Conditions: Chronic Lymphocytic Leukemia
Keywords: Oncology Chronic Lymphocytic Leukemia Cancer of the blood and bone marrow
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 127
Healthy volunteers: no

Brief summary:
This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or refractory chronic lymphocytic leukemia (CLL) after B-cell receptor signaling pathway inhibitors (BCR PI) treatment.

Detailed description:

Arms:
arm 1: Participants with ibrutinib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 593 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. arm 2: Participants with idelalisib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 1023 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. arm 3: Participants with ibrutinib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 622 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants enrolled into the Expansion Cohort with bulky disease at study entry who were non-responders or those who showed signs of clinical progression after completing the ramp up to 400 mg either by clinical disease assessment or by CT/MRI scan between Week 6 to Week 12 may have been permitted to escalate venetoclax to a daily dose of 600 mg. arm 4: Participants with idelalisib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 1189 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants enrolled into the Expansion Cohort with bulky disease at study entry who were non-responders or those who showed signs of clinical progression after completing the ramp up to 400 mg either by clinical disease assessment or by CT/MRI scan between Week 6 to Week 12 may have been permitted to escalate venetoclax to a daily dose of 600 mg.

Interventions: intervention 1: Venetoclax
Intervention descriptions: intervention 1: Each dose of venetoclax was to be taken with approximately 240 mL of water within 30 minutes after the completion of breakfast or the participant's first meal of the day.

Protocol document:
Prot_000.pdf: 


Venetoclax (ABT-199-GDC-0199)
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
21 February 2014
Amendment 1
16 May 2014
Amendment 2
14 January 2015
Amendment 3
22 September 2015
Administrative Change 1
30 November 2015
Amendment 4
13 September 2016
Administrative Change 2
27 September 2016
Amendment 5
12 October 2018
The purpose of this amendment is to:
●
Section 6.1.5, Adverse Event Reporting – to update medical director contact 
information for study.
Rationale:  Provide current study team contacts.
●
Update Section 7.0, Protocol Deviations, to update the primary contact 
information.
Rationale:  Provide current study team contacts.
●
Update Section 15.0, Reference List.
Rationale:  Provide current Investigator Brochure edition.
●
Update Appendix B, List of Protocol Signatories.
Rationale:  Provide current study team contacts.
●
Remove Appendix G, Protocol Amendment:  List of Changes
Rationale:  No longer required per AbbVie processes.
●
Add Appendix G, Summary of COVID-19 Changes
Rationale:  To incorporate necessary protocol modifications in order to align 
with AbbVie's COVID-19 response strategies.
 


Venetoclax (ABT-199-GDC-0199)
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●
Update Section 1.3 List of Abbreviations and Definition of Terms, and correct 
typographical errors and minor language or word revisions throughout the 
document.
 


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-032
Name of Study Drug:  Venetoclax
Phase of Development:  2
Name of Active Ingredient:  Venetoclax
Date of Protocol Synopsis:  15 December 2020
Protocol Title:  A Phase 2 Open-Label Study of the Efficacy and Safety of ABT-199 (GDC-0199) in 
Chronic Lymphocytic Leukemia Subjects with Relapse or Refractory to B-Cell Receptor Signaling 
Pathway Inhibitor Therapy
Objectives:
Primary Objective:
The primary objective of this study is to evaluate the efficacy and safety of venetoclax monotherapy in 
subjects with Chronic Lymphocytic Leukemia (CLL) relapsed after or refractory to treatment with B-cell 
Receptor Signaling Pathway Inhibitors.  Efficacy will be measured by overall response rate (ORR).
Secondary Objectives:
The secondary objectives are to evaluate the duration of response (DOR), time to progression (TTP), 
progression free survival (PFS), and overall survival (OS).
Exploratory Objectives:
Time to Next Anti-CLL Treatment (TNT) and Rate of Minimal Residual Disease (MRD) Status.  Health 
Economic and Patient-Reported Outcome Measures will include the EORTC QLQ C30 and EORTC 
QLQ CLL16 (a measure of health-related quality of life specific to CLL) and the EQ-5D-5L (measure of 
general health status with visual analogue scale).
Note:  Study objectives, with the exception of Safety, will not apply to the Extended Access period 
which will begin 2 years after last subject enrolled.
Investigators:  Investigator information on file at AbbVie.
Study Sites:  Approximately 15 US research sites.
Study Population:  Relapsed or refractory CLL subjects after BCR Signaling Pathway Inhibitors.
Number of Subjects to be Enrolled:  Approximately 120.
 


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Methodology:
This is an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of 
venetoclax in approximately 120 subjects with relapsed or refractory CLL after BCR Signaling Pathway 
Inhibitor (BCR PI) Treatment (specifically Ibrutinib, and Idelalisib).  Two arms and an expansion cohort 
will be implemented:  Arm A is designed to enroll approximately 40 subjects with relapsed or refractory 
CLL after Ibrutinib treatment, Arm B is designed to enroll approximately 20 subjects with relapsed or 
refractory CLL after Idelalisib treatment and the Expansion Cohort is designed to enroll approximately 
60 subjects with relapsed or refractory CLL after either Ibrutinib or Idelalisib treatments.  Screening 
must be performed within 28 days of study drug administration.  PET/CT scans and bone marrow 
aspirate and biopsy must be performed within 28 days prior to study drug administration.  For subjects 
enrolled under Arm A and Arm B, restaging CT/MRI scans will be performed at Week 8, Week 24 and 
every 12 weeks thereafter for a period of 1 year from enrollment and at the subject's Final Visit.  For 
subjects enrolled under the Expansion Cohort, restaging CT/MRI scans will be performed at Week 12, 
Week 36 and at the subject's Final Visit.  All subjects will have study visits conducted on Day 1 of each 
week from Week 1 through Week 5, Week 8, Week 12, Week 16, Week 24, and then every 12 weeks 
thereafter.  A Disease Assessment for clinical response by physical exam and hematologic assessments 
will be performed at Screening, Week 5 Day 1 (or Day 1 of the initiation of 400 mg of venetoclax) and 
beyond.  When an investigator has determined that a subject should discontinue the study, a Final Visit 
will be conducted as well as a 30-Day Safety Follow-Up.  If the subject is discontinued from the study 
due to toxicities attributable to ABT-199, additional Follow-Up Visits will be conducted as clinically 
appropriate until a satisfactory clinical resolution of the adverse event is achieved and progression is 
documented.
Diagnosis and Main Criteria for Inclusion/Exclusion:  CLL Subjects with Relapsed or Refractory to 
B-cell Receptor Signaling Pathway Inhibitor Therapy.
Main Inclusion:

Subject must be ≥ 18 years of age.

Subject must have diagnosis of CLL that meets published 2008 IWCLL NCI-WG criteria.

Subject has relapsed/refractory disease with an indication for treatment.

Subject has refractory disease or developed recurrence after therapy with a BCR signaling 
pathway inhibitor (BCR PI).

Subject must have an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
Main Exclusion:

Subject has undergone an allogeneic stem cell transplant within the past 1 year.

Subject has developed Richter's transformation confirmed by biopsy.

Subject has active and uncontrolled autoimmune cytopenias.

Subject has malabsorption syndrome or other condition that precludes enteral route of 
administration.

Subject is tested positive for HIV or has chronic hepatitis B virus or hepatitis C virus requiring 
treatment.
 


