
time.  In addition, the Investigator may discontinue a subject from study drug treatment at 
any time if the investigator considers it necessary for any reason including:
●
The investigator believes it is in the best interest of the subject; 
 


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●
Subject's response to therapy is unsatisfactory, as evidenced by progression of 
disease while on study drug. 
●
The subject requires other cancer treatment (e.g., radiotherapy, cancer-related 
surgery as a result of tumor progression, alternate anti-neoplastic agents) 
during the study period
●
unacceptable toxicity
●
The subject becomes pregnant while on the study
●
drug/protocol non-compliance
The investigator will inform AbbVie prior to discontinuing a subject from the study by 
contacting the Clinical Team Leader as identified in Section 7.0.  All subjects will be 
included for analysis of safety data.  Subjects who withdraw from the study will not be 
replaced unless they are not evaluable.
Subjects will continue to be followed for unresolved AEs and survival information for any 
subject who has not experienced PD at the time of venetoclax discontinuation.  
Final Visit
Upon study drug discontinuation and/or upon discontinuation from the study, the 
reason(s) for discontinuation will be recorded in electronic case report forms (eCRFs) and 
a final visit will be performed.  The final visit procedures as listed in Appendix D should 
be performed as soon as possible after discontinuation from study drug.
30-Day Safety Follow-Up Visit
A 30-Day Safety Follow-up Visit should be performed approximately 30 days (± 3 days) 
following the last dose of venetoclax.  The 30 day safety follow up procedures listed in 
Appendix D should be performed.
Post Treatment and Survival Follow-Up Calls
For subjects who discontinue venetoclax therapy, but do not discontinue the study (), 
post-treatment follow-up calls will be performed every 6 months (+ 7 days) for survival 
 


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information (i.e., disease progression, the date and cause of death, post-treatment cancer 
therapies, etc.) and will be collected via telephone calls for a period of 2 years and 
recorded in the eCRFs.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Venetoclax tablets should be taken orally once daily with a meal and water in the morning 
at approximately the same time each day.  Venetoclax tablets should be swallowed whole 
and not chewed, crushed, or broken prior to swallowing.
If the subject misses a dose of venetoclax within 8 hours of the time it is usually taken, the 
subject should take the missed dose as soon as possible on the same day and resume the 
normal daily dosing schedule the following day.  If a subject misses a dose by more than 
8 hours, the subject should not take the missed dose and resume the normal daily dosing 
schedule the following day.
In cases of vomiting after taking venetoclax, no additional dose (tablets) should be taken 
that day.  The next dose should be taken at the usual time the following day.
 


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5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 6.
Table 6.
Identity of Investigational Product
Study Drug
Trademark
Formulation
Route of 
Administration
Manufacturer
Venetoclax
N/A
10 mg Tablet
Film coated
Oral
AbbVie
Venetoclax
N/A
50 mg Tablet
Film coated
Oral
AbbVie
Venetoclax
N/A
100 mg Tablet
Film coated
Oral
AbbVie
Each site will be responsible for tracking the lot numbers and expiration dates for all 
non-investigational medicinal products (e.g., generic name and generic name) that are 
dispensed.
5.5.2.1
Packaging and Labeling
The venetoclax tablets will be packaged in blister packs during the dose-titration phase 
and in high density polyethylene (HDPE) plastic bottles thereafter to accommodate the 
study design.  Each container will be labeled as required per country requirements.  
Labels must remain affixed to the container.
5.5.2.2
Storage and Disposition of Study Drug
The venetoclax supplied in this study is for investigational use only, and must only be 
used within this study.  All study drug must be maintained under adequate security and 
stored under conditions specified on the label until dispensed for subject use or returned to 
AbbVie or representative.
The tablets must be stored at a controlled room temperature of 15° to 25°C (59° to 77°F).
 


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5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects are assigned to the same treatment group in this single arm study.  Subjects 
will be allocated a unique consecutive subject number at Screening.  Subject numbers will 
consist of 5 digits (XXX01), with the first three digits denoting site number and the last 
2 digits as the subject number, beginning with 01.  All subjects will be enrolled using an 
Interactive Response Technology (IRT).  Before the study is initiated, each site will be 
provided with the IRT user instructions, which provides direction on how to use the IRT 
via the Web or the telephone.  Since this is an open-label study, subjects will maintain the 
same subject number regardless of the number of re-screens and through the duration of 
the study.  The site, in conjunction with the Sponsor, will be responsible for assignment of 
all unique subject numbers at Screening and dose assignments if the subject is not a 
screening failure.
5.5.4
Selection and Timing of Dose for Each Subject
Venetoclax will be administered orally once daily (QD) beginning with a dose-titration 
phase.  As shown in Figure 2, the initial venetoclax dose is 20 mg QD.  After 1 week of 
treatment at 20 mg QD, the dose will be escalated to 50 mg QD followed by subsequent 
increases, each after 1 week, to 100 mg QD, 200 mg QD and the maximum dose of 
400 mg QD.  The maximum dose of venetoclax for this protocol will not exceed 400 mg 
per day.  The 5-week dose-titration phase is designed to gradually reduce tumor burden 
(debulk) and decrease the risk of tumor lysis syndrome.  All study subjects will be 
categorized at Screening according to their risk for developing TLS.  Their dose 
management, including during the dose-titration phase, will be conducted in accordance 
with their risk for developing TLS (Section 6.1.9.1) and may include dose delay and/or 
dose reduction as required for prophylaxis and management of TLS.
 


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Figure 2.
5-Week Dose-Titration Schematic
5.5.5
Blinding
This is an open-label, single arm study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
To document compliance with the treatment regimen, subjects will be instructed to return 
all unused tablets and/or containers, even if empty and any other study related items as 
necessary, to the study coordinator at scheduled study visits.  Compliance will be 
monitored and documented by the study coordinator on the appropriate form.  The study 
coordinator will question the subject regarding adherence to the dosing regimen, record 
the number of tablets and/or containers returned, the date returned and determine 
treatment compliance before dispensing new venetoclax to the subject.  Compliance 
below 80% will require counseling of the subject by study site personnel.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.5.7
Drug Accountability
Investigator or representative will verify that study drug supplies are received intact and in 
the correct amounts.  Documentation of the receipt of supplies will be supported by a 
signed and dated Proof of Receipt or similar shipping document in IRT.  A current 
(running) and accurate inventory of venetoclax will be kept by the site and will include lot 
number, Proof of Receipt number(s), container numbers, blister pack numbers, subject 
initials, initials of person who dispensed the drug and the date study drug was 
administered for each subject.  An overall accountability of study drug will be performed 
and verified by AbbVie monitor(s) throughout the study and at the study site closeout 
visit.  All study drug unit doses must be inventoried, accounted for, and returned to 
AbbVie or destroyed per instructions from AbbVie and according to local regulations.  
All original containers (containing partially used or unused study drug) will be returned to 
AbbVie according to instructions from AbbVie or the designated monitor(s).  If 
pre-arranged between AbbVie and the site, destruction of used and unused study drug 
containers will be performed onsite.  Empty containers will be destroyed at the site.  
Labels must remain attached to the containers.
The investigator and/or named sub-investigators agree not to supply study medication to 
any persons not enrolled in the study.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
Study M15-889 is being conducted primarily to assess the impact of venetoclax 
monotherapy on the quality of life of the participants.  This study is a single-arm trial; 
therefore, there is no control group or treatment blinding.  The study will be conducted at 
multiple study centers globally to ensure a broad representation of the subject population 
and clinical care settings. 
 


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5.6.2
Appropriateness of Measurements
The quality of life measures selected for this study include a cancer-specific questionnaire 
(EORTC QLQ-C30), a CLL-specific questionnaire (EORTC QLQ-CLL16), and a 
comprehensive generic health status/preference questionnaire (EQ-5D-5L).  These 
measures have been used in previous CLL studies.45,48-52  Standard statistical, clinical, and 
laboratory 
5.6.3
Suitability of Subject Population
Venetoclax monotherapy has shown favorable activity in relapsed/refractory CLL subjects 
including those with 17p deletion.  Venetoclax is expected to be as active in subjects 
selected for TP53 mutations as these subject populations overlap and the oncogenic effect 
of both genetic defects occurs via p53 abrogation.  In addition, venetoclax has shown 
activity in subjects with relapsed or refractory CLL who have been previously treated with 
a B-cell receptor inhibitor.  These subjects can participate in this study and may have 
relapsed or be refractory to ibrutinib or idelalisib containing regimen.
All subjects enrolled in the study will have adequate performance status and hematologic, 
renal and hepatic function to undergo venetoclax treatment.  
5.6.4
Selection of Doses in the Study
Venetoclax dosing will be introduced at an initial dose of 20 mg QD and escalated to a 
final dose of 400 mg QD.  The maximum dose of venetoclax for this protocol will not 
exceed 400 mg per day.  The daily dose will be titrated in the following weekly 
increments, as tolerated:  20 mg, 50 mg, 100 mg, 200 mg, and 400 mg.  The 400 mg final 
dose was selected for the ongoing, Phase II study of venetoclax monotherapy in 
relapsed/refractory CLL subjects with 17p deletion (Study M13-982) based on 
time-to-response and logistic regression modeling of data from CLL/SLL subjects 
enrolled in the Phase I Study M12-175.
The initial 20 mg venetoclax dose and weekly incremental increases in the dose-titration 
phase were implemented for Study M13-982 to reduce the risk of TLS.  Preliminary 
 


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safety data from that study indicate the initial dose, the dose-titration phase and the final 
maximum dose are tolerable.
6.0
Complaints 
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.9.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
 


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6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meets protocol specific criteria (see Section 6.1.9 Toxicity 
Management) or if the investigator considers them to be adverse events.
For this protocol, disease progression is an efficacy endpoint.  These data will be captured 
as efficacy assessment data only.  Thus, events that are clearly consistent with the 
expected pattern of progression of the underlying disease (such as transformation to more 
aggressive histology) will result in discontinuation from the study and should not be 
recorded as adverse events but reported on the Study Completion eCRF.  However, if a 
subject experiences an adverse event (e.g., pneumonia, pyrexia, fatigue, etc.) and is also 
found to have disease progression, report the adverse event.  If there is any uncertainty as 
to whether an event is due to disease progression, it should be reported as an adverse 
event.
An elective surgery/procedure scheduled to occur during a study will not be considered an
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
 


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pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done, will be considered an adverse event.
A treatment-emergent AE is defined as any AE reported by a subject with onset or 
worsening from the time that the first dose of venetoclax is administered until 30 days 
have elapsed following discontinuation of venetoclax administration.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical intervention 
had not been taken.  This does not include an event that 
would have been fatal if it had occurred in a more severe 
form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to 
an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle).
 


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.  Deaths related to disease progression will 
not be recorded as serious adverse events (Section 6.1.3.1).
Hospitalization of a subject to allow observation and management (e.g., for intravenous 
(IV) hydration) for the purpose of TLS prophylaxis will not be captured as an SAE, unless 
there is an additional reason for hospitalization or an additional criterion for seriousness 
other than hospitalization (e.g., abnormal post-dose TLS laboratories that necessitate 
therapeutic medical intervention, etc.).
Hospitalization of a subject following the 30 Day Safety Follow-Up visit due to a 
subsequent line of therapy will not be captured as a SAE.
6.1.1.3
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL
Certain AEs are anticipated to occur in the study population at some frequency 
independent of drug exposure.  Such events include known consequences of CLL 
(e.g., symptoms, disease progression) and events unlikely to be related to the underlying 
 


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disease 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 H. 
These AEs may occur alone or in various combinations and are considered expected for 
reporting purposes for this protocol.
Cytopenias (anemia, neutropenia, or thrombocytopenia) are part of the natural history of 
CLL.  Persistent cytopenias at the same CTCAE grade as reported at baseline are not to be 
captured as adverse events, unless they fulfill a seriousness criteria, result in permanent 
discontinuation of a study drug, or the  investigator had an identifiable cause other than 
the underlying disease.  However, all laboratory data should be entered regardless of 
whether an adverse event is reported.
Although exempted from expedited reporting to certain Health Authorities and ECs/IRBs 
as individual cases, if an event commonly associated with CLL or progression of CLL 
meets seriousness criteria, it must be reported to AbbVie within 24 hours of the site being 
made aware of the SAE (as defined in Section 6.1.6).  However, if the event was 
unequivocally (clearly) due to disease progression, it should not be reported as an adverse 
event if serious or fatal.  For deaths related to disease progression, the date and cause of 
death will be recorded on the appropriate case report form, but the death will not be 
expedited as an individual case safety report (ICSR) to regulatory authorities.
6.1.1.4
Adverse Events of Special Interest
Adverse events of special interest include TLS and neutropenia.
6.1.2
Adverse Event Severity
The Investigator will rate the severity of each AE according to the NCI CTCAE v4.03.  If 
a reported AE increases in severity, the initial AE should be given an outcome date and a 
new AE must be reported with a different onset date than the end date of the previous 
adverse event to reflect the change in severity.  The dates on the AEs cannot overlap.  For 
 


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all reported SAEs that increase in severity, the supplemental eCRFs also need to be 
updated to reflect any changes due to the increase in severity.
For AEs not captured by the NCI CTCAE, the following should be used:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities (moderate).
Grade 3
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating (moderate to severe).
Grade 4
The adverse event is life-threatening requiring urgent intervention 
(severe).
Grade 5
The adverse event resulted in death of the subject (severe).
6.1.3
Adverse Events Expected Due to Study-Related Endpoints
6.1.3.1
Deaths 
For this protocol, overall survival is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (Section 6.1.5) that are attributed by the 
investigator solely to progression of CLL should be recorded ONLY on the Study 
Completion eCRF.  All other on-study deaths, regardless of relationship to study drug, 
must be recorded on the Adverse Event eCRF and immediately reported to the Sponsor 
(Section 6.1.5).  Death should be considered an outcome and not a distinct event.  The 
event or condition that caused or contributed to the fatal outcome should be recorded as 
the single medical concept on the Adverse Event eCRF.  Generally, only one such event 
should be reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a subject with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the subject was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
 


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death later becomes available (e.g., after autopsy), "unexplained death" should be replaced 
by the established cause of death.  During survival follow-up, deaths attributed to 
progression of CLL should be recorded only on the Survival eCRF.
6.1.3.2
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease are also considered an expected outcome for this study and will not be 
subject to expedited reporting.
6.1.4
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other Cause" of event must be provided by the investigator for the SAE.
 






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Phone:  +1 (973) 784-6402
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure. 
6.1.7
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued (Section 5.4.1).
All subjects should be informed that contraceptive measures should be taken throughout 
the study and for 30 days after the last dose of venetoclax.  Male subjects should be 
informed that contraceptive measures should be taken by their female partners.  
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  In the event of a pregnancy occurring in the partner of an 
enrolled subject, written informed consent for release of medical information from the 
partner must be obtained prior to the collection of any pregnancy-specific information and 
the pregnancy will be followed to outcome.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome of 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, stillbirth or congenital anomaly is considered a serious adverse event and must 
be reported to AbbVie within 24 hours of the site becoming aware of the event.
6.1.8
Data Monitoring Committee
The Data Monitoring Committee (DMC) will review safety data intermittently according 
to the DMC charter.  Details of the DMC review are presented in the DMC charter. The 
DMC charter has been created to provide detailed descriptions of the schedule of analyses 
 


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and the DMC meetings.  DMC membership, responsibilities and the description of the 
data coordinating center are documented in the charter.
6.1.9
Toxicity Management
6.1.9.1
Prophylaxis and Management of Tumor Lysis Syndrome
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 
5-week dose-titration phase.  Changes in electrolytes consistent with TLS that require 
prompt management can occur as early as 6 to 8 hours following the first dose of 
venetoclax and at each dose increase. 
Risk Assessment for tumor lysis syndrome:  The risk of TLS is a continuum based on 
multiple factors, including tumor burden and comorbidities.  Subjects with high tumor 
burden (e.g., any lymph node with a diameter ≥ 5 cm or high absolute lymphocyte count 
[ALC > 25 × 109/L]) are a greater risk of TLS.  Reduced renal function (estimated 
creatinine clearance [eCrCl] < 80 mL/min) further increases the risk.  The risk may 
decrease as tumor burden decreases with venetoclax treatment.
Additional comorbidities may further increase the risk for TLS.
Prior to initiating venetoclax, tumor burden assessment, including radiographic evaluation 
(e.g., refer to Section 5.3.1.1 Study Procedures – Disease Assessment) must be performed 
for all subjects during Screening.  The full blood chemistry/hematology panel (refer to 
Table 4 Clinical Laboratory Tests) should be performed in all subjects during the 
Screening period in order to assess eligibility and to correct pre-existing abnormalities. 
If the full chemistry/hematology panel was assessed more than 72 hours prior to the 1st
dose of venetoclax, an additional full lab panel should be performed and reviewed within 
72 hours prior to dosing in order to make a treatment decision.
Prophylaxis for tumor lysis syndrome:  The prophylaxis measures listed below should be 
followed.  More intensive measures (including hospitalization) should be employed as 
overall risk increases: 
 


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Hydration:  Subjects should be adequately hydrated prior to starting treatment with 
venetoclax and during the dose-titration phase.  The recommended volume is 1.5 to 
2.0 L (approximately 6 to 8 glasses) of water each day.  Subjects should be instructed 
to drink water starting 2 days before and on the day of the first dose, and every time 
the dose is increased.  Intravenous (IV) fluids should be administered as indicated 
based on overall risk of TLS or for those who cannot maintain an adequate level of 
oral hydration.  For subjects for whom volume overload is considered a significant 
risk, hospitalization should be considered.
Anti-hyperuricemic agents:  Anti-hyperuricemic agents should be administered 2 to 
3 days prior to starting treatment with venetoclax and may be continued through the 
titration phase. 
Laboratory Assessments: 
PRE-DOSE LABS:
Prior to the initial dose of venetoclax:
●
During the Screening Period:  For all subjects, the chemistry/hematology panel 
(see Table 4 Clinical Laboratory Tests) is required. 
○
Pre-existing abnormalities should be corrected.
●
Within 72 hours of Week 1/Day 1:  If the screening labs were more than 
72 hours before the planned first dose, the chemistry/hematology panel should 
be repeated.  These results should be reviewed before dosing. 
○
Labs should be assessed and pre-existing abnormalities should be 
corrected.
●
On the day of Week 1/Day 1:  Before dosing, the chemistry/hematology panel 
should be drawn.  The results of the labs drawn on Week 1 Day 1 need to be 
reviewed prior to dosing IF an additional lab within 72 hours of the initial dose 
at Week 1 Day 1 was not drawn AND reviewed.  
Prior to each subsequent dose increase, for all subjects:
 


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●
Within 72 hours of each subsequent dose increase:  The chemistry/hematology 
panel should be repeated.  The results should be reviewed prior to dose 
increasing.
●
Prior to dosing, on the day of each subsequent dose increase:  Before dosing, 
the chemistry/hematology panel should be drawn.  The results of the labs 
drawn on Day 1 of each dose increase need to be reviewed prior to dosing IF
an additional lab draw within 72 hours of the dose increase was not drawn
AND reviewed.  
POST-DOSE LABS:
For all subjects, the chemistry/hematology panel (refer to Table 4 Clinical 
Laboratory Tests) should be monitored at 6 to 8 hours and at 24 hours* after the 
first dose of venetoclax (20 mg) and after the first dose increase (50 mg).  
Electrolyte abnormalities should be corrected promptly.  The next venetoclax
doses (Day 2 20 mg venetoclax dose and Day 2 50 mg venetoclax dose) should 
not be administered until the 24-hour* lab results have been evaluated.  Electrolyte 
abnormalities should be corrected promptly.  For subjects who continue to be at 
risk of TLS, the same lab monitoring schedule (i.e., 6 to 8 hour and 24-hr post 
dose) should be followed at the subsequent dose increases.
This monitoring is also recommended during the re-initiation of the therapy after a 
dose interruption.
*All 24 hour post-dose laboratory assessments may be taken within a 2 hour window, if 
necessary.
Hospitalization:  Based on investigator assessment, some subjects, especially those at 
greater risk of TLS may require hospitalization on the day of the first dose of 
venetoclax for more intensive prophylaxis and monitoring through the first 24 hours.  
Hospitalization should be considered for subsequent dose increases based on 
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6.1.9.2
Dose Modifications Based on Toxicities
Dosing interruption and/or dose reduction may be required.  See Table 7 for dose 
modifications for hematologic and other toxicities related to venetoclax.  For subjects who 
have had a dosing interruption greater than 1 week during the first 5 weeks of dose 
titration or greater than 2 weeks when at the daily dose of 400 mg, TLS risk should be 
reassessed to determine if restarting at a reduced dose is necessary (e.g., all or some levels 
of the dose titration.
Tumor Lysis Syndrome 
If a subject experiences blood chemistry changes suggestive of TLS, the following day's 
venetoclax dose should be withheld.  If resolved within 24 to 48 hours of last dose, 
treatment with venetoclax can be resumed at the same dose.  For events of clinical TLS or 
blood chemistry changes requiring more than 48 hours to resolve, treatment should be 
resumed at a reduced dose (Table 7 and Table 8).  When resuming treatment with 
venetoclax after interruption due to TLS, the instructions for Prophylaxis for tumor lysis 
syndrome should be followed.
Other Toxicities 
Treatment with venetoclax should be withheld for any grade 3 or 4 non-haematological, 
grade 3 or 4 neutropenia with infection or fever, or grade 4 haematological toxicities, 
except lymphopenia.  To reduce the risk of infection associated with neutropenia, 
granulocyte-colony stimulating factor (G-CSF) may be administered with venetoclax if 
clinically indicated.  Once the toxicity has resolved to grade 1 or baseline level (recovery), 
therapy with venetoclax may be restarted at the same dose.  If the toxicity recurs, and for 
any subsequent occurrences, the dose reduction guidelines in Table 7 and Table 8 should 
be followed when resuming treatment with venetoclax following resolution.  A larger 
dose reduction may occur at the discretion of the investigator.  For subjects who require 
dose reductions to less than 100 mg for more than 2 weeks, due to adverse events, 
discontinuation of venetoclax should be considered. 
 


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Table 7.
Recommended Dose Modifications for Toxicities
Event
Occurrence
Action
Tumor Lysis Syndrome
Blood chemistry changes or 
symptoms suggestive of TLS
Any
Withhold the next day's dose.  If resolved within 24 –
48 hours of last dose, resume at the same dose.
For any blood chemistry changes requiring more than 
48 hours to resolve, resume at a reduced dose (Table 8) 
For any events of clinical TLS,a resume at a reduced 
dose following resolution (Table 8).
Non-Hematologic Toxicities
Grade 3 or 4 non-hematologic 
toxicities 
1st occurrence
Interrupt venetoclax
Once the toxicity has resolved to Grade 1 or baseline 
level, venetoclax therapy may be resumed at the same 
dose.  No dose modification is required.
2nd and subsequent 
occurrences
Interrupt venetoclax.
Follow dose reduction guidelines in Table 8 when 
resuming treatment with venetoclax after resolution.  A 
larger dose reduction may occur at the discretion of the 
investigator.
Hematologic Toxicities
Grade 3 or 4 neutropenia with 
infection or fever; or Grade 4 
hematologic toxicities (except 
lymphopenia) 
1st occurrence
Interrupt venetoclax.
To reduce the infection risks associated with 
neutropenia, granulocyte-colony stimulating factor (G-
CSF) may be administered with venetoclax if clinically 
indicated.  Once the toxicity has resolved to Grade 1 or 
baseline level, venetoclax therapy may be resumed at 
the same dose.
2nd and subsequent 
occurrence
Interrupt venetoclax.
Consider using G-CSF as clinically indicated.
Follow dose reduction guidelines in Table 8 when 
resuming treatment with venetoclax after resolution.  
Additional dose reductions may occur at the discretion 
of the physician.
Consider discontinuing venetoclax for subjects who require dose reductions to less than 100 mg for more than 
2 weeks.
a.
Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac 
arrhythmias or sudden death and/or seizures.
Note:
Adverse reactions were graded using NCI CTCAE version 4.03.
 


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Table 8.
Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg
Restart Dose, mga
400
300
300
200
200
100
100
50
50
20
20
10
a.
During the dose titration phase, continue the reduced dose for 1 week before increasing the dose. 
Dose Modifications for use with CYP3A Inhibitors
Concomitant use of venetoclax with strong or moderate CYP3A inhibitors increases 
venetoclax exposure and may increase the risk for TLS at initiation and during the 
dose-titration phase.  Concomitant use of venetoclax with strong CYP3A inhibitors at 
initiation and during the dose-titration phase is contraindicated. 
Concomitant use of venetoclax with moderate CYP3A inhibitors at initiation and during 
the dose-titration phase should be avoided.  Alternative treatments should be considered.  
If a moderate CYP3A inhibitor must be used, the initiation and titration doses of 
venetoclax should be reduced by at least 50%.  Subjects should be monitored more closely 
for signs of toxicities. 
For subjects who have completed the dose-titration phase and are on a steady daily dose 
of venetoclax, the venetoclax dose should be reduced by at least 50% when used 
concomitantly with moderate CYP3A inhibitors and by at least 75% when used 
concomitantly with strong CYP3A inhibitors.  Subjects should be monitored more closely 
for signs of toxicities.  The venetoclax dose that was used prior to initiating the CYP3A 
inhibitor should be resumed 2 to 3 days after discontinuation of the CYP3A inhibitor. 
 


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Missed Dose
If a subject misses a dose of venetoclax within 8 hours of the time it is usually taken, the 
subject should take the missed dose as soon as possible and resume the normal daily 
dosing schedule.  If a subject misses a dose by more than 8 hours, the subject should not 
take the missed dose and should resume the usual dosing schedule the following day.
If a subject vomits following dosing, no additional dose should be taken that day.  The 
next prescribed dose should be taken at the usual time the following day.
6.1.9.3
Management of Neutropenia
Nonclinical and clinical experience indicates that venetoclax may cause neutropenia.  
Subjects with a history of neutropenia who have received multiple prior therapies and/or 
have significant bone marrow involvement may be at a particularly high risk.
Grade 3 or 4 neutropenia has been reported in subjects treated with venetoclax.  Complete 
blood counts should be monitored throughout the treatment period.  Dose interruptions or 
dose reductions are recommended for subjects with severe neutropenia.  Supportive 
measures including antimicrobials for any signs of infection and prophylactic use of 
growth factors (e.g., G-CSF) should be considered. 
6.1.9.4
Immunization
Live attenuated vaccines should not be administered prior to, during, or after treatment 
with venetoclax until B-cell recovery occurs.  The safety and efficacy of immunization 
with live attenuated vaccines during or following venetoclax therapy have not been 
studied.  Subjects should be advised that vaccinations may be less effective.
6.1.9.5
Management of Hematologic Toxicities Other Than 
Neutropenia or Lymphopenia
Venetoclax treatment should be withheld for any Grade 4 hematologic toxicity.  Once the 
toxicity has resolved to Grade 1 or baseline level (recovery), venetoclax may be re-started 
at the same dose.  If the toxicity recurs, the dose reduction guidelines in Table 8 should be 
 


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followed when resuming study treatment following resolution.  Additional dose 
reductions may occur at the discretion of the physician.
6.1.9.6
Management of Non-Hematologic Toxicity
Venetoclax treatment should be withheld for any clinically relevant ≥ Grade 3 
non-hematologic toxicity.  Once the toxicity has resolved to Grade 1 or baseline level 
(recovery), venetoclax may be re-started at the same dose.  If the toxicity recurs, the dose 
reduction guidelines in Table 8 should be followed when resuming study treatment 
following resolution.  Additional dose reductions may occur at the discretion of the 
physician.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event by entering the product 
complaint in RAVE, the EDC system.  If the EDC system is not operable, the Product 
Complaint Form should be used and emailed to:  RD_PQC_QA@abbvie.com within 
24 hours of the study site's knowledge of the event.  Product Complaints occurring during 
 


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the study will be followed-up to a satisfactory conclusion.  All follow-up information is to 
be reported to the Sponsor (or an authorized representative) and documented in source as 
required by the Sponsor.  Product Complaints associated with adverse events will be 
reported in the study summary.  All other complaints will be monitored on an ongoing 
basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and their assigned AbbVie Clinical Monitor(s).  In addition, 
the following AbbVie representatives should be contacted: 
 




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8.1.1.1
Demographics
Descriptive statistics will be provided for baseline demographic variables.  Age, height 
and weight will be summarized with means, medians, standard deviations and ranges.  
Frequencies and percentages will be provided for gender and race.
8.1.1.2
Medical Histories
Frequencies and percentages will be summarized for each medical history parameter.
8.1.2
Study Endpoints
8.1.2.1
Primary Endpoint
The primary endpoint will be assessed by the GHS/QoL subscale of the EORTC 
QLQ-C30.  The primary endpoint will be the mean change from baseline (within 72 hours 
prior to the first dose of venetoclax) to Week 48.  Scores will be calculated based on the 
scoring manual.
8.1.2.2
Secondary Endpoints
Secondary quality of life endpoints will include all multi-item scales and single-item 
scales from the EORTC QLQ-C30, EORTC QLQ-CLL16, and EQ-5D-5L.  Scores will be 
calculated based on the scoring manual for each instrument.
Key secondary efficacy endpoints will include Complete Remission rate (CR + CRi), 
Overall Response Rate (ORR), Duration of Overall Response (DOR), Time to 
Progression (TTP), Duration of Progression-Free Survival (PFS) and Overall Survival 
(OS).
Complete remission rate (CR + CRi) defined as the proportion of subjects achieving a CR 
or CRi as their best response (per the investigator assessment) based on IWCLL NCI-WG 
criteria.  In addition, the ninety-five percent (95%) confidence interval based on binomial 
distribution will be constructed for the calculated CR rate.
 


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ORR will be assessed as the proportion of subjects with an overall response (CR + CRi + 
nPR + PR) based on the IWCLL NCI-WG criteria.  The ninety-five percent (95%) 
confidence interval based on binomial distribution will be constructed for the calculated 
CR rate.
Duration of overall response will be defined as the number of days from the date of 
first response (CR, CRi, nPR, or PR) to the earliest recurrence or PD.  If a subject is still 
responding, then the subject's data will be censored at the date of the subject's last 
available disease assessment.  For subjects who never experience response, the subject's 
data will be censored on the date of enrollment.  Duration of overall response will be 
analyzed by Kaplan-Meier methodology using data for all enrolled subjects.  Median 
duration of overall response will be calculated and the corresponding 95% confidence 
interval will be presented.
Time to progression (TTP) will be defined as the number of days from the date of 
first dose or enrollment if not dosed to the date of earliest disease progression.  All disease 
progression will be included regardless whether the event occurred while the subject was 
taking the study drug or had previously discontinued the study drug.  If the subject does 
not experience disease progression, then the data will be censored at the date of last 
available disease assessment.  Data for subjects who receive non-protocol, CLL therapy 
prior to disease progression will be censored at the last disease assessment prior to 
receiving non-protocol therapy.  Data for subjects without any disease assessments 
performed after the baseline visit will be censored at the time of enrollment plus 1 day.  
TTP will be analyzed by Kaplan-Meier methodology using data for all subjects enrolled.  
Median time TTP will be calculated and 95% confidence interval for median time TTP 
will be presented.
Progression-free survival (PFS) will be defined as the number of days from the date of 
first dose to the date of earliest disease progression or death.  All disease progression will 
be included regardless whether the event occurred while the subject was taking the study 
drug or had previously discontinued the study drug.  If the subject does not experience 
disease progression or death, then the data will be censored at the date of last disease 
 


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assessment.  Data for subjects who receive non-protocol, CLL therapy prior to disease 
progression will be censored at the last disease assessment prior to receiving non-protocol 
therapy.  Data for subjects without any disease assessments performed after the baseline 
visit will be censored at the time of enrollment plus 1 day.  PFS will be analyzed by 
Kaplan-Meier methodology using data for all subjects enrolled.  Median time PFS will be 
calculated and 95% confidence interval for median time PFS will be presented.
Overall survival (OS) will be defined as number of days from the date of first dose to the 
date of death for all dosed subjects.  For subjects who did not die, their data will be 
censored at the date of last study visit or the last known date to be alive, whichever is 
later.  OS will be analyzed by Kaplan-Meier methodology using data from all enrolled 
subjects.  Median time survival will be estimated and 95% confidence interval for the 
median time survival will be presented.
8.1.3
Timing of Study Endpoints and Safety Evaluations
The date the last enrolled subject has completed their Week 48 quality of life and disease 
assessments, or after all enrolled subjects have discontinued venetoclax, whichever is 
earlier, will be defined as the data "cutoff" date for the analyses.  Quality of life, efficacy 
and safety data up to and including this date will be collected.  Exact data cutoff date for 
the analysis will be detailed in the SAP which will be signed off prior to the data cut-off 
date.  During this data collection period, active subjects will continue to receive 
venetoclax, as applicable.  When data collection is complete and all data management 
quality assurance (QA) and quality control (QC) procedures are performed, the clinical 
database data will be extracted for documentation and statistical analyses.  Any active 
subjects will continue to receive venetoclax until they discontinue or for up to 2 years.  
Once the last enrolled subject discontinues/completes the study, the study will be 
considered complete and all remaining data will be collected and entered into the clinical 
database.
 


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8.1.4
Safety
The safety of venetoclax will be assessed by evaluating study drug exposure, adverse 
events, serious adverse events, all deaths, and laboratory parameters.
Safety analyses will be performed for all subjects who take at least one dose of 
venetoclax.
8.1.4.1
Adverse Events
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the day of the first dose of study drug.
Analyses will not include those that have an onset greater than 30 days after the last dose 
of study drug.
Treatment-emergent adverse events will be summarized by preferred terms within a 
System and Organ Class according to the most current Medical Dictionary for Regulatory 
Activities (MedDRA).  In addition, the percentage of subjects experiencing an adverse 
event at a NCI CTCAE toxicity grade, and relationship to study drug will be provided.
8.1.4.2
Serious Adverse Events
Serious adverse events will be summarized using the same methods as Adverse Events 
described above.
8.1.4.3
Deaths
The number of subject deaths will be summarized (1) for deaths occurring within 30 days 
of the last dose of study drug, and (2) for deaths occurring more than 30 days of the last 
dose of study drug.
 


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8.1.4.4
Analyses of Laboratory Data 
Where applicable, blood chemistry and hematology determinations will be categorized 
according to NCI CTCAE version 4.03, grades and shifts from baseline NCI CTCAE 
grades to maximum and final post-baseline grades will be assessed.
The baseline and final grades will be defined respectively as the grade of the last 
measurement collected prior to the first dose of study drug, and as the last post-baseline 
measurement collected no more than 30 days after the last dose of study drug.  The 
percentage of subjects experiencing a shift from baseline grades of 0 to 2 to maximum 
post-baseline grades of 3 to 4, and from baseline grades of 0 to 2 to final post-baseline 
grades of 3 to 4 will be summarized.  Detailed listings of data for subjects experiencing 
NCI CTCAE Grade 3 to 4 blood chemistry and hematology values will be provided.  All 
measurements collected, regardless of the number of days after the last dose of study 
drug, will be included in these listings.
8.2
Determination of Sample Size
An improvement in the EORTC QLQ-C30 GHS/QoL subscale of 5 units is considered to 
be a clinically meaningful difference to subjects.  From a prior study of venetoclax 
monotherapy in 17p del R/R CLL subjects (Study M13-982), the standard deviation was 
approximately 20.5 for the GHS/QoL subscale.  Using a one-sided alpha of 0.025, 90% 
power, and a standard deviation of 20.5; 177 subjects are required to reject the null 
hypothesis in favor of the alternative hypothesis that venetoclax improves GHS/QoL by at 
least 5 units.  To account for potential drop-outs at Week 48, a total of 200 subjects to be 
dosed.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
 


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subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval and approval by 
Regulatory Authority(ies), if required by local regulations, prior to implementation of any 
changes made to the study design.  The investigator will be required to submit, maintain 
and archive study essential documents according to ICH GCP and all other applicable 
regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix F.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
 


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be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, or evaluation 
checklists, pharmacy dispensing and other records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-
rays.  Data collected during this study must be recorded on the appropriate source 
documents.  The Investigator Awareness Date (SAE CRF) may serve as the source for this 
data point.  This adverse event data point required for eCRF completion can be entered 
directly in the eCRF.
The following patient reported outcomes (PRO) assessments will be completed by the 
subject and will be considered source documentation:
●
EORTC QLQ-C30
●
EORTC QLQ-CLL16
●
EuroQoL EQ-5D-5L
 


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The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The Investigator or an authorized member of the Investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
Principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
 


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PRO data is collected directly onto paper source by the subjects.  The completion of these 
forms is verified by the site staff.  The forms are entered into the clinical database and 
then can be viewed within the EDC system by the site staff.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigative sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
11.0
Data Quality Assurance
To ensure data integrity and subject safety, a study monitor will continuously, throughout 
the study, verify that all subjects sign the informed consent prior to any study specific 
procedures being conducted, that the protocol procedures are being followed 
appropriately, and that the information provided in the eCRF is complete, accurate, and 
supported by information in source documents.  Computer logic and manual checks will 
be created to identify items such as inconsistent study dates.  Any necessary corrections 
will be made to the eCRF.
12.0
Use of Information
Any research that may be done using research samples from this study will be 
experimental in nature and the results will not be suitable for clinical decision making or 
subject management.  Hence, the subject will not be informed of individual results, should 
analyses be performed, nor will anyone not directly involved in this research.  
Correspondingly, researchers will have no access to subject identifiers.  Individual results 
will not be reported to anyone not directly involved in this research other than for 
regulatory purposes.  Data from research may be provided to investigators and used in 
scientific publications or presented at medical conventions.  Research information will be 
published or presented only in a way that does not identify any individual subject.
 