Venetoclax (ABT-199-GDC-0199)
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Survival Assessment(s)
Survival information will be collected up to 5 years after the last subject has been enrolled.
Richter's Transformation and Second Primary Malignancies Assessment
Richter's transformation and second primary malignancies information will be collected up to 5 years 
after the last subject has been enrolled.
Extended Access:  For subjects continuing into the Extended Access period of the trial, AbbVie will 
provide venetoclax until 5 years from the date of last subject enrolled, until disease progression, or until 
a subject chooses to receive commercial supply of VENCLEXTA.
Investigational Product:
Venetoclax
Doses:
Single daily doses QD starting with 20 mg; dose increments will 
proceed weekly →50 mg →100 mg →200 mg →400 mg as tolerated.  
Expansion Cohort subjects with bulky disease who are non-responders 
at the Week 12 Disease Assessment may be permitted to escalate 
venetoclax to 600mg dose.
Mode of Administration:
Oral
Duration of Treatment:  Subjects may continue receiving study drug for up to 5 years from the date of 
the last subject enrolled provided they continue to tolerate the drug, have no evidence of disease 
progression, and do not meet any of the criteria for subject discontinuation.  The anticipated median 
treatment duration is ≥ 24 months.
Criteria for Evaluation:
Efficacy:
Response will be assessed by the investigator, based on laboratory results, physical examinations, 
CT/MRI scans and bone marrow examinations, using the 2008 Modified IWCLL NCI-WG Criteria for 
Tumor Response.  An Independent Review Committee (IRC) will evaluate disease progression and 
response based on overall response rate, duration of response, time to progression and progression free 
survival. Subject treatment management will be based on review by the local investigator and/or site 
staff.
All measurable disease must be documented at screening by physical examination, laboratory testing, 
and PET/CT scan (or MRI if CT is medically contraindicated).
During the study, subjects will be assessed at each visit by a physical examination and laboratory testing.  
Clinical Disease Assessments will take place at Screening (baseline), on Week 5 Day 1 (or Day 1 of 
initiation of 400 mg of venetoclax) Week 8, Week 12, Week 16, Week 24, Week 36 and then every 
12 weeks thereafter until disease progression, death, discontinuation from the study or study completion.
 


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Criteria for Evaluation (Continued):
Efficacy (Continued):
Radiographic scans will be performed in addition as described below:
For subjects enrolled under Arm A and Arm B, a CT/MRI scan must be performed at Screening, 
Week 8, Week 24 and every 12 weeks thereafter for a period of 1 year from enrollment and at the 
subject's Final Visit – CT scan is not needed for subjects continuing in the Extended Access period of the 
trial.  For subjects enrolled under the Expansion Cohort, a CT/MRI scan must be performed at 
Screening, Week 12, Week 36 and at the subject's Final Visit – CT scan is not needed for subjects 
continuing in the Extended Access period of the trial.  If a subject has study drug interrupted for more 
than 3 days (i.e., adverse event), the site must contact the AbbVie study team or AbbVie medical 
monitor to adjust the subject's visit schedule, procedures and/or dosing on a case by case basis. Subjects 
should have the same method of imaging performed throughout the study for consistency.  For 
determination of CR, both the CT/MRI and bone marrow are required to be free of disease.  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 exam and or changes in the peripheral blood count), a CT/MRI scan 
and/or bone marrow must be performed within 2 weeks to confirm or rule out PD.
Confirmation of CR by Bone Marrow Examination will be performed as described below: 
Once CR is determined by clinical and radiographic criteria, a bone marrow aspiration and biopsy is 
performed for confirmation.  If the marrow is hypocellular, a repeat examination should be performed 
after 4 weeks, or once the peripheral blood counts have recovered.  
Exploratory MRD will be performed as described below:
A peripheral blood specimen will be collected at Screening from all subjects to determine individual 
disease characteristics, and follow up samples will be collected at Week 24 and after a confirmed 
CR/CRi/PR for analysis of MRD levels.  MRD will be assessed using recommended methodologies 
(flow cytometry, PCR and/or sequencing).  MRD negativity will be defined as the presence of less than 
one CLL cell per 10,000 leukocytes (or below 10–4) in either peripheral blood and/or bone marrow.
Pharmacokinetic:
Pharmacokinetic samples will be collected for venetoclax at designated time points throughout the study.  
Values for the PK parameters of venetoclax, including the apparent clearance (CL/F) and the apparent 
volume of distribution (V/F), may be determined using a population PK approach.  Additional 
parameters may be calculated if useful in the interpretation of the data.
Exploratory Biomarkers:
Several putative biomarkers of efficacy and response may be evaluated in this study with the goal of 
defining the relationship between various disease markers and disease status that may predict the 
subject's response to therapy.  Assays to determine Bcl-2 gene amplifications and translocations, 
modifications of TP53 and NOTCH 1 and genomic profile for mutations before and after treatment may 
be performed.  In addition, mutational analysis of genes that may be associated with resistance and 
response to ibrutinib and B-cell receptor targeted agents including but not limited to mutations of BTK 
(C481S), PLC gamma and other genes linked to B-cell receptor activation may also be evaluated.  If 
necessary, aliquots from PK samples will be utilized for pharmacodynamics analyses.  Exploratory 
research analyses may not be included in the clinical study report.
Pharmacogenetic:
DNA samples may be analyzed for genetic factors contributing to the subject's response to venetoclax.
 


Venetoclax (ABT-199-GDC-0199)
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Criteria for Evaluation (Continued):
Safety:
Adverse event monitoring, vital signs, physical examination, 12-lead ECG, and laboratory assessments 
will be evaluated.  Guidelines for the management for TLS are provided.
Statistical Methods:
Efficacy:
The following efficacy endpoints will be analyzed:  Overall Response Rate (ORR), Duration of 
Response (DOR), Time to Progression (TTP), Progression Free Survival (PFS), Overall Survival (OS) 
and Rate of Minimal Residual Disease (MRD) Negativity rate.
Overall Response Rate
The proportion of subjects with overall response (per the investigator assessment) will be calculated for 
all subjects based on IWCLL NCI-CWG criteria.  In addition, a ninety-five percent (95%) confidence 
interval based on binomial distribution will be constructed for the calculated ORR.
Duration of Response
Duration of response will be defined as the number of days from the date of first response per 
investigator assessment to the earliest recurrence or PD per investigator assessment.  If a subject is still 
responding then the subject's data will be censored at the date of the subject's last available clinical 
disease assessment.  For subjects who never experienced response, the subject's data will be censored on 
the date of enrollment.  Duration of response will be analyzed by Kaplan-Meier methodology using data 
for all enrolled subjects.  Median duration of response will be calculated and the corresponding 95% 
confidence interval will be presented.
Time to Progression
Time to progression will be defined as the number of days from the date of first dose (date of enrollment 
if not dosed) to the date of earliest disease progression (per the investigator assessment).  All disease 
progression will be included regardless whether the event occurred while the subject was taking study 
drug or had previously discontinued study drug.  If the subject does not experience disease progression, 
then the data will be censored at the date of the last available disease assessment.  TTP will be analyzed 
by Kaplan-Meier methodology using data for all enrolled subjects.  Median time TTP will be calculated 
and 95% confidence interval for median time TTP will be presented.
Progression-Free Survival
Progression-Free Survival will be defined as the number of days from the date of first dose to the date of 
earliest disease progression (per the investigator assessment) or death.  All disease progression will be 
included regardless whether the event occurred while the subject was taking study drug or had 
previously discontinued study drug.  If the subject does not experience disease progression or death, then 
the data will be censored at the date of the last disease assessment.  PFS will be analyzed by Kaplan 
Meier methodology using data for all dosed subjects.  Median PFS time will be calculated and 95% 
confidence interval for median PFS time will be presented.
Overall Survival
Overall survival will be defined as the 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 dosed subjects.  Median time survival will be calculated and 95% 
confidence interval for the median time survival will be presented.
 