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13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must submit, maintain and archive any records related to the study 
according to ICH GCP and all other applicable regulatory requirements.  If the 
investigator is not able to retain the records, he/she must notify AbbVie to arrange 
alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit or date of the last 
follow up contact, whichever is later.
 


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for venetoclax.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating 
the Impact of Venetoclax on the Quality of Life of 
Relapsed/Refractory Subjects with Chronic Lymphocytic Leukemia 
(CLL) (VENICE II)
Protocol Date:
09 October 2018
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
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Chang BY, Furman RR, Zapatka M, et al.  Use of tumor genomic profiling to 
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33.
Herishanu Y, Katz BZ, Lipsky A, et al.  Biology of chronic lymphocytic leukemia 
in different microenvironments:  clinical and therapeutic implications.  Hematol 
Oncol Clin North Am.  2013;27(2):173-206.
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38.
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obinutuzumab (RO5072759 [GA101]) with chlorambucil in patients with 
previously untreated chronic lymphocytic leukemia (stage 2).  ClinicalTrials.gov 
website.  Available from:  https://clinicaltrials.gov/ct2/show/NCT02053610.  
Accessed on:  February 2016.
39.
Van Oers, Kuliczkowski K, Smolej L, et al.  Health-related quality of life and 
patient-reported outcomes in patients receiving ofatumumab maintenance versus 
observation in the PROLONG trial.  EHA 2015.  Abstract P213.
40.
Manson S, McKeown A, Chang GN, et al.  Health-related quality of life and 
patient-reported outcomes of ofatumumab plus chlorambucil versus chlorambucil 
monotherapy in the COMPLEMENT 1 trial.  EHA 2015.  Abstract P594.
41.
Herdman M, Gudex C, Lloyd A, et al.  Development and preliminary testing of the 
new five-level version of EQ-5D (EQ-5D-5L).  Qual Life Res.  2011;20:1727-36.
42.
Oppe M, Devlin NJ, van Hout B, et al.  A program of methodological research to 
arrive at the new international EQ-5D-5L valuation protocol.  Value Health.  
2014(4);17:445-53.
 


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43.
Pickard AS, Neary MP, Cella D.  Estimation of minimally important differences in 
EQ-5D utility and VAS scores in cancer.  Health Qual Life Outcomes.  
2007;5:70-8.
44.
Cella D, Pickard AS, Duh MS, et al.  Health-related quality of life in patients with 
advanced renal cell carcinoma receiving pazopanib or placebo in a randomized 
phase III trial.  Eur J Cancer.  2012;48(3):311-323.
45.
Catovsky D, Richards S, Matutes E, et al.  Assessment of fludarabine plus 
cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF 
CLL4 Trial):  a randomised controlled trial.  Lancet.  2007;370(9583):230-99.
46.
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and 
treatment of chronic lymphocytic leukemia:  a report from the International 
Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute-Working Group 1996 guidelines.  Blood.  2008;111:5446-56.  [Erratum, 
Blood.  2008;112:5259.]
47.
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the 
Eastern Cooperative Oncology Group.  Am J Clin Oncol.  1982;5(6):649-55.
48.
Eichhorst BF, Busch R, Obwandner T, et al.  Health-related quality of life in 
younger patients with chronic lymphocytic leukemia treated with fludarabine plus 
cyclophosphamide or fludarabine alone for firstline therapy:  a study by the 
German CLL Study Group.  J Clin Oncol.  2007;25(13):1722-31.
49.
Else M, Smith AG, Cocks K, et al.  Patients' experience of chronic lymphocytic 
leukaemia:  baseline health-related quality of life results from the LRF CLL4 trial.  
Br J Haematol.  2008;143(3):690-7.
50.
Mulligan SP, Karlsson K, Stromberg M, et al.  Cladribine prolongs 
progression-free survival and time to second treatment compared to fludarabine 
and high-dose chlorambucil in chronic lymphocytic leukemia.  Leuk Lymphoma.  
2014;55(12):2769-77.
51.
de Wreede LC, Watson M, van Os M, et al.  Improved relapse-free survival after 
autologous stem cell transplantation does not translate into better quality of life in 
 


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chronic lymphocytic leukemia:  lessons from the randomized European Society for 
Blood and Marrow Transplantation-Intergroup study.  Am J Hematol.  
2014;89(2):174-80.
52.
Holtzer-Goor KM, Schaafsma MR, Joosten P, et al.  Quality of life of patients with 
chronic lymphocytic leukaemia in the Netherlands:  results of a longitudinal 
multicentre study.  Qual Life Res.  2015;24(12):2895-906.
 


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
 


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
 


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Associate Director
Statistics
Assistant Medical Director
Medical Affairs
Group Project Director
Clinical
Study Project Manager II
Clinical
 






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Appendix D.
Study Activities:  Screening Through Week 5 Day 2
Activity
Scra
Within 
72 Hours 
of W1 
D1 
W1
D1
W1
D2
Within 
72 Hours 
of W2 
D1 
W2
D1
W2
D2
Within 
72 Hours 
of W3 
D1 
W3
D1
W3
D2
Within 
72 Hours 
of W4 
D1 
W4 
D1
W4
D2
Within 
72 Hours 
of W5 
D1 
W5
D1
W5
D2
Informed Consent
X
17p Deletion or TP53 Mutation
Xb
Medical History/Oncology History 
Assessment
X
X
Pregnancy Testc
X
X
Adverse Event/Concomitant 
Medication Assessment
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examinatione
X
X
X
X
X
X
TLS Risk Assessmentf
X
ECOG Performance Status
X
X
Coagulation Panel
X
Hematology/Chemistryg
X
Xh
Xi
Xj
Xk
Xl
Xj
Xk
Xl
Xm
Xk
Xl
Xm
Xk
Xl
Xm
Disease Assessmentsn
X
Contrasted CT or MRI Scano
X
Bone Marrow Aspirate and Biopsyp
Venetoclax dispensation and 
accountabilityq
X
X
X
X
X
X
X
X
X
X
 


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Activity
Scra
Within 
72 Hours 
of W1 
D1 
W1
D1
W1
D2
Within 
72 Hours 
of W2 
D1 
W2
D1
W2
D2
Within 
72 Hours 
of W3 
D1 
W3
D1
W3
D2
Within 
72 Hours 
of W4 
D1 
W4 
D1
W4
D2
Within 
72 Hours 
of W5 
D1 
W5
D1
W5
D2
Quality of Life Questionnaires 
(EORTC QLQ-30, EORTC QLQ-
CLL16, EQ-5D-5L)r
X
X
X
 


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Week 8 Through Post-Treatment Follow-Up
Activity
W8 
D1
W12
D1
W16 
D1
W20
D1
W24
D1
W28
D1
W32
D1
W36
D1
W40
D1
W44
D1
W48
D1
Every 
12 Weeks 
Starting 
at W60
W108 
/ 
Final 
Visit
30 Day 
Safety 
Visits
Post-
Treatment 
Follow-Upt
Adverse Event/Concomitant 
Medication Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examinatione*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Statusu
X
X
X
X
X
Hematology/Chemistry**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease Assessmentn*
X
X
X
Contrasted CT or MRI Scano
X
Bone Marrow Aspirate and Biopsyp
X
Venetoclax dispensation and 
accountability***
X
X
X
X
X
X
X
X
X
X
X
X
Xw
Quality of Life Questionnaires (EORTC 
QLQ-30, EORTC QLQ-CLL16, 
EQ-5D-5L)r
X
X
X
X
X
X
X
Collection of Survival Informationv
X
X
Scr = Screening; W = Wk = Week; D = Day; Post-Treat = Post-Treatment; FV = Final Visit
Study Windows:
*
Within 72 hours before or after scheduled visit starting with Week 8 Day 1.
**
Within 72 hours prior to scheduled visit starting with Week 8 Day 1.
*** As of Week 8 the visit window for scheduled visits is ± 2 days.
a.
Subjects will undergo screening procedures within 28 days prior to the first study drug administration, except where otherwise indicated.
 


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b.
Subjects who have 17p deletion or TP53 mutation as assessed by local laboratory (in bone marrow or peripheral blood) may be considered for enrollment.  A recent test is 
desirable but any previous positive test is acceptable.  Subjects that do not have the 17p deletion or TP53 mutation or have an unknown status are also eligible.
c.
For females of childbearing potential, as defined in the protocol, a urine pregnancy test must be obtained and processed locally at Week 1 Day 1, if it has been > 7 days since 
obtaining the serum pregnancy results at Screening.  During the study, a urine pregnancy test can be performed at the discretion of the investigator or per local guidelines.
d.
All protocol-related serious adverse events and nonserious adverse events must be collected from the signing of the study-specific informed consent until study drug 
administration.
e.
A complete physical examination will be performed at Screening.  A symptom directed physical examination may be performed as needed.  Refer to Section 5.3.1.1 Physical 
Examination, for more details.
f.
For subjects who have a dose interruption lasting more than 1 week during the first 5 weeks of dose-titration or more than 2 weeks when at the daily dose of 400 mg, the TLS 
risk should be reassessed to determine if restarting at a reduced dose is necessary.
g.
All clinical laboratory tests will be analyzed by the local laboratory.  Required tests are listed in Table 4 Clinical Laboratory Tests, refer to Section 5.3.1.1 Study Procedures, 
sub header Hematology and Chemistry as well as Section 6.1.9 Toxicity Management, for more details. 
h.
For all subjects, if the screening labs were done more than 72 hours before the planned first dose, the chemistry/hematology panel should be repeated and results reviewed 
prior to the initial dose in order to make a treatment decision.  Labs should be assessed and pre-existing abnormalities should be corrected. 
i.
For all subjects, on the day of Week 1 Day 1, before dosing, the chemistry/hematology panel should be collected.  The results of the labs drawn on Week 1 Day 1 need to be 
reviewed prior to dosing IF an additional lab within 72 hours of the initial dose at Week 1 Day 1 was not drawn AND reviewed.  
j.
For all subjects, the chemistry/hematology panel should be monitored at 6 to 8 hours and at 24 hours after the first dose of venetoclax (20 mg) and after the first dose increase 
(50 mg).  The next venetoclax doses should not be administered until the 24 hour lab results have been evaluated.  Electrolyte abnormalities should be corrected promptly.  
Note:  There is a ± 2 hour window around the 24 hour lab draw. 
k.
For all subjects, within 72 hours of each subsequent dose increase, the chemistry/hematology panel should be repeated.  The results should be reviewed prior to dose 
increasing.
l.
Prior to dosing, on the day of each subsequent dose increase, the chemistry/hematology panel is required.  The results of the labs drawn on Day 1 of each dose increase need 
to be reviewed prior to dosing IF additional labs within 72 hours of the dose increase were not drawn AND reviewed. 
m.
For subjects who continue to be at risk of TLS, the same lab monitoring schedule of 6 to 8 hour and 24-hr post dose should be followed at the subsequent dose increases.  
Note:  There is a ± 2 hour window around the 24 hour lab draw.
n.
All measurable disease must be documented at Screening by laboratory testing, physical examination and CT scans (or MRI if CT is medically contraindicated); bone marrow 
examinations are not required at screening but results will be recorded if available.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment.  For all subsequent disease assessments, disease response will be assessed by the investigator based on the analysis of clinical laboratory tests (hematology) and a 
complete physical examination at Week 24, Week 36 and Week 48.
 


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o.
CT scans with contrast (or MRI if CT is medically contraindicated) should include neck, chest, abdomen and pelvic sequences can be accepted if previously performed within 
35 days prior to the initial venetoclax dose.  Otherwise, CT scans (or MRI) must be performed within the 28 day screening period.  To confirm response, a CT scan (or MRI) 
must be performed at Week 48 for all subjects. CT scans (or MRI) may be performed 7 days prior to the scheduled Week 48 visit. If a subject exhibits clinical signs of 
possible disease progression (i.e., increased or de novo enlargement of liver, spleen or lymph nodes on physical examination) without an increase in lymphocytes meeting the 
progression of disease criteria, then additional assessments including contrast-enhanced CT scan and/or bone marrow can be performed to confirm or rule out disease 
progression.  Refer to Section 5.3.1.1 Disease Assessments and Computed Tomography Scans, for more details. For patients with only Partial Remission at Week 48, an 
additional CT and a bone marrow examination can be done between Week 48 and Week 108 to confirm CR if there is a possibility that a patient is in Complete Remission 
based on laboratory tests and a disease assessment physical exam.
p.
For determination of complete remission (CR), the CT scan and bone marrow are required to be negative, per the IWCLL NCI-WG guidelines.  If the subject achieves a CR 
by clinical criteria and confirmatory CT scan, a bone marrow aspirate and biopsy will be performed to confirm the CR.  Refer to Section 5.3.1.1 Disease Assessments and 
Bone Marrow Aspirate and Biopsy, for more details.
q.
Venetoclax tablets should be taken orally once daily with a meal and water in the morning at approximately the same time each day.  Dosing should occur at study visits on 
Week 1 Days 1 & 2 through Week 5 Days 1 & 2.
r.
The Quality of Life Questionnaires should be administered and completed prior to any other study procedures being performed at these visits.  Refer to Section 5.3.1.1, 
Quality of Life Assessments for further information.  
s.
30-Day Safety Follow-up visit should occur approximately 30 days (± 3 days) after the last dose of venetoclax.
t.
Upon discontinuation of study drug treatment, survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 6 months (+
7days) for a period of 2 years.
u.
ECOG performance status may be performed within 72 hours before or after the scheduled visit starting with Week 24.
v.     Survival information includes i.e., the date/cause of death, post treatment cancer therapies, etc.
w.    In countries where venetoclax is not commercially available, subjects who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 
2 additional years. AbbVie will work with the investigator on a case by case basis to consider the potential continuation of venetoclax therapy. Subjects who participate in 
the 2 year Extended Access phase will have study drug assigned at Week 108.  For patients that are not participating in the 2 year Extended Access phase the Week 108 visit 
is the Final visit.  The specific study assessments to be performed at the Extended Access visits are detailed in Appendix E, Study Activities.
 


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Appendix E.
Schedule of Extended Access Phase*
Procedure
W108 
D1
W120 
D1
W132 
D1
W144 
D1
W156 
D1
W168 
D1
W180 
D1
W192 
D1
W204 
D1
W216/ Final 
Visit
30 Day 
Safety 
Visitd
Post 
Treatment 
Follow upe
Vital signs**
X
X
X
Physical Examinationa**
X
X
X
ECOG Performance Status**
X
X
X
Hematology/Chemistry***
X
X
X
Adverse Event/Concomitant 
Medication Assessment
X
X
X
X
X
X
X
X
X
X
X
X
Venetoclax dispensation and 
accountability****
X
X
X
X
X
X
X
X
X
Collection of Survival 
Informationb
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life 
Questionnaires (EORTC 
QLQ-30, EORTC QLQ-
CLL16, EQ-5D-5L)c
X
*
In countries where venetoclax is not commercially available, subjects who continue to derive benefit after 2 years of treatment may be able to extend their treatment for 
up to 2 additional years.  AbbVie will work with the investigator on a case by case basis to consider the potential continuation of venetoclax therapy.
**
Within 72 hours before or after scheduled visit.
***
Within 72 hours prior to scheduled visit.
****
The visit window for scheduled visits is ± 2 days.
a.
Refer to Section 5.3.1.1 Physical Examination, for more details.
b.
Survival information includes i.e., the date/cause of death, post treatment cancer therapies, etc.
 


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c.
The Quality of Life Questionnaires should be administered and completed prior to any other study procedures being performed at these visits.  Refer to Section 5.3.2.2.1
Health Economic and Patient-Reported Outcome Measures, for further information.  
d.
30-Day Safety Follow-up visit should occur approximately 30 days (± 3 days) after the last dose of venetoclax.
e.
Upon discontinuation of study drug treatment, survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 6 months 
(± 7 days) for a period of 2 years
 


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Appendix F.
Definitions of Laboratory and Clinical Tumor Lysis Syndrome
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl  J Med.  
2011;364(19):1844-54.
Metabolic 
Abnormality
Criteria for Classification of Laboratory 
Tumor Lysis Syndrome
Criteria for Classification of 
Clinical Tumor Lysis Syndrome
Hyperruricemia
Uric acid > 8.0 mg/dL (475.8 µmol/liter) 
in adults or above the upper limit of the 
normal range for age in children
Hyperphosphatemia
Phosphorus > 4.5 mg/dL (1.5 mmol/liter) 
in adults or > 6.5 mg/dL (2.1 mmol/liter) 
in children
Hyperkalemia
Potassium > 6.0 mmol/liter
Cardiac dysrhythmia or sudden
death probably or definitely caused 
by hyperkalemia
Hypocalcemia
Corrected calcium < 7.0 mg/dL 
(1.75 mmol/liter) or ionized calcium 
< 1.12 (0.3 mmol/liter)†
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesias, muscle 
twitching, carpopedal spasm, 
Trousseau's sign, Chvostek's sign, 
laryngospasm, or bronchospasm), 
hypotension, or heart failure 
probably or definitely caused by 
hypocalcemia
Acute kidney 
injury‡
Not applicable
Increase in the serum creatinine 
level of 0.3 mg/dL 
(26.5 µmol/liter) (or a single value 
> 1.5 times the upper limit of the 
age-appropriate normal range if no 
baseline creatinine measurement is 
available) or the presence of 
oliguria, defined as an average 
urine output < 0.5 mL/kg/hr for 
6 hrs
†
The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × 
(4-albumin in grams per deciliter).
‡
Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 µmol per 
liter) or a period of oliguria lasting 6 hours or more.  By definition, if acute kidney injury is present, the subject has 
clinical tumor lysis syndrome.  Data about acute kidney injury from Levin at al.
 


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Note:
In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be present during the same 
24-hour period within 3 days before the start of therapy or up to 7 afterward.  Clinical tumor lysis syndrome 
requires the presence of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac 
dysrhythmia, or death.
 


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Appendix G.
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS)
Section 1:  First Dose of Venetoclax  or Dose Escalation
●
Within the first 24 hours after either the first dose or dose escalation, if any 
laboratory criteria below are met, the subject should be hospitalized for 
monitoring and the investigator notified. No additional venetoclax doses 
should be administered until resolution.  Rapidly rising serum potassium is a 
medical emergency.
●
Nephrology (or other acute dialysis service) should be contacted/consulted (per 
institutional standards to ensure emergency dialysis is available) on admission 
for any subject hospitalized prophylactically or in response to laboratory 
changes.
●
IV fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at 
least1 mL/kg/hr rounded to the nearest 10 mL (target 150 to 200 mL/hr; not 
< 50 mL/hr). Modification of fluid rate should also be considered for
individuals with specific medical needs.
●
Monitor for symptoms or signs of TLS (e.g., fever, chills, tachycardia, nausea, 
vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, 
paresthesias, mental status changes, confusion and seizures). If any clinical 
features are observed, recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour STAT.
●
Vital signs should be taken at time of all blood draws or any intervention.
●
The management recommendations below focus on the minimum initial 
responses required. If a diagnosis of TLS is established, ongoing intensive 
monitoring and multi-disciplinary management will be per institutional 
protocols.
In addition to the recommendations in the table below, for subjects receiving the first dose 
of venetoclax.
 


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●
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.
Abnormality
Management Recommendations
Hyperkalemia (Including Rapidly Rising Potassium)
Potassium ≥ 0.5 mmol/L increase from
prior value (even if potassium within 
normal limits [WNL])

Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hour STAT.  If further 
≥0.2 mmol/L increase in potassium, but still < upper 
limit of normal (ULN), manage as per potassium ≥ 
ULN.  Otherwise recheck in 1 hour.

Resume per protocol testing if change in potassium is 
< 0.2 mmol/L, and potassium < ULN, and no other 
evidence of tumor lysis.

At the discretion of the investigator, may recheck 
prior to hospitalization.  If stable or decreased, and 
still WNL, hospitalization is at the discretion of the 
investigator.  Potassium, phosphorus, uric acid, 
calcium and creatinine must be rechecked within 
24 hours.
Potassium > upper limit of normal

Perform STAT ECG and commence telemetry.

Nephrology (or other acute dialysis service) 
notification with consideration of initiating dialysis.

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV × 1.

Administer calcium gluconate 100 to 200 mg/kg IV 
slowly if there is ECG/telemetry evidence of life-
threatening arrhythmias.

Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hour STAT.
o
If potassium < ULN 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 1, 2 and 4 hrs., if no other evidence of 
tumor lysis.
 


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Abnormality
Management Recommendations
Hyperkalemia (Including Rapidly Rising Potassium) (continued)
Potassium ≥ 6.0 mmol/L
(6.0 mEq/L) and/or symptomatic 
(e.g., muscle cramps, weakness, 
paresthesias, nausea, vomiting, 
diarrhea)

Perform STAT ECG and commence telemetry.

Nephrology (or other acute dialysis service) 
assessment with consideration of initiating dialysis.

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV × 1.

Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV.

Administer sodium bicarbonate 1 to 2 mEq/kg IV 
push.
o
If sodium bicarbonate is used, rasburicase should 
not be used as this may exacerbate calcium 
phosphate precipitation.

Administer calcium gluconate 100 to 200 mg/kg IV 
slowly if there is ECG/telemetry evidence of 
life-threatening arrhythmias.  Do not administer in 
same IV line as sodium bicarbonate.

Recheck potassium, phosphorus, uric acid, calcium 
and creatinine every hour STAT.
Hyperuricemia
Uric acid ≥ 8.0 mg/dL (476 µmol/L)

Consider rasburicase* (dose based on local 
guidelines and/or institutional standards).
o
If rasburicase is used, sodium bicarbonate should 
not be used as this may exacerbate calcium 
phosphate precipitation.

Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hr STAT.
Hyperuricemia
Uric acid ≥ 10 mg/dL (595 µmol/L)
OR
Uric acid ≥ 8.0 mg/dL
(476 µmol/L) with 25% increase and 
creatinine increase ≥ 0.3 mg/dL 
(≥0.027 mmol/L) from pre-dose level

Administer rasburicase* (dose based on local 
guidelines and/or institutional standards).
o
When rasburicase is used, sodium bicarbonate 
should not be used as this may exacerbate 
calcium phosphate precipitation.

Notify nephrology (or other acute dialysis service).

Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hour STAT.
o
If uric acid < 8.0 mg/dL 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hrs., later, if no other evidence 
of tumor lysis.
 


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Abnormality
Management Recommendations
Hypocalcemia
Calcium ≤ 7.0 mg/dL (1.75 mmol/L)
AND
Subject symptomatic (e.g., muscle 
cramps, hypotension, tetany, cardiac 
arrhythmias)

Administer calcium gluconate 50 to 100 mg/kg IV 
slowly with ECG monitoring.

Telemetry.

Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hr STAT.
o
If calcium normalized 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hrs., later, if no other evidence 
of tumor lysis.

Calculate corrected calcium and check ionized 
calcium if albumin low.
Hyperphosphatemia
Phosphorus ≥ 5.0 mg/dL 
(1.615 mmol/L) with ≥ 0.5 mg/dL 
(0.16 mmol/L) increase

Administer a phosphate binder (e.g., aluminum 
hydroxide, calcium carbonate, sevelamer hydroxide, 
or lanthanum carbonate).

Nephrology (or other acute dialysis service) 
notification (dialysis required for phosphorus ≥ 10 
mg/dL).

Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hr STAT.
o
If phosphorus < 5.0 mg/dL 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hrs., later, if no other evidence 
of tumor lysis.
Creatinine
Increase ≥ 25% from baseline

Start or increase rate of IV fluids.

Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 to 2 hours STAT.
*
Check rasburicase label for contraindications.
Section 2:  Ongoing Dosing of Venetoclax
Management of electrolyte changes from last value at intervals > 24 hours after either the 
first dose or dose escalation (e.g., 48 or 72 hours) are as below.
Note:  If the subject is hospitalized, no additional venetoclax doses should be 
administered until resolution.
 


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●
For potassium, admit subject for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or 
any level > upper limit of normal.
○
Refer to the management guidelines for electrolyte changes observed 
within the first 24 hours after either the first dose or dose escalation (see 
prior table).
●
If a smaller potassium increase is observed that does not meet the criteria for 
admission above, recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 24 hours and confirm no evidence of tumor lysis prior to further 
venetoclax dosing.
●
For uric acid, calcium, phosphorus and creatinine, refer to the management 
guidelines for electrolyte changes observed within the first 24 hours after 
either the first dose or dose escalation (see prior table).
 


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Appendix H.
Adverse Events Commonly Associated with CLL Study Population 
and/or Progression of CLL
Disease-Related Events – CLL
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 primary cancers, all types Fatigue
Unexplained weight loss
Pyrexia
Bruising
Minor hemorrhages
Pain, all types
Malignant neoplasm progression, including death
Population-Related Comorbidities
Hypertension
Rheumatoid arthritis/osteoarthritis
Hyperlipidemia
Peptic ulcer
Inflammatory bowel disease
Coronary artery disease
Peripheral vascular disease
 


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Cardiomyopathy 
Valvular disease 
Atrial fibrillation 
Diabetes mellitus
Chronic obstructive pulmonary disease
Cerebrovascular accident
Transient ischemia attack
 




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Section 1.2  Synopsis
Subsection Study Population:
Previously read:
Subjects with relapsed/refractory (R/R) CLL with or without the 17p deletion or TP53
mutation, including subjects with an unknown status, as well as R/R CLL subjects who 
have been previously treated with B-cell receptor inhibitor therapy (BCRi).
Has been changed to read:
Subjects with relapsed/refractory (R/R) CLL with or without the 17p deletion or TP53 
mutation, including subjects with an unknown status, as well as R/R CLL subjects who 
have been previously treated with B-cell receptor inhibitor (BCRi) therapy.
Section 1.2  Synopsis
Subsection Methodology:
Second paragraph
Add:  new second sentence
In countries where venetoclax is not commercially available, subjects who continue to 
derive benefit after 2 years of treatment may be able to extend their treatment for up to 
2 additional years.
Section 1.2  Synopsis
Subsection Methodology:
Last paragraph, first and second sentence previously read:
A Data Monitoring Committee (DMC) has been organized to support the review safety 
data associated with venetoclax monotherapy dosing.  The DMC will review 
Study M15-889 safety data along with a data from a similar study, Study M15-550, with 
an initial review to occur when approximately 20 subjects have completed a minimum 
12 weeks of treatment.  
 


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Has been changed to read:
The Data Monitoring Committee (DMC) will review safety data intermittently according 
to the DMC charter.
Section 1.2  Synopsis
Subsection Duration of Treatment:
Last paragraph previously read:
For subjects who continue to derive benefit after 2 years of treatment, AbbVie will work 
with the investigator to consider the potential continuation of venetoclax therapy.
Has been changed to read:
In countries where venetoclax is not commercially available, subjects who continue to 
derive benefit after 2 years of treatment, may be able to extend their treatment for up to 
2 additional years.  AbbVie will work with the investigator on a case by case basis to 
consider the potential continuation of venetoclax therapy.
Section 1.2  Synopsis
Subsection Criteria for Evaulation:
Heading "Efficacy:"
First paragraph previously read:
Disease response will be assessed by the investigator, based on laboratory results, 
physical examinations, using the  2008 modified IWCLL NCI-WG Criteria for Tumor 
Response with the addition of CT imaging (or MRI in the case CT is medically 
contraindicated)  when available.
Has been changed to read:
Disease response will be assessed by the investigator, based on laboratory results, 
physical examinations, using the 2008 modified IWCLL NCI-WG Criteria for Tumor 
Response including CT imaging (or MRI in the case CT is medically contraindicated) and 
bone marrow biopsy and aspirate for subjects with CR to confirm the response.
 


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Section 1.2  Synopsis
Subsection Statistical Methods:
First paragraph, last sentence previously read:
All subjects participating in the study who received at least one dose of venetoclax will be 
included in the analyses unless otherwise noted in the separate, statistical analysis plan.
Has been changed to read:
All subjects participating in the study who received at least one dose of venetoclax will be 
included in the analyses unless otherwise noted in the separate, statistical analysis plan 
(SAP).
Section 1.2  Synopsis
Subsection Statistical Methods:
Heading "Efficacy Analyses Include:"
Sub-heading "Duration of Overall Response (DOR):
First sentence previously read:
Defined as the number of days from the date of first response (per the 2008 modified 
IWCLL NCI-WG criteria) to the date of disease progression.
Has been changed to read:
Defined as the number of days from the date of first response (per the 2008 modified 
IWCLL NCI-WG criteria) to the date of disease progression or death.  
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
Bcl-2
B-Cell Lymphoma 2
 


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
"BIM" and "BM" previously read:
BIM
Bone marrow
BM
Bcl-2 interacting mediator
Has been changed to read:
BM
Bone marrow
BIM
Bcl-2 interacting mediator
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Delete:
SGPT
Serum Glutamic-pyruvic Transaminase
Section 3.0  Introduction
Subsection Bcl-2 Family Proteins
Subsection title previously read:
Bcl-2 Family Proteins
Has been changed to read:
B-Cell Lymphoma-2 (Bcl-2) Family Proteins
Section 3.0  Introduction
Subsection Venetoclax (ABT-199)
Last paragraph previously read:
A detailed discussion of the non-clinical toxicology, metabolism, and pharmacology can 
be found in the Investigator's Brochure.8
Has been changed to read:
For further details, please see findings from completed and ongoing studies, including 
safety data in the current Venetoclax Investigator's Brochure.8
 


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Section 3.0  Introduction
Subsection Venetoclax Clinical Data
Delete:  first and second paragraph
In the Investigator's Brochure,8 a total of over 2500 oncology subjects received at least 
1 dose of venetoclax in AbbVie and Genentech/Roche studies and had data available as of 
28 November 2016.  Of these subjects, 1429 subjects had CLL/small lymphocytic 
lymphoma (SLL), 637 subjects had Non-Hodgkin's Lymphoma (NHL), 180 subjects had 
multiple myeloma (MM), 327 had acute myeloid leukemia (AML), and 114 were healthy 
volunteers.  A total of 749 received the drug as monotherapy and 1922 received the drug 
in combination with other therapies.  Doses administered in venetoclax clinical studies 
have ranged from 20 mg to 1200 mg.
The most common adverse events reported for all subjects in monotherapy studies were 
nausea (41.9%), diarrhea (41.1%), and neutropenia (31.1%).  The most common adverse 
event that was grade 3 and above was neutropenia (22.4%).  The most common serious 
adverse events were pneumonia (6.8%), febrile neutropenia (5.4%) and malignant 
neoplasm progression (5.9%).
Section 3.0  Introduction
Subsection Venetoclax Clinical Data
Fourth paragraph, last sentence previously read:
The overall response rate (ORR) in subjects with CLL/SLL was 77% to 82% (dose 
escalation and safety expansion cohorts, respectively), with a complete remission rate (CR 
+ CRi) of 30% in dose escalation and 10% in safety expansion cohort for venetoclax 
monotherapy (Study M12-175).9
Has been changed to read:
The overall response rate (ORR) in subjects with CLL/SLL was 75.0% to 81.7% (dose 
escalation and safety expansion cohorts, respectively), with a complete remission rate (CR 
+ CRi) of 32.1% in dose escalation and 11.7% in safety expansion cohort for venetoclax 
monotherapy (Study M12-175 as of 10Jun2016).9
 


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Section 3.0  Introduction
Subsection CLL Subjects Who Have Received Prior B-Cell Receptor Inhibitor 
Therapy
Subsection title previously read:
Subjects Who Have Received Prior B-Cell Receptor Inhibitor Therapy
Has been changed to read:
CLL Subjects Who Have Received Prior B-Cell Receptor Inhibitor (BCRi) Therapy
Section 3.0  Introduction
Subsection CLL Subjects Who Have Received Prior B-Cell Receptor Inhibitor 
Therapy
First paragraph, first sentence previously read:
Ibrutinib and idelalisib cause rapid response with reduction in lymph node size and 
splenic mass accompanied by increased peripheral blood lymphocytosis likely reflecting 
that microenvironment modulation could prevent these cells from receiving the survival 
signals delivered by the microenvironment.31
Has been changed to read:
Ibrutinib and idelalisib cause rapid response with reduction in lymph node size and 
splenic mass accompanied by increased peripheral blood (PB) lymphocytosis likely 
reflecting that microenvironment modulation could prevent these cells from receiving the 
survival signals delivered by the microenvironment.31
Section 5.1  Overall Study Design and Plan:  Description
Second paragraph, last sentence previously read:
All efforts will be made to adhere to these specific enrollment numbers; however, it might 
not be ethical to deny treatment to subjects in screening as they may have undergone 
study related procedures.
 


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Has been changed to read:
All efforts will be made to adhere to these specific enrollment numbers; however, it would 
not be ethical to deny treatment to eligible subjects in screening as they may have 
undergone study related procedures.
Section 5.1  Overall Study Design and Plan:  Description
Fourth paragraph
Add:  new eighth sentence
As of Week 8, the visit window for scheduled visits is ± 2 days.
Section 5.1  Overall Study Design and Plan:  Description
Sixth paragraph, first sentence previously read:
Disease response will be assessed by the investigator based on laboratory results and 
physical examinations using the 2008 Modified International Workshop on CLL National 
Cancer Institute – Working Group (IWCLL NCI-WG) Guidelines for Tumor Response 
with the addition of CT imaging (or MRI) when available.  
Has been changed to read:
Disease response will be assessed by the investigator based on laboratory results and 
physical examinations using the 2008 Modified International Workshop on CLL National 
Cancer Institute – Working Group (IWCLL NCI-WG) Guidelines for Tumor Response 
with the addition of CT imaging (or MRI).  
Section 5.1  Overall Study Design and Plan:  Description
Sixth paragraph, last sentence previously read:
To confirm the response, a CT scan (or MRI if CT is medically contraindicated) will be 
performed at Week 48 on all subjects.
 