Venetoclax (ABT-199-GDC-0199)
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Statistical Methods (Continued):
Efficacy (Continued):
Additional Exploratory Efficacy Analyses
Rate of Minimal Residual Disease (MRD) Negativity Status
MRD negativity will be defined as less than one CLL cell per 10,000 leukocytes (or below 10–4) on 
peripheral blood and/or bone marrow based flow cytometry and/or nucleic acid based methods.  Rate of 
MRD status will be defined as the proportion of subjects who have MRD negativity status.  
Ninety-five percent (95%) confidence intervals based on the binomial distribution will be provided.
Time to Next Anti-CLL Treatment
Time to next anti-CLL treatment will be defined as the number of days from the date of the first dose of 
venetoclax to the date of first dose of new non-protocol anti-leukemia therapy (NPT) or death from any 
cause.  For subjects who did not take NPT, the data will be censored at the last known date to be free of 
NPT.  TTNT will be analyzed by Kaplan-Meier methodology using data for all dosed subjects.  Median 
TTNT time will be calculated.
Pharmacokinetic/Pharmacodynamic:
An analysis may be performed using a nonlinear mixed-effect population modeling approach with 
NONMEM software to describe the disposition of venetoclax, to identify significant covariates and 
explore relationship between pharmacokinetics and pharmacodynamics by combining data from this 
study with other venetoclax clinical studies.  Additional analyses may be performed if useful in the 
interpretation of the data.
Health Economic and Patient Reported Outcome (PRO) Measures
Descriptive statistics will be calculated for all scales of the EORTC QLQ-C30 and EORTC QLQ 
CLL16, the EQ-5D-5L utility score, and the EQ-5D-VAS score, including mean change from baseline to 
the visits identified in Table 5 (Week 1 Day 1, Week 24 Day 1, every 12 weeks starting with Week 24 
and Final Visit).  Only the EORTC QLQ C30 will be utilized in the Expansion Cohort.
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.
 


Venetoclax (ABT-199-GDC-0199)
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ABT-199
Study Drug Compound, "Venetoclax"
AE
Adverse Event
ALL
Acute Lymphoblastic Leukemia
ALT
Alanine aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
aPTT
Activated Partial Thromboplastin Time
Bcl
B-Cell Lymphoma
BCR
B-cell receptor
BCR PI
B-cell receptor pathway inhibitor
BUN
Blood Urea Nitrogen
CLL
Chronic Lymphocytic Leukemia
cm
Centimeter
COSTART
Coding Symbols for Thesaurus of Adverse Reaction Terms
COVID-19
Coronavirus Disease - 2019
CR
Complete Remission
CRi
Complete Remission with Incomplete Marrow Recovery
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTLS
Clinical Tumor Lysis Syndrome
CYP2B6
Cytochrome P450 2B6
CYP2C8
Cytochrome P450 2C8
CYP2C9
Cytochrome P450 2C9
CYP2C19
Cytochrome P450 2C19
CYP2D6
Cytochrome P450 2D6
CYP3A
Cytochrome P450 3A
DLBCL
Diffuse Large B-cell Lymphoma
DLT
Dose Limiting Toxicity
 


Venetoclax (ABT-199-GDC-0199)
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DNA
Deoxyribonucleic Acid
DTP
Direct-to-patient
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCCr
Estimated creatinine clearance rate using Cockcroft-Gault Formula
eCRF
Electronic Case Report Form
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
EMA
European Medicines Agency
EP
European Pharmacopoeia
ERIC
European Research Initiative on CLL
FCR
Fludarabine, cyclophosphamide, and rituximab
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin Fixed, Paraffin Embedded
FISH
Fluorescence in situ Hybridization
FL
Follicular Lymphoma
G-CSF
Granulocyte-colony stimulating factor
GCP
Good Clinical Practice
GM-CSF
Granulocyte-macrophage colony-stimulating factor
HAV-IgM
Hepatitis A virus immunoglobulin M
HBsAg
Hepatitis B Surface Antigen
HCV Ab
Hepatitis C virus antibody
HDPE
High Density Polyethylene
HIV
Human Immunodeficiency Virus
HNSTD
Highest Nonseverely Toxic Dose
hr
Hour
HT
Histologic transformation
IBM
Ideal Body Mass
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IRC
Independent Review Committee
IRB
Institutional Review Board
 


Venetoclax (ABT-199-GDC-0199)
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IV
Intravenous
IWCLL
International Workshop for Chronic Lymphocytic Leukemia
IxRS
Interactive Response System
kg
Kilogram
LDH
Lactate Dehydrogenase
LN
Lymph Node
LTLS
Laboratory Tumor Lysis Syndrome
LVEF
Left Ventricular Ejection Fraction
MCHC
Mean Corpuscular Hemoglobin Concentration
mRNA
Messenger Ribonucleic Acid
MCL
Mantle Cell Lymphoma
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
µg
Microgram
mg
Milligram
mL
Milliliter
µM
Micromolar
MPV
Mean Platelet Volume
MRD
Minimal Residual Disease
MRI
Magnetic Resonance Imaging
MUGA
Multi Gated Acquisition Scan
NCI
National Cancer Institute
NCI-WG
National Cancer Institute-Working Group
NDC
National Drug Code
NHL
Non-Hodgkin's Lymphoma
nM
Nanomolar
nPR
Nodular Partial Remission
ORR
Overall Response Rate
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PD
Progressive Disease
PET
Positron Emission Tomography
PG
Pharmacogenetic
PK
Pharmacokinetic
 


Venetoclax (ABT-199-GDC-0199)
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PR
Partial Remission
PT
Prothrombin Time
QD
Once Daily
qPCR
Quantitative Polymerase Chain Reaction
QTc
QT interval corrected for heart rate
QTcF
QT interval measurement corrected by Fridericia's formula
RBC
Red Blood Cell
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
Stable Disease
SGOT
Serum Glutamic-oxaloacetic Transaminase
SGPT
Serum Glutamic-pyruvic Transaminase
SLL
Small Lymphocytic Lymphoma
SPD
Sum of the products of the greatest diameters
STD
Severely Toxic Dose
TLS
Tumor Lysis Syndrome
TTP
Time to Tumor Progression
ULN
Upper Limit of Normal
US
Ultrasound
USP
United States Pharmacopoeia
VAS
Visual Analog Scale
WBC
White Blood Cell
 


Venetoclax (ABT-199-GDC-0199)
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Definition of Terms
AUC
Area under the plasma concentration-time curve
AUC0-24
Area under the plasma concentration-time curve from time zero to hour 24
Cmax
Maximum observed plasma concentration
CL/F
Apparent oral clearance
IC
Inhibitory concentration
Ki
Inhibition constant
nM
Nanomolar
QRS Duration
The interval between the beginning of the Q wave to the end of the S wave in an 
ECG
QT Interval
The interval between the beginning of the QRS complex to the end of the T wave in 
an ECG
t1/2
Terminal phase elimination half-life
Tmax
Time to maximum observed plasma concentration
V/F
Apparent volume of distribution
 


Venetoclax (ABT-199-GDC-0199)
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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 .....................................................................................................4
1.3
List of Abbreviations and Definition of Terms........................................10
2.0
Table of Contents...................................................................15
3.0
Introduction ...........................................................................20
3.1
Differences Statement..............................................................................29
3.2
Benefits and Risks....................................................................................29
4.0
Study Objectives....................................................................29
5.0
Investigational Plan...............................................................30
5.1
Overall Study Design and Plan:  Description ..........................................30
5.2
Selection of Study Population..................................................................36
5.2.1
Inclusion Criteria .....................................................................................36
5.2.2
Exclusion Criteria ....................................................................................39
5.2.3
Prior and Concomitant Therapy...............................................................42
5.3
Efficacy and Safety Assessments/Variables ............................................44
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................44
5.3.1.1
Study Procedures .....................................................................................68
5.3.1.2
Blood Samples for Pharmacogenetic Analysis (Optional) ......................87
5.3.1.3
Collection and Handling of Biomarker Testing.......................................88
5.3.2
Drug Concentration Measurements .........................................................93
5.3.2.1
Collection of Samples for Analysis .........................................................93
5.3.2.2
Handling/Processing of Samples .............................................................93
5.3.2.3
Disposition of Samples ............................................................................94
5.3.2.4
Measurement Methods.............................................................................94
5.3.3
Efficacy Variables....................................................................................94
5.3.3.1
Primary Variables ....................................................................................95
5.3.3.2
Secondary Variables ..............................................................................102
5.3.4
Safety Variables.....................................................................................102
5.3.5
Pharmacokinetic Variables ....................................................................102
5.3.6
Pharmacogenetic Variables....................................................................103
 


Venetoclax (ABT-199-GDC-0199)
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5.3.7
Biomarker Variables ..............................................................................103
5.3.8
Health Economic and Patient-Reported Outcome Measures.................104
5.4
Removal of Subjects from Therapy or Assessment...............................106
5.4.1
Discontinuation of Individual Subjects..................................................106
5.4.2
Discontinuation of Entire Study.............................................................108
5.5
Treatments..............................................................................................108
5.5.1
Treatments Administered.......................................................................108
5.5.2
Identity of Investigational Product.........................................................108
5.5.2.1
Packaging and Labeling.........................................................................109
5.5.2.2
Storage and Disposition of Study Drugs................................................109
5.5.3
Method of Assigning Subjects to Treatment Groups.............................109
5.5.4
Selection and Timing of Dose for Each Subject....................................110
5.5.5
Blinding..................................................................................................110
5.5.6
Treatment Compliance...........................................................................110
5.5.7
Drug Accountability...............................................................................110
5.6
Discussion and Justification of Study Design........................................111
5.6.1
Discussion of Study Design and Choice of Control Groups..................112
5.6.2
Appropriateness of Measurements.........................................................112
5.6.3
Suitability of Subject Population ...........................................................112
5.6.4
Selection of Doses in the Study .............................................................112
6.0
Complaints ...........................................................................113
6.1
Medical Complaints...............................................................................113
6.1.1
Definitions..............................................................................................114
6.1.1.1
Adverse Event........................................................................................114
6.1.1.2
Serious Adverse Events .........................................................................115
6.1.2
Adverse Event Severity..........................................................................117
6.1.3
Relationship to Study Drug....................................................................118
6.1.4
Adverse Event Collection Period...........................................................118
6.1.5
Adverse Event Reporting.......................................................................119
6.1.6
Pregnancy...............................................................................................121
6.1.7
Toxicity Management ............................................................................122
6.1.7.1
Prophylaxis and Management of Tumor Lysis Syndrome (TLS)..........122
6.1.7.1.1
Risk Categories for Developing TLS.....................................................123
 


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6.1.7.1.2
TLS Prophylaxis Guidelines..................................................................123
6.1.7.2
Management of Neutropenia..................................................................138
6.1.7.3
Management of Lymphopenia ...............................................................138
6.1.7.4
Management of Decrease in Spermatogenesis.......................................139
7.0
Protocol Deviations..............................................................139
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................141
8.1
Statistical and Analytical Plans..............................................................141
8.1.1
Baseline Characteristics.........................................................................141
8.1.1.1
Demographics ........................................................................................141
8.1.1.2
Medical Histories...................................................................................141
8.1.2
Efficacy Endpoints Per Investigator Assessment ..................................142
8.1.2.1
Primary Efficacy Endpoints...................................................................142
8.1.2.2
Secondary Efficacy Endpoints...............................................................142
8.1.3
Efficacy Endpoints Per Independent Review Committee......................144
8.1.4
Timing of Efficacy Endpoints and Safety Evaluations..........................144
8.1.5
Pharmacokinetics ...................................................................................144
8.1.6
Additional Exploratory Efficacy Analyses ............................................145
8.1.7
Safety .....................................................................................................145
8.1.7.1
Adverse Events ......................................................................................146
8.1.7.2
Serious Adverse Events .........................................................................146
8.1.7.3
Deaths ....................................................................................................146
8.1.7.4
Longitudinal Analyses of Laboratory and Vital Signs Data..................146
8.1.7.5
Analyses of Laboratory Data Using NCI CTCAE.................................147
8.2
Determination of Sample Size ...............................................................147
9.0
Ethics.....................................................................................148
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................148
9.2
Ethical Conduct of the Study.................................................................149
9.3
Subject Information and Consent...........................................................149
10.0
Source Documents and Case Report Form 
Completion ...........................................................................150
10.1
Source Documents .................................................................................150
 


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10.2
Case Report Forms.................................................................................150
11.0
Data Quality Assurance ......................................................151
12.0
Use of Information...............................................................152
13.0
Completion of the Study .....................................................153
14.0
Investigator's Agreement....................................................155
15.0
Reference List ......................................................................156
List of Tables
Table 1.
Excluded and Cautionary Medications/Food Items (See Appendix 
C for Examples of the Medications) ........................................................43
Table 2.
Sample of Permitted Medications............................................................44
Table 3.
Study Activities for Arm A and Arm B...................................................45
Table 4.
Study Activities for Expansion Cohort Standard Lead-In .......................51
Table 5.
Study Activities for Expansion Cohort Modified Lead-In.......................57
Table 6.
Schedule of PK Blood Collection for Venetoclax (and Possible 
Metabolite[s]) for All Subjects ................................................................63
Table 7.
Schedule of Biomarker and Pharmacogenetic Sample Collection 
for Arm A and Arm B..............................................................................64
Table 8.
Schedule of Biomarker and Pharmacogenetic Sample Collection 
for Expansion Cohort...............................................................................66
Table 9.
Clinical Laboratory Tests for All Subjects ..............................................76
Table 10.
2008 Modified IWCLL NCI-WG Criteria for Tumor Response...........100
Table 11.
Identity of Investigational Product.........................................................109
Table 12.
Dose Reduction Guidelines for Management of Neutropenia...............138
Table 13.
Sample Size Calculation ........................................................................148
List of Figures
Figure 1.
Lead-In Dosing Schematic.......................................................................32
Figure 2.
Expansion Cohort: Modified Dose Ramp-Up for Select High Risk 
Subjects Only...........................................................................................33
Figure 3.
Adverse Event Collection ......................................................................119
 