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Has been changed to read:
To confirm the response, a CT scan (or MRI if CT is medically contraindicated) will be 
performed at Week 48 on all subjects and BM samples will be collected for subjects with 
CR to confirm the response.
Section 5.1  Overall Study Design and Plan:  Description
Eleventh and twelfth paragraph previously read:
All study procedures will be performed as outlined in Section 5.3.1.1 and Appendix D. 
For subjects who continue to derive benefit after 2 years of treatment, AbbVie will work 
with the investigator on a case by case basis to consider the potential continuation of 
venetoclax therapy.
Has been changed to read:
All study procedures will be performed as outlined in Section 5.3.1.1 and Appendix D and 
Appendix E. 
For subjects who continue to derive benefit after 2 years of treatment, AbbVie will work 
with the investigator on a case by case basis to consider the potential continuation of 
venetoclax therapy.  In countries where venetoclax is commercially available, extension 
of therapy may not be allowed.
Section 5.2.2  Exclusion Criteria
Criterion 11 previously read:
Subject is known to be positive for HIV (due to potential drug-drug interactions between 
anti-retroviral medications and venetoclax, as well as anticipated venetoclax mechanism 
based lymphopenia that may potentially increase the risk of opportunistic infections).
Has been changed to read:
Subject is known to be positive for Human Immunodeficiency Virus (HIV) (due to 
potential drug-drug interactions between anti-retroviral medications and venetoclax, as 
 


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well as anticipated venetoclax mechanism based lymphopenia that may potentially 
increase the risk of opportunistic infections).
Section 5.3.1  Study Assessments and Flow Chart
First paragraph previously read:
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix D.
Has been changed to read:
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix D and Appendix E.
Section 5.3.1.1  Study Procedures
First paragraph, first sentence previously read:
All study procedures outlined in Appendix D are discussed in detail in this section, with 
the exception of adverse event (AE) information (discussed in Section 6.0).  
Has been changed to read:
All study procedures outlined in Appendix D and Appendix E are discussed in detail in 
this section, with the exception of adverse event (AE) information (discussed in 
Section 6.0).  
Section 5.3.1.1  Study Procedures
Subsection Physical Examination (Disease Assessment)
First paragraph, first sentence previously read:
All physical examinations (complete or symptom-directed) are to include the evaluation 
of the presence and degree of enlarged lymph nodes in two dimension (cervical, 
supraclavicular, axillary, inguinal and femoral nodes), hepatomegaly, and splenomegaly.  
 


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Has been changed to read:
Physical examinations performed as a part of Disease Assessments (Screening, Weeks 24, 
36, 48) are to include the evaluation of the presence and degree of enlarged lymph nodes 
in two dimension (cervical, supraclavicular, axillary, inguinal and femoral nodes), 
hepatomegaly, and splenomegaly.  
Section 5.3.1.1  Study Procedures
Subsection Physical Examination (Disease Assessment)
Fifth paragraph previously read:
Please refer to Appendix D for timing of all physical examinations.
Has been changed to read:
Please refer to Appendix D and Appendix E for timing of all physical examinations.
Section 5.3.1.1  Study Procedures
Subsection Eastern Cooperative Oncology Group (ECOG) Performance Status
First paragraph previously read:
For all subjects, the ECOG performance status47 will be performed as outlined in 
Appendix D.
Has been changed to read:
For all subjects, the ECOG performance status47 will be performed as outlined in 
Appendix D and Appendix E.
Section 5.3.1.1  Study Procedures
Subsection Hematology and Chemistry
Heading "PRE-DOSE LABS:"
Sub-heading "Prior to each subsequent dose ramp up, for all subjects:"
Sub-heading previously read:
Prior to each subsequent dose ramp up, for all subjects:
 


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Has been changed to read:
Prior to Each Subsequent Dose Increase, for all Subjects:
Section 5.3.1.1  Study Procedures
Subsection Disease Assessments (2008 Modified IWCLL NCI-WG Criteria)
First paragraph, last sentence previously read:
Bone marrow examination is not required but results will be recorded if available.
Has been changed to read:
Bone marrow examinations at screening are not required but results will be recorded if 
available.
Section 5.3.1.1  Study Procedures
Subsection Disease Assessments (2008 Modified IWCLL NCI-WG Criteria)
Third paragraph, second sentence previously read:
It is recommended that the CT scan is performed first; if it does confirm a clinical 
response, then a bone marrow biopsy should be obtained.  
Has been changed to read:
It is recommended that the CT scan is performed first; if it does confirm a clinical 
response, then a bone marrow biopsy will be obtained.  
Section 5.3.1.1  Study Procedures
Subsection Disease Assessments (2008 Modified IWCLL NCI-WG Criteria)
Add:  new last paragraph
For patients with Partial Remission at Week 48 an additional CT scan and a bone marrow 
examination can be done between Week 48 and Week 108 to confirm CR if there is a 
possibility that a patient achieved Complete Remission based on laboratory tests and a 
disease assessment physical examination.
 


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Section 5.3.1.1  Study Procedures
Subsection Bone Marrow Aspirate and Biopsy
First paragraph, second sentence previously read:
If the subject achieves a CR by clinical criteria and confirmatory CT scan, a bone marrow 
aspirate and biopsy should be performed to confirm the CR.
Has been changed to read:
If the subject achieves a CR by clinical criteria and confirmatory CT scan, a bone marrow 
aspirate and biopsy will be performed to confirm the CR.
Section 5.3.1.1  Study Procedures
Subsection Final Visit
First paragraph, last sentence previously read:
The Final Visit procedures as listed in Appendix D should be performed as soon as 
possible after study drug discontinuation.
Has been changed to read:
The Final Visit procedures as listed in Appendix D and Appendix E should be performed 
as soon as possible after study drug discontinuation.
Section 5.3.1.1  Study Procedures
Subsection 30-Day Safety Visit
First paragraph, last sentence previously read:
Refer to Appendix D for procedures to be performed.  
Has been changed to read:
Refer to Appendix D and Appendix E for procedures to be performed.  
 


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Section 5.3.1.1  Study Procedures
Subsection 30-Day Safety Visit
Second paragraph previously read:
If a subject is discontinued from the study with an ongoing AE or an unresolved clinically 
significant laboratory result, the site will attempt to provide follow-up until the AE has 
resolved to a ≤ Grade 1 or baseline or it is the investigator's judgment that the event is 
unlikely to resolve.  
Has been changed to read:
If a subject has an ongoing AE or an unresolved clinically significant laboratory result 
30 days following last dose of study drug, the site will attempt to provide follow-up until 
the AE has resolved to a ≤ Grade 1 or baseline or it is the investigator's judgment that the 
event is unlikely to resolve.  
Section 5.3.1.1  Study Procedures
Subsection Extended Access Phase
Add:  new subsection title and text
Extended Access Phase
In countries where venetoclax is not commercially available, subjects who continue to 
derive benefit after 2 years of treatment may be able to extend their treatment for up to 
2 additional years.  AbbVie will work with the investigator on a case by case basis to 
consider the potential continuation of venetoclax therapy.  The Extended Access Visits 
will include:
●
Collection of Survival information
●
AE/SAE/Con Med assessment
●
Study drug reconciliation and dispensing
All other procedures should be performed as standard of care.  The specific study 
assessments to be performed during these visits are detailed in Appendix E Study 
Activities.
 


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Section 5.3.2.2.2  Disease Assessments
First paragraph
Add:  new last sentence
A BM assessment is required to confirm CR.
Section 5.3.2.2.2  Disease Assessments
Second paragraph
Add:  new last sentence
For subjects with CR as response at Week 48, a BM is required to confirm the response.
Section 5.3.2.2.2  Disease Assessments
Subsection Methods of Measurement
First bullet, second sentence previously read:
Target nodal lesions must be abnormal (> 1.5 cm in longest diameter [LDi] at baseline), 
clearly measurable and suitable for consistent, reproducible measurement in at least 
two perpendicular dimensions.
Has been changed to read:
Target nodal lesions must be abnormal (> 1.5 cm in LDi [Longest Diameter at baseline), 
clearly measurable and suitable for consistent, reproducible measurement in at least 
two perpendicular dimensions.
Section 5.3.2.2.2  Disease Assessments
Subsection Tumor Response Criteria
Heading "Complete Remission (CR)"
Last bullet, last sentence previously read:
Immunohistochemistry should be performed to define whether these nodules are 
composed of primarily T cells or lymphocytes other than CLL cells, or CLL cells.
Has been changed to read:
Immunohistochemistry (IHC) should be performed to define whether these nodules are 
composed of primarily T cells or lymphocytes other than CLL cells, or CLL cells.
 


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Table 5.  2008 Modified IWCLL NCI-WG Criteria for Tumor Response
First page of table
Delete:  subsection title "Other Considerations"
Parameter
Complete Remission 
(CR) All Criteria 
Must be Meta
Partial Remission 
(PR) at Least 
2 Criteria from 
Group A AND at 
Least 1 Criterion 
from Group B 
Must be Met
Progressive Disease 
(PD) at Least 
1 Criterion from Group 
A OR 1 Criterion from 
Group B Must be Metb
Stable Disease 
(SD) All Criteria 
Must be Met
Other Considerations
Section 5.4.1  Discontinuation of Individual Subjects
First paragraph previously read:
Each subject has the right to withdraw from the study at any time.  In addition, the 
Investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason including:
Has been changed to read:
Each subject has the right to withdraw from the study and/or study drug treatment at any 
time.  In addition, the Investigator may discontinue a subject from study drug treatment at 
any time if the investigator considers it necessary for any reason including:
Section 5.4.1  Discontinuation of Individual Subjects
Fifth and sixth bullet previously read:
●
pregnancy
●
protocol non-compliance
Has been changed to read:
●
The subject becomes pregnant while on the study
●
drug/protocol non-compliance
 


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Section 5.4.1  Discontinuation of Individual Subjects
Subsection Post Treatment and Survival Follow-Up Calls
Previously read:
For subjects who discontinue venetoclax therapy, but do not discontinue the study 
(i.e., have not had an event of progression, do not require alternate therapy, etc.), 
post-treatment follow-up calls will be performed every 6 months for survival information 
(i.e., disease progression, the date and cause of death, post-treatment cancer therapies, 
etc.) and will be collected via telephone calls for a period of 2 years and recorded in the 
eCRFs.
Has been changed to read:
For subjects who discontinue venetoclax therapy, but do not discontinue the study (), 
post-treatment follow-up calls will be performed every 6 months (+ 7 days) for survival 
information (i.e., disease progression, the date and cause of death, post-treatment cancer 
therapies, etc.) and will be collected via telephone calls for a period of 2 years and 
recorded in the eCRFs.
Section 5.6.3  Suitability of Subject Population
First paragraph, third sentence previously read:
In addition, subjects with relapsed or refractory CLL who have been previously treated 
with a B-cell receptor inhibitor have shown to have activity when treated with venetoclax.  
Has been changed to read:
In addition, venetoclax has shown activity in subjects with relapsed or refractory CLL 
who have been previously treated with a B-cell receptor inhibitor.  
 




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an initial review to occur when approximately 20 subjects have completed a minimum 
12 weeks of treatment.
A  charter will be created to provide detailed descriptions of the schedule of analyses and 
the DMC meetings.  DMC membership, responsibilities and the description of the data 
coordinating center are documented in the charter.
Subsequent reviews may be conducted based on recommendations from the DMC or 
requests from the Sponsor.  Details of the DMC review will be presented in the DMC 
charter.
Has been changed to read:
The Data Monitoring Committee (DMC) will review safety data intermittently according 
to the DMC charter.  Details of the DMC review are presented in the DMC charter.  The 
DMC charter has been created to provide detailed descriptions of the schedule of analyses 
and the DMC meetings.  DMC membership, responsibilities and the description of the 
data coordinating center are documented in the charter.
Table 7.  Recommended Dose Modifications for Toxicities
Table note "a." previously read:
Clinical TLS was defined as laboratory TLS with clinical consequences such as acute 
renal failure, cardiac arrhythmias or sudden and/or seizures.
Has been changed to read:
Clinical TLS was defined as laboratory TLS with clinical consequences such as acute 
renal failure, cardiac arrhythmias or sudden death and/or seizures.
Section 7.0  Protocol Deviations
"Primary Contact:," title previously read:
Study Project Manager I
 


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Has been changed to read:
Study Project Manager II
Section 8.1.3  Timing of Study Endpoints and Safety Evaluations
First paragraph, third sentence previously read:
Exact data cutoff date for the analysis will be detailed in the statistical analysis plan (SAP) 
which will be signed off prior to the data cut-off date.  
Has been changed to read:
Exact data cutoff date for the analysis will be detailed in the SAP which will be signed off 
prior to the data cut-off date.  
Section 10.1  Source Documents
Second paragraph previously read:
The following PRO assessments will be completed by the subject and will be considered 
source documentation:
Has been changed to read:
The following patient reported outcomes (PRO) assessments will be completed by the 
subject and will be considered source documentation:
Section 15.0  Reference List
Reference 8 previously read:
AbbVie.  Venetoclax Investigator's Brochure Edition 8.  03 May 2017.
Has been changed to read:
AbbVie.  Venetoclax Investigator's Brochure.  Current Version.
 


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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Associate Director
Statistics
Medical Director
Medical Affairs
Group Project Director
Clinical
Study Project Manager I
Clinical
Has been changed to read:
Name
Title
Functional Area
Associate Director
Statistics
Assistant Medical Director
Medical Affairs
Group Project Director
Clinical
Study Project Manager II
Clinical
 


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Appendix D.  Study Activities:  Screening Through Week 5 Day 2
Previously read:
Activity
Scra
Within 
72 Hours 
of W1 
D1 
W1
D1
W1
D2
Within 
72 Hours 
of W2 
D1 
W2
D1
W2
D2
Within 
72 Hours 
of W3 
D1 
W3
D1
W3
D2
Within 
72 Hours 
of W4 
D1 
W4 
D1
W4
D2
Within 
72 Hours 
of W5 
D1 
W5
D1
W5
D2
Informed Consent
X
17p Deletion or TP53 Mutation
Xb
Medical History/Oncology History 
Assessment
X
X
Pregnancy Testc
X
X
Adverse Event/Concomitant 
Medication Assessment
Xd
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examinatione
X
X
X
X
X
X
TLS Risk Assessmentf
X
ECOG Performance Status
X
X
Coagulation Panel
X
Hematology/Chemistryg
X
Xh
Xi
Xj
Xk
Xl
Xj
Xk
Xl
Xm
Xk
Xl
Xm
Xk
Xl
Xm
Disease Assessmentsn
X
Contrasted CT or MRI Scano
X
Bone Marrow Aspirate and Biopsyp
Dispense Venetoclaxq
X
X
X
X
X
X
X
X
X
X
 


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Activity
Scra
Within 
72 Hours 
of W1 
D1 
W1
D1
W1
D2
Within 
72 Hours 
of W2 
D1 
W2
D1
W2
D2
Within 
72 Hours 
of W3 
D1 
W3
D1
W3
D2
Within 
72 Hours 
of W4 
D1 
W4 
D1
W4
D2
Within 
72 Hours 
of W5 
D1 
W5
D1
W5
D2
Quality of Life Questionnaires 
(EORTC QLQ-30, EORTC QLQ-
CLL16, EQ-5D-5L)r
X
X
X
 


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Week 8 Through Post-Treatment Follow-Up
Activity
W8 
D1
W12
D1
W16 
D1
W20
D1
W24
D1
W28
D1
W32
D1
W36
D1
W40
D1
W44
D1
W48
D1
Every 
12 Weeks 
Starting 
at W60
W108 
/ 
Final 
Visit
30 Day 
Safety 
Visits
Post-
Treatment 
Follow-Upt
Adverse Event/Concomitant 
Medication Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examinatione*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Statusu
X
X
X
X
X
Hematology/Chemistry**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease Assessmentn*
X
X
X
Contrasted CT or MRI Scano
X
Bone Marrow Aspirate and Biopsyp
Dispense Venetoclax 
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life Questionnaires (EORTC 
QLQ-30, EORTC QLQ-CLL16, 
EQ-5D-5L)r
X
X
X
X
X
X
X
Scr = Screening; W = Wk = Week; D = Day; Post-Treat = Post-Treatment; FV = Final Visit
Study Windows:
*
within 72 hours before or after scheduled visit starting with Week 8 Day 1.
**
within 72 hours prior to scheduled visit starting with Week 8 Day 1.
a.
Subjects will undergo screening procedures within 28 days prior to the first study drug administration, except where otherwise indicated.
b.
Subjects who have 17p deletion or TP53 mutation as assessed by local laboratory (in bone marrow or peripheral blood) may be considered for enrollment.  A recent test is 
desirable but any previous positive test is acceptable.  Subjects that do not have the 17p deletion or TP53 mutation or have an unknown status are also eligible.
 


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c.
For females of childbearing potential, as defined in the protocol, a urine pregnancy test must be obtained and processed locally at Week 1 Day 1, if it has been > 7 days since 
obtaining the serum pregnancy results at Screening.  During the study, a urine pregnancy test can be performed at the discretion of the investigator or per local guidelines.
d.
All protocol-related serious adverse events and nonserious adverse events must be collected from the signing of the study-specific informed consent until study drug 
administration.
e.
A complete physical examination will be performed at Screening.  A symptom directed physical examination may be performed as needed.  Refer to Section 5.3.1.1 Physical 
Examination, for more details.
f.
For subjects who have a dose interruption lasting more than 1 week during the first 5 weeks of dose-titration or more than 2 weeks when at the daily dose of 400 mg, the TLS 
risk should be reassessed to determine if restarting at a reduced dose is necessary.
g.
All clinical laboratory tests will be analyzed by the local laboratory.  Required tests are listed in Table 4 Clinical Laboratory Tests, refer to Section 5.3.1.1 Study Procedures, 
sub header Hematology and Chemistry as well as Section 6.1.9 Toxicity Management, for more details. 
h.
If the screening labs were done more than 72 hours before the planned first dose, the chemistry/hematology panel should be repeated and results reviewed prior to the initial 
dose in order to make a treatment decision.  Labs should be assessed and pre-existing abnormalities should be corrected. 
i.
On the day of Week 1 Day 1, before dosing, the chemistry/hematology panel should be collected.  The results of the labs drawn on Week 1 Day 1 need to be reviewed prior to 
dosing IF an additional lab within 72 hours of the initial dose at Week 1 Day 1 was not drawn AND reviewed.  
j.
For all subjects, the chemistry/hematology panel should be monitored at 6 to 8 hours and at 24 hours after the first dose of venetoclax (20 mg) and after the first dose increase 
(50 mg).  The next venetoclax doses should not be administered until the 24 hour lab results have been evaluated.  Electrolyte abnormalities should be corrected promptly. 
Note:  There is a ± 2 hour window around the 24 hour lab draw. 
k.
For all subjects, within 72 hours of each subsequent dose increase, the chemistry/hematology panel should be repeated.  The results should be reviewed prior to dose 
increasing.
l.
Prior to dosing, on the day of each subsequent dose increase, the chemistry/hematology panel is required.  The results of the labs drawn on Day 1 of each dose increase need 
to be reviewed prior to dosing IF additional labs within 72 hours of the dose increase were not drawn AND reviewed. 
m.
For subjects who continue to be at risk of TLS, the same lab monitoring schedule of 6 to 8 hour and 24-hr post dose should be followed at the subsequent dose increases.  
Note:  There is a ± 2 hour window around the 24 hour lab draw.
n.
All measurable disease must be documented at Screening by laboratory testing, physical examination and CT scans (or MRI if CT is medically contraindicated); bone marrow 
examinations are not required but results will be recorded if available.  All baseline evaluations should be performed as closely as possible to the beginning of treatment.  For 
all subsequent disease assessments, disease response will be assessed by the investigator based on the analysis of clinical laboratory tests (hematology) and a complete 
physical examination at Week 24, Week 36 and Week 48.
 