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List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................159
Appendix B.
List of Protocol Signatories....................................................................161
Appendix C.
Sample List of Excluded and Cautionary Medications..........................162
Appendix D.
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS)..........164
Appendix E.
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL ..................................................169
Appendix F.
Definitions of Laboratory and Clinical Tumor Lysis Syndrome ...........171
Appendix G.
Summary of COVID-19 Processes ........................................................172
 


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3.0
Introduction
Bcl-2 Family Proteins
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway.  
The Bcl-2 oncogene was first identified in follicular lymphoma 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  Many hematologic malignancies are highly dependent upon the anti-apoptotic 
protein Bcl-2 for survival.  Over-expression of Bcl-2 is associated with tumor initiation, 
disease progression, and drug resistance, and is thus a compelling target for anti-tumor 
therapy.  Bcl-2 is 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 in vitro/in vivo Activity and Preclinical Pharmacokinetic Profile
Venetoclax is a potent, selective and orally bioavailable small molecule inhibitor of Bcl-2 
that binds with > 1,000-fold higher affinity for Bcl-2 (Ki < 0.010 nM) than for Bcl-XL
(Ki – 48 nm) or Mcl-1 (Ki > 444 nM).7
In vitro, venetoclax demonstrated broad cell killing activity against a panel of lymphoma 
and leukemia cells including B-cell follicular lymphomas (FLs), mantle cell lymphomas 
(MCLs), diffuse large B-cell lymphomas (DLBCLs), and acute myeloid leukemias 
(AMLs).  Venetoclax was especially potent against cell lines expressing high levels of 
Bcl-2.  Leukemia and lymphoma cell lines bearing the t(14;18) translocation were 
significantly more sensitive to venetoclax than non-mutated cell lines.
Venetoclax inhibited subcutaneous murine xenograft growth of human tumor cell lines 
derived from acute lymphoblastic leukemia (ALL) and Non-Hodgkin's Lymphoma 
(NHL).  The drug was also active in a model of disseminated ALL.
 


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The pharmacokinetic profile of venetoclax was evaluated in multiple animal species.  In 
mouse, rat, monkey and dog, the venetoclax pharmacokinetic profile was characterized by 
low plasma clearance and low volumes of distribution.  Half-lives ranged from 2.2 hours 
in monkey to 12 hours in dog.  Food had a marked effect on the oral bioavailability in 
dog.
Venetoclax has high protein binding to human, rat, dog, and monkey plasma proteins 
(> 99.9%).  In rats, venetoclax was widely distributed into liver, kidneys, spleen, heart, 
lungs, small intestine, and white fat, but was poorly distributed in testes, brain, muscle, 
and bone.  Metabolism was the major route of elimination with biliary excretion of the 
parent drug playing the secondary role in rats.  Venetoclax showed moderate metabolic 
stability in in vitro hepatic systems across species tested, except for low to moderate 
stability in dog hepatocytes.
Venetoclax is a CYP3A4 substrate and both venetoclax and its major human metabolite, 
M27, are predominately metabolized by CYP3A4 in vitro.  Therefore, CYP3A4 inhibitors 
or inducers are expected to cause changes in venetoclax and M27 exposures.  At the 
400 mg QD dose, venetoclax and M27 are not predicted to be perpetrators of the major 
CYP or UGT enzymes, and venetoclax is predicted to weakly inhibit UGT1A1.  
Venetoclax and M27 are predicted to cause clinical interaction via inhibition with drugs 
that are substrates of P-gp (e.g., digoxin, dabigatran) and BCRP (e.g., rosuvastatin).  
Venetoclax is predicted to inhibit OATP1B1 and cause weak interaction with drugs that 
are substrates of this transporter (e.g., statins).
Venetoclax exhibited potent activity against patient-derived CLL cells treated ex vivo, 
killing these cells with an average concentration required for 50% effect (EC50) of 
0.006 µM (n = 35; note that not all subject samples are from venetoclax trials).  
Venetoclax was equally potent against the subset of CLL samples bearing the high-risk 
17p deletion, with an average EC50 of 0.008 µM (n = 5), indicating that venetoclax may 
have a significant utility in treating subjects with this high-risk disease.
 


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Venetoclax Preclinical Toxicology
The nonclinical toxicology of venetoclax has been evaluated in repeated-dose studies in 
mice and dogs with up to 4 weeks of once daily oral dosing (and with 4-week recovery 
periods) and in dogs with 2 weeks of dosing (18-week recovery period); safety 
pharmacology studies (cardiovascular, neurofunctional, and pulmonary); and in genetic 
toxicity tests (Ames and in vitro chromosome aberrations assays).  The primary toxicities 
associated with venetoclax administration included effects on the hematologic system 
(lymphocytes and red blood cell parameters) in mice and dogs and on the male dog 
reproductive system.  There was no evidence of genotoxicity of venetoclax.  A severely 
toxic dose (STD10) was not identified in mice up to and including the top dose of 
600 mg/kg/day (overall mean AUC0-24 = 91.5 µg•hr/mL and Cmax = 7.2 µg/mL).  In dogs, 
the highest non-severely toxic dose (HNSTD) was 150 mg/kg/day, but due to overlapping 
exposures between the mid and high doses, the HNSTD was defined as the mid dose of 
50 mg/kg/day (overall mean AUC0-24 = 472 µg•hr/mL and Cmax = 27.4 µg/mL).
Venetoclax causes decreases in circulating lymphocytes and lymphocytes in lymphoid 
tissue.  After 4 weeks of dosing, the lymphocyte effects were reversible or partially 
reversible in the mouse but generally were less reversible in the dog at the end of a 
4-week recovery period.  However, in a 2-week dog study focused on lymphocyte 
recovery over an extended (18-week) period, reversibility of lymphocyte effects were 
demonstrated.  Immunophenotyping was used to assess changes in peripheral blood 
lymphocyte subsets (i.e., mature T cells, helper T cells, cytotoxic T cells, and mature 
B cells).  At the end of the 18-week recovery period, both total and lymphocyte subset 
counts returned to within range of baseline and control values, and all effects on lymphoid 
tissue reversed.  The venetoclax-related decreases in lymphocytes in blood and lymphoid 
tissues are considered pharmacologically mediated and non-adverse.8
Additional hematological effects of venetoclax treatment included reversible decreases in 
red blood cell parameters (primarily, hematocrit and hemoglobin concentration) in mice 
and dogs.
 


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The decreases in red cell parameters were adverse only at the high dose levels in the 
4-week studies (i.e., at 600 mg/kg/day in mice and at 150 mg/kg/day in dogs, but all red 
cell parameters were reversible at the end of a 4-week recovery period.
Effects on both lymphocytes and red cell mass are readily monitored in subjects.
Male dog reproductive effects consisted of markedly reduced numbers of spermatogonia 
in the testes at all venetoclax dose levels after 4 weeks of dosing, with progression to 
severe decreases in the numbers of all germ cells in testes during the 4-week recovery 
period.  Male mice did not have testicular changes associated with venetoclax 
administration.  The translatability of the testicular findings in dogs to humans is 
unknown, but this change may be related to venetoclax pharmacology, as one or more 
members of the Bcl-2 family of proteins play a role in spermatogenesis.9-11  In view of the 
potential treatment benefits of venetoclax, this finding is anticipated not to impact the 
treatment of subjects with advanced hematologic malignancies.
Dogs at the high dose of 150 mg/kg/day in the 4-week study had clinical signs of itching 
and swelling of the skin on the ears, head (cranial area), and forepaws and/or hindpaws.  
Most of the animals (8 of 10 dogs) were affected.  The clinical signs were mild to 
moderate in severity, transient and sporadic in occurrence, and were absent during the 
recovery period.  The swelling reactions were observed after the first dose in 3 dogs, and 
therefore not consistent with drug-induced immediate (IgE-mediated, Type I) 
hypersensitivity; however, other immune-mediated mechanisms could be involved.  
Although the basis for the swelling reactions was not established, there were no signs of 
anaphylaxis.  Any occurrences of swelling reactions in patients can be monitored and 
treated.
In an ongoing 9-month chronic toxicity study of dogs with venetoclax, hypopigmented 
(white) facial hair was observed after approximately 3 months of dosing (ongoing study 
AbbVie R&D/12/384).  The finding was limited to the mid and high doses (6 and 
20 mg/kg/day), and was observed in both males and females.  Evidence from Bcl-2 
knockout mouse (bcl-2-/-) studies indicates that hair hypopigmentation is consistent with 
 


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the pharmacological effect of Bcl-2 functional loss, and occurs due to loss of hair follicle 
melanocytes dependent on Bcl-2 for survival.12  A dedicated physical examination of the 
skin and extensive ophthalmic examinations determined that pigmentation of the skin and 
in the eye (particularly in the iris and fundus) appears unaffected.  The potential for 
development of white (hypopigmented) hair in humans is unknown.
In an anesthetized dog cardiovascular model given intravenous doses of venetoclax, mild 
reductions in myocardial contractility (maximum rate of rise of left ventricular pressure 
[dP/dtmax]:  –6% to –13%) and cardiac output (–11% to –19%) were observed at plasma 
concentrations of ≥ 16 µg/mL and ≥ 32 µg/mL, respectively.  However, no effects on 
blood pressure, heart rate, or electrocardiogram (ECG) parameters were observed relative 
to baseline or controls in either the anesthetized dog study or in the conscious dog 
cardiovascular study using telemeterized animals at maximum drug concentrations of 
46 µg/mL and 16 µg/mL, respectively.
Venetoclax was tested in a battery of safety pharmacology assays and produced no effects 
in central nervous system/neurobehavioral, or respiratory studies in mice at oral doses up 
to 600 mg/kg.  In dogs, mild reductions in cardiac contractility and cardiac output were 
observed at plasma concentrations of ≥ 16 µg/mL.  However, no effects on blood 
pressure, heart rate, or electrocardiogram (ECG) parameters were observed in dogs at a 
maximum drug concentration of 46 µg/mL.
On the basis of nonclinical safety pharmacology and toxicology evaluations of 
venetoclax, and on the basis of nonclinical and human studies of related antiapoptotic 
Bcl-2 family protein inhibitors, potential mechanism-based toxicities may include 
lymphopenia and neutropenia,13 signs of tumor lysis, reduction in red cell mass, decreased 
spermatogenesis, skin swelling, and hair hypopigmentation.  Thrombocytopenia has not 
been observed in toxicology studies in mice and dogs.  These findings are consistent with 
venetoclax as a Bcl-2 specific (Bcl-XL sparing) inhibitor.  Consequently, 
thrombocytopenia is not expected to be a dose limiting toxicity (DLT) clinically.
 


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Venetoclax is a CYP3A4 substrate and both venetoclax and its major human metabolite, 
M27, are predominately metabolized by CYP3A4 in vitro.  Therefore, CYP3A4 inhibitors 
or inducers are expected to cause changes in venetoclax and M27 exposures.
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the current version of the Investigator's Brochure.14
Venetoclax Clinical Data
As of 28 November 2015, based on the available data in the AbbVie and 
Genentech/Roche clinical databases, a total of 1662 subjects have been exposed to at least 
1 dose of venetoclax in the oncology and immunology development programs.  A total of 
1498 oncology subjects had data available in AbbVie and Genentech/Roche studies as of 
28 November 2015.  Of these 1498, 935 subjects had CLL/small lymphocytic leukemia 
(SLL), 346 subjects had NHL, 115 subjects had MM, and 102 had AML.  An additional 
66 subjects were healthy volunteers.  A total of 564 oncology subjects received the drug 
as monotherapy, 933 received the drug in combination with other therapies, and 1 subject 
received venetoclax as a single dose in a DDI study who did not re-enroll into a 
subsequent monotherapy clinical study.  As of 28 November 2015, an additional 
98 subjects were exposed to at least 1 dose of venetoclax in the AbbVie immunology 
study, Study M13-093, 
Venetoclax doses in clinical studies have ranged from 20 mg to 1200 mg.  Multiple 
ongoing Phase 1/2 AbbVie and Phase 1/2/3 Genentech/Roche clinical studies are 
evaluating safety, tolerability, pharmacokinetics, and efficacy of venetoclax as 
monotherapy or in combination with other therapies (rituximab [R], obinutuzumab 
(GA101) [G], rituximab or obinutuzumab plus CHOP [cyclophosphamide, doxorubicin, 
vincristine, and prednisone; R-CHOP or G-CHOP, respectively], BR, bendamustine plus 
obinutuzumab [BG], bortezomib plus dexamethasone, azacitidine or decitabine, and 
cytarabine) in subjects with hematologic malignancies.  Additionally, two Phase 3 studies 
are ongoing:  one study in relapsed/refractory (R/R) CLL exploring the combination of 
venetoclax and rituximab against BR and one Phase 3 study in first-line CLL exploring 
 


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the combination of venetoclax and obinutuzumab against obinutuzumab plus 
chlorambucil.
Based on the mechanism of action, nonclinical and clinical data available to date, the 
safety profile of venetoclax is well described.  The most common adverse drug reactions 
across all indications are nausea, diarrhea, hematological effects, and serious and/or 
opportunistic infections.  The important risks identified with venetoclax administration 
based on nonclinical and clinical data are tumor lysis syndrome (TLS) and neutropenia, 
particularly in the CLL indication.  Infection is a potential risk.  Other adverse events 
commonly observed with venetoclax include nausea, diarrhea, and other hematological 
effects (including, anemia, thrombocytopenia, and lymphopenia).  In addition, as 
venetoclax is being evaluated in subjects with relapsed/refractory (R/R) disease who had 
previously been treated with various cytotoxic agents, second primary malignancies are 
closely being monitored.
Tumor lysis syndrome (TLS) is an important risk, particularly in subjects with R/R 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 
ramp-up period of 5 weeks and enhanced TLS prophylaxis and monitoring measures were 
implemented in all CLL studies.  A subsequent analysis of data from subjects with 
CLL/SLL following the implementation of prophylaxis measures, who completed 
monotherapy indicated a marked reduction in severity and frequency of TLS when 
compared to the previous analysis.  None of the subjects experienced any serious 
(including fatal) or nonserious event of clinical TLS (CTLS) or laboratory TLS (LTLS) or 
had study treatment discontinued because of TLS.  Overall, the clinical data strongly 
support that the risk of TLS with venetoclax in CLL/SLL subjects is highest when 
 