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o.
CT scans with contrast (or MRI if CT is medically contraindicated) should include neck, chest, abdomen and pelvic sequences can be accepted if previously performed within 
35 days prior to the initial venetoclax dose.  Otherwise, CT scans (or MRI) must be performed within the 28 day screening period.  To confirm response, a CT scan (or MRI) 
must be performed at Week 48 for all subjects.  If a subject exhibits clinical signs of possible disease progression (i.e., increased or de novo enlargement of liver, spleen or 
lymph nodes on physical examination) without an increase in lymphocytes meeting the progression of disease criteria, then additional assessments including contrast-
enhanced CT scan and/or bone marrow can be performed to confirm or rule out disease progression.  Refer to Section 5.3.1.1 Disease Assessments and Computed 
Tomography Scans, for more details.
p.
For determination of complete remission (CR), the CT scan and bone marrow are required to be negative, per the IWCLL NCI-WG guidelines.  If the subject achieves a CR 
by clinical criteria and confirmatory CT scan, a bone marrow aspirate and biopsy should be performed to confirm the CR.  Refer to Section 5.3.1.1 Disease Assessments and 
Bone Marrow Aspirate and Biopsy, for more details.
q.
Venetoclax tablets should be taken orally once daily with a meal and water in the morning at approximately the same time each day.  Dosing should occur at study visits on 
Week 1 Days 1 & 2 through Week 5 Days 1 & 2.
r.
The Quality of Life Questionnaires should be administered and completed prior to any other study procedures being performed at these visits.  Refer to Section 5.3.1.1, 
Quality of Life Assessments for further information.  
s.
30-Day Safety Follow-up visit should occur approximately 30 days (± 3 days) after the last dose of venetoclax.
t.
Upon discontinuation of study drug treatment, survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 6 months for a 
period of 2 years.
u.
ECOG performance status may be performed within 72 hours before or after the scheduled visit starting with Week 24.
 


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Has been changed to read:
Activity
Scra
Within 
72 Hours 
of W1 
D1 
W1
D1
W1
D2
Within 
72 Hours 
of W2 
D1 
W2
D1
W2
D2
Within 
72 Hours 
of W3 
D1 
W3
D1
W3
D2
Within 
72 Hours 
of W4 
D1 
W4 
D1
W4
D2
Within 
72 Hours 
of W5 
D1 
W5
D1
W5
D2
Informed Consent
X
17p Deletion or TP53 Mutation
Xb
Medical History/Oncology History 
Assessment
X
X
Pregnancy Testc
X
X
Adverse Event/Concomitant 
Medication Assessment
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examinatione
X
X
X
X
X
X
TLS Risk Assessmentf
X
ECOG Performance Status
X
X
Coagulation Panel
X
Hematology/Chemistryg
X
Xh
Xi
Xj
Xk
Xl
Xj
Xk
Xl
Xm
Xk
Xl
Xm
Xk
Xl
Xm
Disease Assessmentsn
X
Contrasted CT or MRI Scano
X
Bone Marrow Aspirate and Biopsyp
Venetoclax dispensation and 
accountabilityq
X
X
X
X
X
X
X
X
X
X
 


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Activity
Scra
Within 
72 Hours 
of W1 
D1 
W1
D1
W1
D2
Within 
72 Hours 
of W2 
D1 
W2
D1
W2
D2
Within 
72 Hours 
of W3 
D1 
W3
D1
W3
D2
Within 
72 Hours 
of W4 
D1 
W4 
D1
W4
D2
Within 
72 Hours 
of W5 
D1 
W5
D1
W5
D2
Quality of Life Questionnaires 
(EORTC QLQ-30, EORTC QLQ-
CLL16, EQ-5D-5L)r
X
X
X
 


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Week 8 Through Post-Treatment Follow-Up
Activity
W8 
D1
W12
D1
W16 
D1
W20
D1
W24
D1
W28
D1
W32
D1
W36
D1
W40
D1
W44
D1
W48
D1
Every 
12 Weeks 
Starting 
at W60
W108 
/ 
Final 
Visit
30 Day 
Safety 
Visits
Post-
Treatment 
Follow-Upt
Adverse Event/Concomitant 
Medication Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examinatione*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Statusu
X
X
X
X
X
Hematology/Chemistry**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease Assessmentn*
X
X
X
Contrasted CT or MRI Scano
X
Bone Marrow Aspirate and Biopsyp
X
Venetoclax dispensation and 
accountability***
X
X
X
X
X
X
X
X
X
X
X
X
Xw
Quality of Life Questionnaires (EORTC 
QLQ-30, EORTC QLQ-CLL16, 
EQ-5D-5L)r
X
X
X
X
X
X
X
Collection of Survival Informationv
X
X
Scr = Screening; W = Wk = Week; D = Day; Post-Treat = Post-Treatment; FV = Final Visit
Study Windows:
*
Within 72 hours before or after scheduled visit starting with Week 8 Day 1.
**
Within 72 hours prior to scheduled visit starting with Week 8 Day 1.
*** As of Week 8 the visit window for scheduled visits is ± 2 days.
a.
Subjects will undergo screening procedures within 28 days prior to the first study drug administration, except where otherwise indicated.
 


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b.
Subjects who have 17p deletion or TP53 mutation as assessed by local laboratory (in bone marrow or peripheral blood) may be considered for enrollment.  A recent test is 
desirable but any previous positive test is acceptable.  Subjects that do not have the 17p deletion or TP53 mutation or have an unknown status are also eligible.
c.
For females of childbearing potential, as defined in the protocol, a urine pregnancy test must be obtained and processed locally at Week 1 Day 1, if it has been > 7 days since 
obtaining the serum pregnancy results at Screening.  During the study, a urine pregnancy test can be performed at the discretion of the investigator or per local guidelines.
d.
All protocol-related serious adverse events and nonserious adverse events must be collected from the signing of the study-specific informed consent until study drug 
administration.
e.
A complete physical examination will be performed at Screening.  A symptom directed physical examination may be performed as needed.  Refer to Section 5.3.1.1 Physical 
Examination, for more details.
f.
For subjects who have a dose interruption lasting more than 1 week during the first 5 weeks of dose-titration or more than 2 weeks when at the daily dose of 400 mg, the TLS 
risk should be reassessed to determine if restarting at a reduced dose is necessary.
g.
All clinical laboratory tests will be analyzed by the local laboratory.  Required tests are listed in Table 4 Clinical Laboratory Tests, refer to Section 5.3.1.1 Study Procedures, 
sub header Hematology and Chemistry as well as Section 6.1.9 Toxicity Management, for more details. 
h.
For all subjects, if the screening labs were done more than 72 hours before the planned first dose, the chemistry/hematology panel should be repeated and results reviewed 
prior to the initial dose in order to make a treatment decision.  Labs should be assessed and pre-existing abnormalities should be corrected. 
i.
For all subjects, on the day of Week 1 Day 1, before dosing, the chemistry/hematology panel should be collected.  The results of the labs drawn on Week 1 Day 1 need to be 
reviewed prior to dosing IF an additional lab within 72 hours of the initial dose at Week 1 Day 1 was not drawn AND reviewed.  
j.
For all subjects, the chemistry/hematology panel should be monitored at 6 to 8 hours and at 24 hours after the first dose of venetoclax (20 mg) and after the first dose increase 
(50 mg).  The next venetoclax doses should not be administered until the 24 hour lab results have been evaluated.  Electrolyte abnormalities should be corrected promptly.  
Note:  There is a ± 2 hour window around the 24 hour lab draw. 
k.
For all subjects, within 72 hours of each subsequent dose increase, the chemistry/hematology panel should be repeated.  The results should be reviewed prior to dose 
increasing.
l.
Prior to dosing, on the day of each subsequent dose increase, the chemistry/hematology panel is required.  The results of the labs drawn on Day 1 of each dose increase need 
to be reviewed prior to dosing IF additional labs within 72 hours of the dose increase were not drawn AND reviewed. 
m.
For subjects who continue to be at risk of TLS, the same lab monitoring schedule of 6 to 8 hour and 24-hr post dose should be followed at the subsequent dose increases.  
Note:  There is a ± 2 hour window around the 24 hour lab draw.
n.
All measurable disease must be documented at Screening by laboratory testing, physical examination and CT scans (or MRI if CT is medically contraindicated); bone marrow 
examinations are not required at screening but results will be recorded if available.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment.  For all subsequent disease assessments, disease response will be assessed by the investigator based on the analysis of clinical laboratory tests (hematology) and a 
complete physical examination at Week 24, Week 36 and Week 48.
 


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o.
CT scans with contrast (or MRI if CT is medically contraindicated) should include neck, chest, abdomen and pelvic sequences can be accepted if previously performed within 
35 days prior to the initial venetoclax dose.  Otherwise, CT scans (or MRI) must be performed within the 28 day screening period.  To confirm response, a CT scan (or MRI) 
must be performed at Week 48 for all subjects. CT scans (or MRI) may be performed 7 days prior to the scheduled Week 48 visit. If a subject exhibits clinical signs of 
possible disease progression (i.e., increased or de novo enlargement of liver, spleen or lymph nodes on physical examination) without an increase in lymphocytes meeting the 
progression of disease criteria, then additional assessments including contrast-enhanced CT scan and/or bone marrow can be performed to confirm or rule out disease 
progression.  Refer to Section 5.3.1.1 Disease Assessments and Computed Tomography Scans, for more details. For patients with only Partial Remission at Week 48, an 
additional CT and a bone marrow examination can be done between Week 48 and Week 108 to confirm CR if there is a possibility that a patient is in Complete Remission 
based on laboratory tests and a disease assessment physical exam.
p.
For determination of complete remission (CR), the CT scan and bone marrow are required to be negative, per the IWCLL NCI-WG guidelines.  If the subject achieves a CR 
by clinical criteria and confirmatory CT scan, a bone marrow aspirate and biopsy will be performed to confirm the CR.  Refer to Section 5.3.1.1 Disease Assessments and 
Bone Marrow Aspirate and Biopsy, for more details.
q.
Venetoclax tablets should be taken orally once daily with a meal and water in the morning at approximately the same time each day.  Dosing should occur at study visits on 
Week 1 Days 1 & 2 through Week 5 Days 1 & 2.
r.
The Quality of Life Questionnaires should be administered and completed prior to any other study procedures being performed at these visits.  Refer to Section 5.3.1.1, 
Quality of Life Assessments for further information.  
s.
30-Day Safety Follow-up visit should occur approximately 30 days (± 3 days) after the last dose of venetoclax.
t.
Upon discontinuation of study drug treatment, survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 6 months (+
7days) for a period of 2 years.
u.
ECOG performance status may be performed within 72 hours before or after the scheduled visit starting with Week 24.
v.     Survival information includes i.e., the date/cause of death, post treatment cancer therapies, etc.
w.    In countries where venetoclax is not commercially available, subjects who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 
2 additional years. AbbVie will work with the investigator on a case by case basis to consider the potential continuation of venetoclax therapy.  Subjects who participate in 
the 2 year Extended Access phase will have study drug assigned at Week 108.  For patients that are not participating in the 2 year Extended Access phase the Week 108 visit 
is the Final visit.  The specific study assessments to be performed at the Extended Access visits are detailed in Appendix E, Study Activities.
 


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Appendix E.  Schedule of Extended Access Phase*
Add:  new appendix title and text
Appendix E.
Schedule of Extended Access Phase*
Procedure
W108 
D1
W120 
D1
W132 
D1
W144 
D1
W156 
D1
W168 
D1
W180 
D1
W192 
D1
W204 
D1
W216/ Final 
Visit
30 Day 
Safety 
Visitd
Post 
Treatment 
Follow upe
Vital signs**
X
X
X
Physical Examinationa**
X
X
X
ECOG Performance Status**
X
X
X
Hematology/Chemistry***
X
X
X
Adverse Event/Concomitant 
Medication Assessment
X
X
X
X
X
X
X
X
X
X
X
X
Venetoclax dispensation and 
accountability****
X
X
X
X
X
X
X
X
X
Collection of Survival 
Informationb
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life 
Questionnaires (EORTC 
QLQ-30, EORTC QLQ-
CLL16, EQ-5D-5L)c
X
*
In countries where venetoclax is not commercially available, subjects who continue to derive benefit after 2 years of treatment may be able to extend their treatment for 
up to 2 additional years.  AbbVie will work with the investigator on a case by case basis to consider the potential continuation of venetoclax therapy.
**
Within 72 hours before or after scheduled visit.
***
Within 72 hours prior to scheduled visit.
****
The visit window for scheduled visits is ± 2 days.
 


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a.
Refer to Section 5.3.1.1 Physical Examination, for more details.
b.
Survival information includes i.e., the date/cause of death, post treatment cancer therapies, etc.
c.
The Quality of Life Questionnaires should be administered and completed prior to any other study procedures being performed at these visits.  Refer to Section 5.3.2.2.1
Health Economic and Patient-Reported Outcome Measures, for further information.  
d.
30-Day Safety Follow-up visit should occur approximately 30 days (± 3 days) after the last dose of venetoclax.
e.
Upon discontinuation of study drug treatment, survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 6 months 
(± 7 days) for a period of 2 years
 

SAP_001.pdf: 
Venetoclax (ABT-199)
M15-889 – Statistical Analysis Plan
Version 1.0 – 09 May 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M15-889
Open-Label, Single Arm, Phase 3b, Multi-Center 
Study Evaluating the Impact of Venetoclax on the 
Quality of Life of Relapsed/Refractory Subjects with 
Chronic Lymphocytic Leukemia (CLL) (VENICE II)
Date:  09 May 2018
Version 1.0
 
NCT02980731


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................4
4.0
Study Objectives, Design and Procedures............................4
4.1
Objectives .............................................................................................. 4
4.2
Study Design and Plan............................................................................ 5
4.3
Sample Size............................................................................................ 6
4.4
Interim Analysis..................................................................................... 6
4.5
Timing of Quality of life and Efficacy Analyses and Safety 
Evaluations............................................................................................. 7
5.0
Analysis Populations .............................................................8
5.1
Definition for Analysis Populations ........................................................ 8
5.1.1
Quality of Life, Efficacy, and Safety Populations ................................... 8
5.2
Variables Used for Stratification of Randomization ................................ 8
6.0
Analysis Conventions ............................................................8
6.1
Baseline.................................................................................................. 8
6.2
Treatment Days ...................................................................................... 8
6.3
Definition of Analysis Windows............................................................. 9
6.4
Missing Data Imputation ...................................................................... 10
7.0
Subject Disposition..............................................................10
8.0
Demographics, Baseline Characteristics, Medical 
History, and Previous Concomitant Medications..............11
8.1
General Consideration.......................................................................... 11
8.2
Demographic and Baseline Characteristics ........................................... 11
8.3
Medical History.................................................................................... 13
8.4
Previous Treatment and Concomitant Medications ............................... 13
9.0
Venetoclax Exposure and Compliance...............................14
10.0
Quality of Life and Efficacy Analyses ................................14
10.1
General Considerations......................................................................... 14
10.1.1
Definitions for Quality of Life Assessments ......................................... 15
10.1.2
Definitions for Efficacy Endpoints ....................................................... 17
 


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10.2
Quality of Life and Efficacy Analyses .................................................. 19
10.2.1
Primary Endpoint Analysis................................................................... 20
10.2.2
Secondary Efficacy Analyses ............................................................... 20
10.3
Subgroup Analyses of Quality of Life and Efficacy .............................. 21
10.4
Handling of Multiplicity....................................................................... 22
11.0
Safety Analysis.....................................................................22
11.1
General Considerations......................................................................... 22
11.2
Analysis of Treatment-Emergent Adverse Events................................. 22
11.3
Analysis of Laboratory and Vital Signs Data ........................................ 25
11.3.1
Analyses of Shift from Baseline in Clinical Laboratory Data ................ 26
11.3.2
Assessment of Potentially Clinically Significant Vital Signs 
Values .................................................................................................. 27
11.3.3
ECG/2D Echocardiogram..................................................................... 28
12.0
References............................................................................28
List of Tables
Table 1.
Summary of Analyses with Cutoff Dates and Data Included................... 7
Table 2.
Time Windows for Quality of Life Measures........................................ 10
Table 3.
Adverse Events of Special Interest........................................................ 25
Table 4.
Criteria for Potentially Clinically Significant Laboratory Values –
Vital Signs Variables............................................................................ 27
List of Figures
Figure 1.
5-Week Dose-Titration Schedule............................................................ 6
List of Appendices
Appendix A.
List of Abbreviations............................................................................ 30
 


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3.0
Introduction
This statistical analysis plan (SAP) describes the full statistical analyses for venetoclax 
(ABT-199) Protocol M15-889.  Study M15-889 evaluates the quality of life of subjects 
with relapsed or refractory chronic lymphocytic leukemia (CLL).  Quality of life is 
assessed based on patient-reported outcome (PRO) measures, including the European 
Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 
(EORTC QLQ-C30), the European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Chronic Lymphocytic Leukemia Module (EORTC QLQ-
CLL16), and the EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L).
This statistical analysis plan (SAP) provides details to elaborate the statistical methods 
outlined in Study Protocol M15-889 Amendment 1 dated 11 July 2016 and Amendment 2 
dated 30 January 2018.  It will provide details of statistical methods and describe analysis 
conventions to guide the statistical programming work.
Unless noted otherwise, all analyses will be performed using SAS® version 9.3 or newer 
(SAS Institute Inc., Cary, NC USA).
The SAP will not be updated in case of future administrative or minor amendments to the 
protocol unless the changes have any impact on the analysis of the study data. 
4.0
Study Objectives, Design and Procedures
4.1
Objectives
Primary Objective
The primary objective of this study is to evaluate the impact of venetoclax monotherapy 
on the quality of life of subjects with relapsed or refractory chronic lymphocytic leukemia 
(CLL).  Quality of life will be assessed by the Global Health Status/Quality of Life 
(GHS/QoL) subscale of the EORTC QLQ-C30.
 