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initiating venetoclax dosing, especially with a higher initial dose of venetoclax, as well as 
being greater in subjects with a large tumor burden.
Additional safety and efficacy data are described in detail in the Investigator Brochure.14
Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia 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.15  Chronic lymphocytic leukemia primarily affects elderly individuals; 
however, approximately one third of patients are less than 60 years of age at diagnosis.16  
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.17  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 – 2002.15,18  The approximate 5-year survival rate for patients with CLL is 
73%.19  CLL presents with a variable clinical course.  Approximately one-third of patients 
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 patients 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 patients with 
CLL.20
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 patients with CLL are 
made on the basis of considerations such as age, clinical stage, expected survival, and 
 


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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.
Study Rationale
During recent years, evidence accumulated suggesting that signaling via the BCR could 
have an important role in the development of CLL and that it could determine the clinical 
heterogeneity of the disease.  The advent of new therapies that target the signalosome 
brings new evidence in favor of this view.  Clinical trials with drugs that inhibit SYK 
kinase (Fostamatimib), reversible pan-Src kinase (Dasatinib), the BTK inhibitor AVL 292 
and PI3Kinase inhibitor SF1126 and others, are underway.  Ibrutinib (IMBURVICA) and 
idelalisib (Zydelig) are currently approved for relapsed CLL patients.  These drugs cause 
rapid response with reduction in lymph node size and splenic mass accompanied by 
increased PB lymphocytosis likely reflecting that microenvironment modulation could 
prevent these cells from receiving the survival signals delivered by the 
microenvironment.21  However, in early trials of Ibrutinib, approximately 10% of the 
patients developed progressive disease.  Few of these patients developed resistance after 
achieving partial response lasting ≥ 6 months.  Distinct single nucleotide variations were 
noted in these patients.22
The mechanism of action of venetoclax is independent of the BCR pathway.23  Briefly, 
venetoclax inhibits Bcl-2 allowing the release of BIM, which 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.
 


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3.1
Differences Statement
This is a Phase 2 study of venetoclax monotherapy for patients who have progressed or 
developed recurrence after treatment with BCR signaling kinase inhibitors.  Safety data 
and preliminary efficacy responses in the CLL population from the Phase 1 trial support 
this Phase 2 trial.  All subjects will be evaluated for histologic transformation (HT) to 
high grade lymphoma at screening with a positron emission tomography using 
18F-fluorodeoxyglucose (FDG) and subsequent biopsy of PET avid areas to exclude 
subjects with histological and immunophenotypical confirmation of HT.
3.2
Benefits and Risks
The preliminary clinical data of venetoclax monotherapy in subjects with CLL/SLL, MCL 
and NHL have shown a favorable benefit to risk ratio drug during Study M12-175.  In 
Arm A (CLL and SLL) 47 of 52 (90%) evaluable subjects achieved a best response of CR.  
CR with incomplete bone marrow recovery (CRi), or partial response (PR):  12 (21%) 
subjects experienced CR/CRi and 35 (63%) subjects experienced PR of which 30 were 
confirmed.
Additional safety and efficacy data can be found in the current Investigator Brochure.
The encouraging preliminary data from the ongoing venetoclax studies in R/R CLL 
indicate that venetoclax may be beneficial in subjects with relapsed CLL after multiple 
treatment regimens.
Refer to Appendix G for COVID-19 (coronavirus disease 2019)-related processes.
4.0
Study Objectives
The primary objective of this study is to evaluate the efficacy and safety of venetoclax
monotherapy in subjects with Chronic Lymphocytic Leukemia (CLL) relapsed after or 
refractory to treatment with B-cell Receptor Signaling Pathway Inhibitors (specifically 
Ibrutinib or Idelalisib).  Efficacy will be measured by overall response rate (ORR).
 


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The secondary objectives are to evaluate the duration of response, time to progression 
(TTP), progression free survival (PFS) and overall survival (OS).
Additional exploratory objectives will be evaluated.  Time to next anti-CLL treatment 
(TNT) and minimal residual disease (MRD) will be assessed in the peripheral blood and 
bone marrow (BM) by flow cytometry and PCR.  Health Economic and Patient-Reported 
Outcome Measures will include the EORTC QLQ-C30 and EORTC QLQ CLL16 
(a measure of health-related quality of life specific to CLL) and the EQ 5D 5L (measure 
of general health status) including EQ-5D-VAS.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is an open-label, non-randomized, two arm, multicenter study to determine the 
efficacy and safety of venetoclax (GDC-0199) monotherapy in subjects with Chronic 
Lymphocytic Leukemia (CLL) relapsed/refractory to treatment with B-cell Receptor 
Signaling Pathway Inhibitors (specifically Ibrutinib and Idelalisib) sponsored by AbbVie 
in collaboration with Genentech/Roche.
This study is designed to enroll approximately 120 subjects who have CLL that is 
refractory to treatment with ibrutinib and/or idelalisib, has relapsed on treatment or 
experienced progression after discontinuation of either one of these agents.
Two arms and an expansion cohort will be implemented to enroll as follows:  
●
Arm A with approximately 40 subjects that have ibrutinib-resistant with 
relapsed or refractory CLL.
●
Arm B with approximately 20 subjects that have idelalisib-resistant with 
relapsed or refractory CLL.
●
Expansion Cohort with approximately 60 subjects that have either 
ibrutinib-resistant or idelalisib-resistant with relapsed or refractory CLL.  
Subjects who have received both agents and any additional interim therapy 
 


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will be enrolled into the corresponding arm based on their most recent 
treatment.
Subjects in this study will be enrolled at approximately 15 research sites.
The study was designed to enroll approximately 120 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.
Dosing Schedule Overview (All Subjects)
Venetoclax will be administered orally once daily (QD), continuously.  Each dose of 
venetoclax should be taken with approximately 240 mL of water within 30 minutes after 
the completion of breakfast or the subject's first meal of the day.  To mitigate the risk for 
TLS, a lead-in period of 5 weeks will be employed with step wise dose increments.  For 
tumor lysis syndrome prophylaxis, all subjects will be classified into 3 risk categories 
based on the risk for developing TLS prior to venetoclax administration.
Subjects in low risk category and medium risk category with CrCl ≥80 ml/min and low 
tumor burden will begin the lead-in period in the outpatient setting with an initial dose of 
20 mg venetoclax on Week 1 Day 1.  If no significant findings suggestive of clinical or 
lab TLS occur within 24 hours, the same dose will be continued until Day 7 in the 
outpatient setting.  Subjects with no laboratory abnormalities suggestive of LTLS will 
escalate to a dose of 50 mg venetoclax on Week 2 Day 1 in the outpatient setting.
Medium risk subjects with CrCl < 80 mL/min and/or higher tumor burden (i.e., ALC 
> 100 × 109/L or multiple bulky nodes) may be admitted to the hospital at the investigator 
discretion to begin the lead-in period with an initial dose of 20 mg venetoclax on Week 1 
Day 1.  If no significant findings suggestive of clinical or lab TLS occur within 24 hours, 
the same dose will be continued until Day 7 in the outpatient setting.  Subjects with no 
laboratory abnormalities suggestive of LTLS will escalate to a dose of 50 mg venetoclax
on Week 2 Day 1 in the outpatient setting.  Subjects may be hospitalized prior to the 
 