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Secondary Objectives
The secondary objectives are to 
●
evaluate the impact of venetoclax monotherapy on quality of life based on the 
EORTC QLQ-CLL16, EQ-5D-5L, and the remaining subscales from the 
EORTC QLQ-C30 
●
complete remission rate (CR + CRi) 
●
overall response rate (ORR) 
●
duration of  overall response (DOR)
●
time to progression (TTP) 
●
duration of progression-free survival (PFS)
●
overall survival (OS)
●
complete remission rate (CR + CRi) in BCRi treated subjects 
The safety and tolerability of venetoclax in subjects with relapsed/refractory CLL will 
also be evaluated.
4.2
Study Design and Plan
This is an open-label, single arm, Phase 3b, multi-center study evaluating the impact of 
venetoclax monotherapy on the quality of life in relapsed/refractory CLL.
This study is designed to enroll approximately 200 subjects to meet scientific objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.  
Subjects meeting the eligibility criteria will be treated with venetoclax once daily (QD), 
continuously up to 2 years provided they continue to tolerate the drug, have no evidence 
of disease progression (based on Investigator's assessment), do not have unacceptable 
toxicity, and do not meet any of the protocol specified criteria for discontinuation. 
 


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Dosing Schedule Overview
Venetoclax is administered orally once daily (QD), continuously.  To mitigate the risk for 
tumor lysis syndrome (TLS), a lead-in period (up to 5 weeks) is employed to evaluate a 
step wise dose-titration as specified in the protocol, and Figure 1.
Figure 1.
5-Week Dose-Titration Schedule
Week
VENETOCLAX 
Daily Dose
1
20 mg
2
50 mg
3
100 mg
4
200 mg
5 and beyond
400 mg
4.3
Sample Size
An improvement in the EORTC QLQ-C30 GHS/QoL subscale of 5 units is considered to 
be a clinically meaningful difference to subjects.  From a prior study of venetoclax 
monotherapy in 17p del R/R CLL subjects (Study M13-982), the standard deviation was 
approximately 20.5 for the GHS/QoL subscale.  Using a one-sided alpha of 0.025, 90% 
power, and a standard deviation of 20.5; 177 subjects are required to reject the null 
hypothesis in favor of the alternative hypothesis that venetoclax improves GHS/QoL by at 
least 5 units.  To account for potential drop-outs at Week 48, a total of 200 subjects to be 
dosed.
4.4
Interim Analysis
Data Monitoring Committee (DMC)
A Data Monitoring Committee (DMC) has been independently organized to support the 
review of safety data associated with venetoclax monotherapy dosing.  The DMC will 
 


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review the safety data with an initial review to occur when approximately 20 subjects 
have completed a minimum of 12 weeks of treatment. 
A separate charter will be created to provide detailed descriptions of the schedule of 
analyses and the DMC meetings.  DMC membership, responsibilities and the description 
of the data coordinating center are documented in the charter.
4.5
Timing of Quality of life and Efficacy Analyses and Safety 
Evaluations
Table 1.
Summary of Analyses with Cutoff Dates and Data Included
Reason
Database Version
Cutoff Date
QoL/Efficacy Data 
Included
Safety Data 
Included
DMC
A
24 Apr 2017
Not included
All safety dataa
DMC
F
03 Nov 2017
Not included
All safety dataa
DMC
G
30 Apr 2018
Included
All safety dataa
a.
Safety population is defined in Section 5.1.1.
Quality of life, efficacy, and safety analysis occur when all subjects participating in the 
study have completed the 48-week disease assessment or have discontinued venetoclax 
(including early termination of the study). Quality of life, efficacy, and safety data up to 
the cutoff date specified in Table 1 will be considered. During this data collection period, 
active subjects continue to receive venetoclax, as applicable. When data collection is 
complete and all data management quality assurance (QA) and quality control (QC) 
procedures are performed, the clinical database data should be extracted for 
documentation and statistical analyses. The study will be considered completed when the 
last enrolled subject discontinues or completes the dosing regimen.
 


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5.0
Analysis Populations
5.1
Definition for Analysis Populations
5.1.1
Quality of Life, Efficacy, and Safety Populations
All enrolled subjects who receive at least one dose of venetoclax will be included in this 
analysis unless otherwise specified.
5.2
Variables Used for Stratification of Randomization
There is no randomization for this open-label single-arm study.
6.0
Analysis Conventions
6.1
Baseline
The baseline value (except for laboratory variables) is defined as the last non-missing 
measurement collected before the first dose of venetoclax. The baseline value for the 
laboratory variables is defined as:
●
For subject with IV hydration for TLS prophylaxis, the baseline value is the 
lab value taken before the subject receiving IV hydration for TLS prophylaxis 
prior to the first dose of venetoclax. 
●
For subject without IV hydration for TLS prophylaxis, the baseline value is the 
lab value taken before the first dose of venetoclax on Day 1.
6.2
Treatment Days
Definition of Treatment Days (Days Relative to the First Dose of Venetoclax)
Treatment (Rx) days are calculated for each time point relative to the first dose date of 
venetoclax. They are defined as the number of days between the day of the first dose of 
venetoclax and the specific time point. Rx days are negative values when the time point 
of interest is prior to the first venetoclax dose day. Rx days are positive values when the 
time point of interest is after the first venetoclax dose day. The day of the first dose of 
 


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venetoclax is defined as Rx Day 1, while the day prior to the first venetoclax dose is 
defined as Rx Day –1 (there is no Rx Day 0).
Definition of Final Observation
The final observation (Final Visit) is defined as the last non-missing observation collected 
within 30 days following the last dose of venetoclax, unless otherwise specified.
6.3
Definition of Analysis Windows
For visit wise analyses including quality of life and safety analyses, the time windows 
specified in Table 2 and Table 3, describe how the data will be assigned to protocol 
specified visits. Analysis time windows will be constructed using the following 
algorithm:
●
Determine the nominal study Rx day for each scheduled visit.
●
Determine the time window around a specific nominal study Rx day as in 
Table 2.
●
If more than one assessment is included in a time window the most 
conservative value (i.e., the smallest score) should be used for the analysis of 
quality of life measures. A sensitivity analysis should be performed based on 
considering the most favorable (i.e., the largest value) assessment of the 
quality of life measures.  Except the quality of life measures, if there are 
two observations with equal distance to the nominal day, the latest one will be 
used in analyses.
 


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Table 2.
Time Windows for Quality of Life Measures 
Scheduled Visit
Nominal Day
Time Window (study Rx day range)
Baseline (Week 1 Day -1 
or Week 1 Day 1)
≤ 1
See the baseline definition (Section 6.0)
Week 4 Day 1
22
2 to 43
Week 8 Day 1
50
44 to 71
Week 12 Day 1
75
72 to 153
Week 24 Day 1
162
154 to 237
Week 36 Day 1
246
238 to 321
Week 48 Day 1
330
322 to 405
Week 60 Day 1
414
406 to 489
Week 72 Day 1
498
490 to 573
Week 84 Day 1
582
574 to 657
Week 96 Day 1
666
658 to 743
Week 108 Day 1
750
742 to 825
Final Observation 
Last non-missing value within 30 days of last dose of Venetoclax
6.4
Missing Data Imputation
Subjects with missing disease progression date, missing death date, or missing last known 
alive date will be considered as censored subjects for time to progression, progression free 
survival analysis, and survival analysis.  And the subject will be censored at the interim 
data cutoff date.  
If a respondent answers at least 50% of the items in quality of life measures, the missing 
items will be imputed with the average score of the answered items in the same scale.  In 
cases where the respondent did not answer at least 50% of the items, the score for that 
domain will be considered missing.
7.0
Subject Disposition
The number and percentage of subjects will be summarized for each of the following 
categories, for overall and by country and region:
 


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●
Subjects enrolled into the study.
●
Subjects who discontinued venetoclax – overall and for each reported primary 
reason.
●
Subjects who discontinued the study – overall and for each reported primary 
reason.
The number and percentage of subjects who discontinued venetoclax will be summarized 
by reason (all reasons) and by primary reason (per eCRF).  Similar summaries will be 
provided for discontinuations from the study.
The number and percentage of subjects with reported venetoclax interruptions will be 
summarized.  Reasons for venetoclax interruptions will be presented in the listings.
8.0
Demographics, Baseline Characteristics, Medical 
History, and Previous Concomitant Medications
8.1
General Consideration
The safety population will be used to summarize baseline variables. The safety 
population also will be used to summarize medical history and previous, concomitant, and 
post-treatment medications.
8.2
Demographic and Baseline Characteristics
Categorical baseline variables will be summarized with the number and percentage of 
subjects in each category.  Continuous baseline variables will be summarized with 
descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, maximum and minimum).
Categorical baseline variables include:
●
Sex (male, female)
●
Race (White, Black or African American, Asian, and Other)
●
Geographic region (EUROPE, and ROW)
 


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●
Ethnicity (Not Hispanic or Latino, and Hispanic or Latino)
●
Age (< 65, ≥ 65, < 75, and ≥ 75)
●
Tobacco use (current, former, never, and unknown)
●
Alcohol use (current, former, never, and unknown)
●
ECOG performance status (grade: 0, 1, 2)
●
LDH (≤ ULN, > ULN)
●
Prior number of oncology therapies (1, 2, ≥ 3)
●
Previous line of Ibrutinib failure (1, > 1)
●
Previous line of Idelalisib failure (1, > 1)
●
17p deletion status (deleted, not deleted, indeterminate)
●
Rai stage (0, 1, 2, 3, 4)
●
Binet stage (A, B, C)
●
IgVH status (mutated, unmutated)
●
ZAP-70 (positive, negative, indeterminate)
●
CD-38 (positive, negative, indeterminate)
●
Beta 2-microglobulin (< 3 mg/L, ≥ 3 mg/L)
●
TP53 mutation (yes, no, unknown)
●
11q (deleted, not deleted, indeterminate)
●
13q (deleted, not deleted, indeterminate)
●
12q trisomy (present, not present, indeterminate)
●
Absolute lymphocyte count (ALC) (< 25 × 109/L, ≥ 25 × 109/L; < 100 × 109/L, 
≥ 100 × 109/L)
●
Bulky disease nodes (< 5 cm, 5 cm To 10 cm, ≥ 10 cm) 
●
Prior BCRi treated (yes, no)
●
TLS risk category (low/medium, high)
●
Hospitalized for TLS prophylaxis before venetoclax (yes, no)
Continuous baseline variables include:
●
Age (year)
 


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●
Weight (kg) by male and female
●
Height (cm)
●
Number of prior oncology therapy 
●
Beta-2 microglobulin (MG/L) 
●
Lactate dehydrogenase (LDH)
●
Absolute lymphocytes count (109/L)
●
Bulky disease nodes (cm)
●
Duration of BCRi therapy before venetoclax
8.3
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the CRF. The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system. The number and percentage of subjects with a particular 
condition/diagnosis will be summarized.  Subjects reporting more than 
one condition/diagnosis within a body system will be counted only once for that body 
system.
8.4
Previous Treatment and Concomitant Medications
A prior medication is defined as any medication taken prior to the first dose of venetoclax.  
A concomitant medication is defined as any medication that started prior to the first dose 
of venetoclax and continued to be taken after the first dose of venetoclax or any 
medication that started after the first dose of venetoclax, but not after the last dose of 
venetoclax.  The number and percentage of subjects who have taken medications will be 
summarized by generic drug name for prior medications, concomitant medication, and 
prior oncology therapies.  In addition, the number and percentage of subjects who have 
taken, one, two, three, four, and five or more drugs will be summarized for prior 
medications, concomitant medications, and prior oncology therapies.
 


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For summaries of concomitant medications, if an incomplete start date was collected for a 
medication, the medication will be assumed to be a concomitant medication unless there 
is evidence that confirms that the medication was not a concomitant medication (e.g., the 
medication end date was prior to the first dose of venetoclax).
A subject who reports the use of two or more medications will be counted only once in the 
summary of "Any Concomitant Medication."  A subject who reports two or more uses of 
the same medication will be counted only once in the total for the associated generic drug 
name.  Similar rules apply to prior medications as well.
9.0
Venetoclax Exposure and Compliance
The duration of exposure to venetoclax will be summarized.  Duration of exposure is 
defined for each subject as (last dose date – first dose date) + 1.  Duration of exposure will 
be summarized using the following statistics:  sample size (N), mean, standard deviation, 
median, and range.  In addition, the number and percentage of subjects exposed to 
venetoclax will be summarized for the following categories of exposure duration:  0 to 
5 weeks, > 5 weeks to 8 weeks, > 8 weeks to 12 weeks, > 12 weeks to 16 weeks, 
> 16 weeks to 20 weeks, > 20 weeks to 24 weeks, > 24 weeks to 28 weeks, > 28 weeks to 
32 weeks, > 32 weeks to 36 weeks, > 36 weeks to 48 weeks, > 48 weeks to 60 weeks, and 
> 60 weeks.
The compliance based on investigator opinion for each subject will be provided in the 
listing.
10.0
Quality of Life and Efficacy Analyses
10.1
General Considerations
Details on the analysis sets used will be specified in quality of life and efficacy analyses 
described below.
 


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10.1.1
Definitions for Quality of Life Assessments
EORTC QLQ-C30
Quality of life and symptoms will be assessed with the European Organization for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 
(EORTC-QLQ-C30) version 31.  The QLQ-C30 is a 30-item subject self-report 
questionnaire composed of both multi-item and single scales, including five functional 
scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, 
nausea and vomiting, and pain), a global health status/quality of life (GHS/QoL) scale, 
and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties).  Subjects rate items on a four-point scale, with 1 as "not at all" and 
4 as "very much."  The EORTC QLQ-C30 was developed and validated for use in a 
cancer subject population, and its reliability and validity is highly consistent across 
different language cultural groups.  A change of 5 – 10 points is considered a small 
change, and the lower bound (5) is being used to define the minimum important difference 
(MID).  A change of 10 – 20 points is considered a moderate change.
The EORTC-QLQ-C30 domains (global health status/quality of life, physical, role, 
emotional, social, cognitive, fatigue, nausea and vomiting, pain, dyspnoea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties) will be summarized (mean, 
standard deviation, and median) at each assessment.  In addition the mean change in each 
of these values (visit-level assessment versus baseline) will be calculated to identify any 
statistically significant differences.  The ninety-five percent (95%) confidence interval of 
the mean change will be constructed based on (a) without model assumption and (b) with 
model assumption.  A linear model will be used for the analysis of repeated measures 
where the covariance pattern will be assumed as compound symmetry (CS).  
EORTC QLQ-CLL16
The EORTC QLQ-CLL16 was designed specifically for subjects with stage 0 to stage 4 
CLL2.  It is comprised of sixteen questions that address five domains of HRQoL 
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and Treatment Effects (7 items), and Infection (5 items), and two single-item scales 
assessing Social Activities and Future Health Worries.  Subjects rate items on a four-point 
scale, with 1 as "not at all" and 4 as "very much."  A negative change in score from 
baseline represents an improvement in symptoms.  A change of 5 – 10 points is 
considered a small change, and the lower bound (5) is being used to define the minimum 
important difference (MID).  A change of 10 – 20 points is considered a moderate 
change.3
The EORTC-QLQ-CLL16 domains (Fatigue, Treatment Side Effects and Disease 
Symptoms, Infection, Social Activities, Future Health Worries) will be summarized 
(mean, standard deviation, and median) at each assessment.  In addition the mean change 
in each of these values (visit-level assessment versus baseline) will be calculated to 
identify any statistically significant differences.  The ninety-five percent (95%) 
confidence interval of the mean change will be constructed based on (a) without model 
assumption and (b) with model assumption.  A linear model will be used for the analysis 
of repeated measures where the covariance pattern will be assumed as compound 
symmetry (CS).  
EQ-5D-5L
The EuroQol EQ-5D-5L is a generic preference instrument that has been validated in 
numerous populations4-5.The EQ-5D-5L has five dimensions:  mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression.  These dimensions are measured on a 
five-level scale:  no problems, slight problems, moderate problems, severe problems, and 
extreme problems.  The scores for the 5 dimensions are used to compute a single utility 
index score ranging from zero (0.0) to 1 (1.0) representing the general health status of the 
individual.  The EQ-5D-5L also contains a visual analog scale (VAS) to assess the 
subject's overall health.  The MID for the EQ-5D utility index score in cancer subjects is 
0.08, and the MID for EQ-5D VAS is 76.
Each of the five dimensions of the EQ-5D-5L, the VAS and overall utility score will be 
calculated using the EuroQol scoring manual, and summarized (mean, std. dev., median) 
 


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at each assessment.  The impact of treatment over time will be assessed by calculating the 
change in score from baseline at each assessment time point.  The ninety-five percent 
(95%) confidence interval of the mean score change will be constructed based on 
(a) without model assumption and (b) with model assumption.  A linear model will be 
used for the analysis of repeated measures where the covariance pattern will be assumed 
as compound symmetry (CS).  
10.1.2
Definitions for Efficacy Endpoints
Complete Remission Rate (CR + CRi)
Complete response rate, complete remission (CR) or complete remission with incomplete 
marrow recovery (CRi), will be defined as the proportion of subjects who achieved per the 
2008 Modified IWCLL NCI-WG criteria as assessed by investigator using the best 
response at any time during the study.  In addition, the 95% confidence interval for 
complete response rate (CR) rate based on the binomial distribution (Clopper-Pearson 
exact method) will be provided.  Subjects who do not achieve a CR or CRi will be 
considered to be non-responders in the calculation of complete response rate.
Overall Response Rate (ORR)
ORR (CR + CRi + nPR + PR) will be defined as the proportion of subjects who achieved 
complete remission (CR), complete remission with incomplete marrow recovery (CRi), 
nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 
Modified IWCLL NCI-WG criteria as assessed by investigator using the best response at 
any time during the study.  The corresponding exact 95% confidence interval for the 
proportion (Clopper-Pearson exact method) will be constructed.  Subjects who do not 
respond will be considered non-responders.
Duration or Response (DOR)
The DOR for a given subject will be defined as the number of days from the day the 
criteria are met for CR, CRi, nPR, or PR (whichever is recorded first) to the earliest date 
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(i.e., DoR = PD/death/censoring date – earliest CR/CRi/nPR/PR date + 1 day).  For 
subjects who have a PR before CR, CRi, or nPR in subsequent visits, the DOR is 
computed from the earliest PR. If a subject is still responding then the subject's data will 
be censored at the date of the last available disease evaluation or at the cut-off date for the 
interim analysis if the subject has a disease evaluation that is after the cut-off date.  Only 
subjects with the iWCLL response criteria will be included in the analysis of DOR.  The 
distribution of the duration of overall response will be estimated using the Kaplan-Meier 
methodology.  Median duration of response will be calculated and the corresponding 95% 
confidence interval will be presented.
Time to Progression (TTP)
Time to progression for a given subject will be defined as the number of days from the 
date the subject started venetoclax to the date of earliest PD (radiographic or clinical) 
(i.e., TTP = PD/censoring date – first dose date + 1 day).  All PD will be included 
regardless of whether the event occurred while the subject was taking venetoclax or had 
previously discontinued venetoclax. If the subject does not experience PD, then the 
subject's data will be censored at the date of the last available disease evaluation or at the 
cut-off date for the interim analysis if the subject has a disease evaluation that is after the 
cut-off date.  If a subject does not have any post baseline disease assessments, the data 
will be censored at the first dose date plus 1 day.  The distribution of the time to 
progression will be estimated using Kaplan-Meier methodology.  Median time to 
progression and the corresponding 95% confidence interval will be estimated.
Progression Free Survival (PFS)
Progression-free survival (PFS) will be defined as the number of days from the date of 
first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death
(i.e., PFS = PD/death/censoring date – first dose date + 1 day).  All disease progression 
will be included regardless of whether the event occurred while the subject was taking 
venetoclax or had previously discontinued the study drug.  If the subject does not 
experience disease progression or death, then the subject's data will be censored at the 
 


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date of the last available disease evaluation, last known alive date, or at the cut-off date 
for the interim analysis if the subjects has a disease evaluation or death that is after the 
cut-off date.  If a subject does not have any post baseline tumor assessment or clinical 
assessment for progression, the data will be censored at the date of first dose plus 1 day.  
Progression-free survival will be analyzed by Kaplan-Meier methodology.  Median 
duration of PFS will be calculated and 95% confidence interval for median duration of 
PFS will be presented.
Overall Survival (OS)
Overall survival (time to death) for a given subject will be defined as the number of days 
from the date the subject started venetoclax to the date of the subject's death (i.e., 
OS = death/censoring date – first dose date + 1 day).  All events of death will be included, 
regardless of whether the event occurred while the subject was still taking venetoclax, or 
after the subject discontinued venetoclax.  If a subject has not died, then the data will be 
censored at the date of the last study visit, the last contact date, the date the subject was 
last known to be alive, or at the cut-off date for the interim analysis if the subject has a 
death that is after the cut-off date. The date of the last study visit will be determined by 
selecting the last available date of the following study procedures for a subject:  tumor 
assessment, clinical disease progression, physical examination, vital signs assessment, 
clinical laboratory collection, study drug, adverse event and concomitant medication 
assessment, performance status, quality of life evaluation, survival form, and drug and 
study completion form.  The distribution of the time to death will be estimated using 
Kaplan-Meier methodology.  Median survival time and the corresponding 95% 
confidence interval will be estimated.
10.2
Quality of Life and Efficacy Analyses  
Data collected at any point prior to the specified interim cutoff date during the study will 
be used in the analyses, unless otherwise specified. The population of these analyses is 
defined in Subsection 5.1.1.
 


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10.2.1
Primary Endpoint Analysis
The primary endpoint will be assessed by the GHS/QoL subscale of the EORTC 
QLQ-C30.  Summary stats will be on mean change. The endpoint (at subject level) will 
be mean change from baseline to Week 48.  Scores will be calculated based on the scoring 
manual. Mean score for baseline visit and post-baseline visit (Week 4, Week 12, 
Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96, and 
Week 108/Final visit) will be reported with standard deviation (SD). The 95% confidence 
interval for mean change additionally will be provided for each post-baseline versus 
baseline.
10.2.2
Secondary Efficacy Analyses
ORR and CR will be assessed as the proportion of subjects with an overall response based 
on the IWCLL NCI-WG criteria.  The 95% confidence interval based on the Clopper-
Pearson exact method for binomial distribution will be constructed for the calculated ORR 
and CR rates.
DOR, TTP, PFS, and OS will be analyzed by Kaplan-Meier methodology using data for 
all subjects defined in Section 5.1.1.  Median time of each endpoint will be calculated and 
95% confidence interval for median time of each endpoint will be presented. 
Secondary quality of life endpoints will include all multi-item scales and single-item 
scales from the EORTC QLQ-C30, EORTC QLQ-CLL16, and EQ-5D-5L.  Scores will be 
calculated based on the scoring manual for each instrument.  The mean change score from 
baseline to post-baseline (Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, 
Week 72, Week 84, Week 96, and Week 108/Final visit) will be summarized  with the 
95% confidence interval.  Mean score with SD of baseline and each post-baseline visit 
also will be presented.  
 


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10.3
Subgroup Analyses of Quality of Life and Efficacy
To evaluate the impact of baseline conditions on quality of life subgroup analyses will be 
performed on the analysis population defined in Section 5.1.1. The following subgroups 
below will be used for quality of life analyses:
●
17p deletion status (deleted, not deleted)
●
TP53 mutation (yes, no)
●
Prior BCRi treated (yes, no)
●
Prior number of oncology therapies (1, 2, ≥ 3)
●
Baseline ALC (< 25 × 109/L, ≥ 25 × 109/L; < 100 × 109/L, ≥ 100 × 109/L)
●
Baseline node size (< 5 cm, 5 cm to 10 cm, ≥ 10 cm) 
●
Hospitalized for TLS prophylaxis before venetoclax (yes, no)
The following subgroups below will be used for ORR and CR analyses on the analysis 
population defined in Section 5.1.1 and on previously untreated BCRi subjects, and on 
previously treated BCRi subjects:
●
Sex (male, female) 
●
Race (White, Non-White)
●
Age (< 65, ≥ 65; < 75, ≥ 75)
●
ECOG status (0, 1, 2)
●
17p deletion status (deleted, not-deleted)
●
TP53 mutation status (yes, no)
●
Prior number of oncology therapies (1, 2, ≥ 3)
●
Baseline ALC (< 25 × 109/L, ≥ 25 × 109/L; < 100 × 109/L, ≥ 100 × 109/L)
●
Baseline node size (< 5 cm, 5 cm To 10 cm, ≥ 10 cm)
ORR and CR and their 95% CIs will be reported for each level of subgroups in a forest 
plot.  KM plot for DOR and PFS will be also be provided for 17p deleted versus non-17p 
 


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del., TP53 mutation versus TP53 non-mutation, and prior BCRi treated versus prior BCRi 
naïve.
10.4
Handling of Multiplicity
There will be no multiplicity adjustments performed in this open arm study.
11.0
Safety Analysis
11.1
General Considerations
Safety data will be summarized for the safety population, and the population is defined in 
Subsection 5.1.1.
11.2
Analysis of Treatment-Emergent Adverse Events
All summaries/analyses involving AEs will include treatment-emergent adverse events 
(TEAE) only, unless otherwise specified.  TEAE are defined as any event with onset after 
the first dose of venetoclax and no more than 30 days after the last dose of venetoclax.  
Events where the onset date is the same as the venetoclax start date are assumed to be 
treatment-emergent, unless the venetoclax start time and the AE start time are collected 
and the AE start time is prior to the venetoclax start time.  If an incomplete onset date was 
collected for an AE, the AE will be assumed to be treatment-emergent unless there is 
evidence that confirms that the AE was not treatment-emergent (e.g., the AE end date was 
prior to the date of the first dose of venetoclax).
Treatment-emergent adverse events will be summarized by maximum severity grade level 
of each preferred term.  Each adverse event will be assigned a grade level (grade 1, 2, 3, 4, 
or 5) by the investigator.  If a subject has an AE with unknown severity, then the subject 
will be counted in the severity grade level category of "unknown," even if the subject has 
another occurrence of the same event with a severity present.  The only exception is if the 
subject has another occurrence of the same AE with the highest grade level (grade 5).  In 
this case, the subject will be counted under the "Grade 5" category.
 


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Treatment-emergent adverse events will be summarized by relationship of each preferred 
term to venetoclax, as assessed by the investigator.  If a subject has an adverse event with 
unknown relationship, then the subject will be counted in the relationship category of 
"unknown," even if the subject has another occurrence of the same event with a 
relationship present.  The only exception is if the subject has another occurrence of the 
same adverse event with a relationship assessment of "Reasonable Possibility."  In this 
case, the subject will be counted under the "Reasonable Possibility" category.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
clinical study report. 
The number and percentage of subjects with treatment-emergent adverse events will be 
tabulated by primary MedDRA System Organ Class (SOC) and preferred term (PT).  The 
system organ classes will be presented in alphabetical order, and the preferred terms will 
be presented in alphabetical order within each system organ class.
Adverse Event
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent adverse event;
●
Any treatment-emergent adverse event with reasonable possibility related to 
venetoclax by the investigator;
●
Any treatment-emergent NCI toxicity (CTCAE V4.0) grade 3, or 4 adverse 
events;
●
Any treatment-emergent NCI toxicity (CTCAE V4.0) grade 3, 4, or 5 adverse 
events;
●
Adverse events broken down by NCI toxicity grade (Severity);
●
Any treatment-emergent serious adverse event;
●
Any treatment-emergent adverse event leading to discontinuation of 
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●
Any treatment-emergent adverse event leading to venetoclax interruption;
●
Any treatment-emergent adverse event leading to venetoclax dose reduction;
●
Any treatment-emergent adverse event leading to death;
●
Deaths.
The deaths in the overview summary include all deaths that occurring while the subject is 
still receiving venetoclax in this study and occurring off treatment within 30 days after the 
last dose of venetoclax.
For summary tables of AE by PT, subjects reporting more than one AE for a given PT 
will be counted only once for that term (most severe/highest grade incident for the 
severity tables and most related incident for the relationship tables).  Subjects reporting 
more than one AE within an SOC will be counted only once for that SOC.  Subjects 
reporting more than one AE will be counted only once in the overall total.
Adverse Events of Special Interest
Adverse events of special interest will be summarized.  The list of adverse events of 
special interest is shown in Table 3.
For each of the adverse event of interest, the number and percentage of subjects 
experiencing at least one treatment-emergent adverse event will be presented overall and 
by SOC and PT.  In addition, a listing of treatment-emergent adverse events for subjects 
meeting each of the search criterions will be provided.
 


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Table 3.
Adverse Events of Special Interest
Risk
Search Criteria
Tumor Lysis Syndrome 
(three searches) 
1)
SMQ – "Tumour lysis syndrome" (Narrow-scope)
2)
SMQ – "Tumuor lysis syndrome" (Narrow) plus PT terms of 
"Hyperkalaemia," "Hyperuricaemia," "Hyperphosphataemia," 
"Hypocalaemia," "Blood potassium increased," "Blood uric acid 
increased," "Blood phosphorus increased," "Blood calcium 
decreased"
3)
SMQ – "Tumuor lysis syndrome" (Narrow) plus broad-scope terms 
with algorithm applied (ie., two events from category B and one 
event from category C required for a subject to be counted as having 
a TLS event)
Neutropenia
PT terms – "Neutropenia," "Neutrophil count decreased," "Febrile 
neutropenia," "Agranulocytosis," "Neutropenic infection," and 
"Neutropenic sepsis"
Serious Infection, Including 
Opportunistic Infections
SAEs in the SOC of "Infections and Infestations"
Second Primary 
Malignancy
SMQ – "Malignant tumours" (Narrow) and "Myelodysplastic syndromes" 
(Narrow)
Lymphopenia
PT terms – "Lymphopenia" and "Lymphocyte count decreased"
Anemia
PT terms – "Anaemia" and "Haemoglobin decreased"
Thrombocytopenia
PT terms – "Thrombocytopenia" and "Platelet count decreased"
Drug Induced Liver Injury 
(DILI)
SMQ – "Drug related hepatic disorders – comprehensive search"
Medication Error
SMQ – "Medication error" (broad)
SMQ = Standardised MedDRA Query;
11.3
Analysis of Laboratory and Vital Signs Data
Data collected from the central and local laboratories, including additional laboratory 
testing due to an SAE, will be used in all analyses.
The value for baseline used in laboratory and vital sign analyses is defined in Section 6.0.  
Post baseline visits windows are specified in Table 3. 
 


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Hematology variables include:  hematocrit, hemoglobin, red blood cell (RBC) count, 
white blood cell (WBC) count, neutrophils, lymphocytes, platelet count, and reticulocyte 
count.
Chemistry variables include:  blood urea nitrogen (BUN), creatinine, total bilirubin, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, 
sodium, potassium, calcium, inorganic phosphorus, uric acid, glucose, albumin, Lactate 
dehydrogenase (LDH).
Mean changes from baseline at each scheduled post-baseline visit will be summarized 
with the baseline mean, visit mean, change from baseline mean, standard deviation, and 
median.
11.3.1
Analyses of Shift from Baseline in Clinical Laboratory Data
For shifts relative to National Cancer Institute Common Toxicity Criteria for Adverse 
Events (NCI CTCAE version 4.0), baseline and post-baseline laboratory observations 
(maximum and final) will be categorized as grade 0, grade 1, grade 2, grade 3, or grade 4 
according to NCI CTCAE grade version 4.0.
The baseline and final grades will be defined respectively as the grade of the last 
measurement collected prior to the first dose of venetoclax unless specified differently in 
Section 6.0, and as the last post-baseline measurement collected no more than 30 days 
after the last dose of venetoclax.  
The maximum NCI toxicity grade value is the value with highest NCI toxicity grade 
collected after the first dose of venetoclax and within 30 days following the last dose of 
venetoclax.  In cases where multiple values are collected on the same day, the maximum 
grade value will be selected as the value for that day.
For each variable, shift tables will be generated that cross tabulate the number of subjects 
with baseline values of grade 0, grade 1, grade 2, grade 3, or grade 4 versus maximum or 
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Detailed listings of data for subjects experiencing NCI CTCAE grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of venetoclax, will be included in 
these listings.
Potential Drug-Induced Liver Injury (DILI)
Potential DILI will be determined by searching post-dose laboratory ALT or AST 
> 3 × ULN in combination with total bilirubin > 2 × ULN that occur within 72 hours of 
each other.
11.3.2
Assessment of Potentially Clinically Significant Vital Signs 
Values
Vital sign variables are systolic blood pressure, diastolic blood pressure, heart rate, and 
body temperature. 
Pre-defined criteria for potentially clinically significant vital signs values are given in 
Table 4:
Table 4.
Criteria for Potentially Clinically Significant Laboratory Values –
Vital Signs Variables
Vital Signs Variables
Criterion
Definition of Potentially Clinically Significant
Systolic blood pressure
High
Value ≥ 160 mmHg
Diastolic blood pressure
High
Value ≥ 100 mmHg
Heart rate
Low
Value < 50 bpm
High
Value ≥ 120 bpm
Temperature
Low
Value < 36°C
High
Value ≥ 38.5°C
The number and percentage of subjects who have at least one post-baseline observation 
meeting the pre-defined criteria for potentially clinically significant values will be 
provided for each vital sign. A listing of all observations collected will be generated for 
 


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subjects that had at least one post-baseline observation meeting pre-defined criteria for 
potentially clinically significant values.
11.3.3
ECG/2D Echocardiogram
For ECG testing, subjects were only required to have a screening and a final visit 
assessment.  If an ECG was clinically indicated, additional measurement could have been 
performed.  Only ECG results that were abnormal were collected in the database.
For 2D echocardiogram testing, subjects had a screening assessment if clinically 
indicated.  If an echocardiogram was clinically indicated, additional measurement could 
have been performed.
Data from ECG or 2D Echocardiogram that were collected will be provided in data 
listings.
No analyses are planned given the limited collection of data.
12.0
References
1.
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(5):365-76.
2.
EORTC.  Chronic lymphocytic leaukemia (QLQ-CLL16).  Available from:  
http://groups.eortc.be/qol/chronic-lymphocytic-leaukemia-qlq-cll16.  Accessed on:  
February 2016.
3.
Hoffmann-La Roche, German CLL Study Group.  CLL11:  a study of 
obinutuzumab (RO5072759 [GA101]) with chlorambucil in patients with 
previously untreated chronic lymphocytic leukemia (stage 2).  ClinicalTrials.gov 
website.  Available from:  https://clinicaltrials.gov/ct2/show/NCT02053610.  
Accessed on:  February 2016.
4.
Herdman M, Gudex C, Lloyd A, et al.  Development and preliminary testing of the 
new five-level version of EQ-5D (EQ-5D-5L).  Qual Life Res.  2011;20:1727-36.
 


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5.
Oppe M, Devlin NJ, van Hout B, et al.  A program of methodological research to 
arrive at the new international EQ-5D-5L valuation protocol.  Value Health.  
2014(4);17:445-53.
6.
Pickard AS, Neary MP, Cella D.  Estimation of minimally important differences in 
EQ-5D utility and VAS scores in cancer.  Health Qual Life Outcomes.  
2007;5:70-8.
 


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Appendix A.
List of Abbreviations
AE
Adverse Event
CLL
Chronic Lymphocytic Leukemia
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DILI
Drug-Induced Liver Injury
DOR
Duration of Overall Response
ECOG
Eastern Cooperative Oncology Group
EORTC QLQ C30
European Organization for Research and Treatment of Cancer Quality of 
Life Core Questionnaire
EORTC QLQ CLL 16
European Organization for Research and Treatment of Cancer Quality of 
Life Core Questionnaire Chronic Lymphocytic  Leukemia Module
EQ-5D-5L
EuroQoL 5 Dimension 5 Level Questionnaire
IWCLL
International Workshop for Chronic Lymphocytic Leukemia
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NCI-WG
National Cancer Institute-Working Group
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-free Survival
QA
Quality Assurance
QC
Quality Control
QD
Once Daily
SAP
Statistical Analysis Plan
SMQ
Standard MedDRA Query
TEAE
Treatment-emergent Adverse Event
TLS
Tumor Lysis Syndrome
TTP
Time to Progression
ULN
Upper Limit of Normal