Venetoclax (ABT-199-GDC-0199)
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32
first dose of 50 mg if they continue to have Cr Cl < 80 mL/min and/or higher tumor 
burden (i.e., ALC > 100 × 109/L or multiple bulky nodes) at the investigator's discretion.
All high risk subjects will be admitted to the hospital and begin the lead-in period with an 
initial dose of 20 mg venetoclax on Week 1 Day 1.  If no significant findings suggestive 
of clinical or lab TLS occur within 24 hours, the same dose will be continued until Day 7 
in the outpatient setting.  Subjects will be hospitalized prior to the first dose increment to 
50 mg beginning on W2D1.  Each subject's risk status may be reassessed prior to 
subsequent dose escalations per the guidelines in Section 6.1.7.1, Prophylaxis and 
Management of Tumor Lysis Syndrome.
If no significant findings occur within 24 hours at dose escalation, the study drug will be 
continued at the same dose from Days 2 through 7 in the outpatient setting.  If there is 
indication of lab or clinical TLS, the study drug dose will be held until resolution of all 
findings.  TLS management will be implemented as appropriate.  If aggressive correction 
of electrolytes was performed, the next dose of venetoclax can only be given when 
electrolytes have been stable without any further treatment for at least 24 hours.
A lower starting dose to the lead-in regimen may be implemented for individual subject(s) 
at particularly high risk for TLS.  For these individual cases, a discussion must occur 
between the investigator and the AbbVie medical monitor.
Figure 1.
Lead-In Dosing Schematic
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Venetoclax (ABT-199-GDC-0199)
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Dosing Schedule Details
Lead-In Period (All Subjects)
Every subject will receive an initial dose of 20 mg on Week 1, Day 1 of the lead-in 
period.
If one or more electrolyte changes (from the 0 hour pre-dose value) suggestive of TLS 
occurs within 24 hours of the 20 mg dose, no additional venetoclax doses will be 
administered until resolution.  See Appendix D, Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome 
(TLS), for procedures to follow.  If aggressive correction of electrolytes was performed, 
the subsequent dose of venetoclax can only be given when electrolytes have been stable 
without any further treatment for at least 24 hour.  Upon resolution of laboratory
abnormalities, the subject will remain on the 20 mg dose through Week 1 (e.g., Week 1 
Day 2 – Week 1 Day 7).
Subjects who had drug interruptions may escalate to 50 mg after they have been on a 
20 mg dose for 7 days.
After a week at 50 mg, weekly dose increments will be implemented as follows:  
100 mg →200 mg →400 mg (or additional lead-in steps to designated 400 mg dose) as 
tolerated.
Figure 2.
Expansion Cohort: Modified Dose Ramp-Up for Select High Risk 
Subjects Only
 
  
  
  
 
  
  
 
 
  
  
 
  
 
 
 
 
 
  


Venetoclax (ABT-199-GDC-0199)
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Expansion Cohort:  Modified Dose Ramp-Up for Select High Risk Subjects Only 
For subjects in the Expansion Cohort, a modified lead in period may be implemented if a 
high risk subject has clinical signs of progression during the screening period, to allow 
dose escalation to 400 mg by Week 3 Day 1.  A discussion between the investigator and 
the AbbVie medical monitor must occur prior to approval of this modified lead-in period.  
These subjects will be admitted to the hospital and begin the lead-in period with an initial 
dose of 20 mg venetoclax on Week 1 Day 1.  If no significant findings suggestive of 
clinical or lab TLS occur within 24 hours, the dose will be increased to 50 mg on Week 1 
Day 2.  If no significant findings suggestive of clinical or lab TLS occur within 24 hours 
the same dose will be administered for two days prior to the next dose increment.  The 
dose of venetoclax will be further increased to 100 mg on Week 1 Day 4 and will be 
continued through Week 1 Day 7.  If there are no significant findings suggestive of 
clinical or lab TLS that occur within 24 hours at this dose level, then the venetoclax dose 
will be increased to 200 mg on Week 2 Day 1.  Subjects will remain in the hospital for at 
least 24 hours after reaching the 200 mg dose.  If no significant findings suggestive of 
clinical or lab TLS occur within 24 hours, then the subject will continue at the 200 mg 
dose through Week 2 Day 7.  Subjects will be hospitalized the night before venetoclax 
dose is to be increased to 400 mg on Week 3 Day 1 and remain in the hospital at least till 
the post dose 24 hours lab results are reviewed by the investigator and show no concerns 
for TLS related electrolyte changes. 
Subjects enrolled into the Expansion Cohort with bulky disease at study entry who are 
non-responders or subjects who show signs of clinical progression after completing the 
ramp up to 400 mg either by clinical disease Assessment or by CT/MRI scan between 
Week 6 to Week 12 may be permitted to escalate venetoclax to 600 mg dose.  A 
discussion between the investigator and the AbbVie medical monitor must occur prior to 
this dose escalation.
For all dose escalations, laboratory values for subject management must be reviewed in 
real time by the investigator and prior to the subject's next dose to ensure appropriate 
subject management.  Based upon the laboratory values, the subject may continue dosing, 
 


Venetoclax (ABT-199-GDC-0199)
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35
may need to hold dose until resolution, may require hospitalization for further monitoring 
or may need additional post-dose laboratory checks.  (See Appendix D, Recommendations 
for Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS], for procedures to follow.)
Refer to Section 6.1.7.1, Prophylaxis and Management of Tumor Lysis Syndrome, 
for additional details on TLS prophylaxis.
Option to Continue Venetoclax Treatment
Subjects may continue receiving study drug for up to 2 years following the date of the last 
subject enrolled provided they continue to tolerate the drug, have no evidence of disease 
progression, and do not meet any of the criteria for subject discontinuation. 
(Section 5.4.1).  
Extended Access
AbbVie will provide venetoclax for monotherapy use until 5 years from the date of the 
last subject enrolled, until disease progression, or until a subject chooses to receive 
commercial supply of VENCLEXTA.
For subjects continuing into the Extended Access period of the trial, venetoclax will be 
dispensed at the Final Visit that will occur prior to 31Dec2018. Extended Access visits 
will continue every 12 weeks (+/– 7 days) until disease progression or until a subject 
chooses to receive commercial supply of VENCLEXTA.  Extended Access visits will 
include study drug administration, collection of AEs/SAEs and concomitant medication 
information, hemoglobin, hematocrit, absolute neutrophil count, absolute lymphocyte 
count, platelet counts and white blood cell counts, disease progression, and dispensing 
and collection of subject diaries.  All other procedures for disease assessments will be 
performed as standard of care.
 


Venetoclax (ABT-199-GDC-0199)
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5.2
Selection of Study Population
Subjects must undergo screening procedures within 28 days prior to initial study drug 
administration including disease assessment with PET/CT and bone marrow aspirate.
Histologic transformation to high grade lymphoma needs to be excluded at screening with 
a positron emission tomography using 18F-fluorodeoxyglucose (FDG).  Subjects with 
(FDG) uptake on PET scan above maximum standardized uptake value (SUV max) of 
10 will be excluded, unless confirmed by biopsy of the suspicious area to rule out 
Richter's transformation and other malignancies.  Additionally, subjects who have 
CD38+, ZAP 70+, TP 53 mutated and unmutated IGHV CLL whose PET has SUV max 
between 7 – 9 with at least one of the following parameters:  B symptoms, nodal diameter 
> 5 cm, and/or unexplained lactate dehydrogenase (LDH) elevation will need biopsy of 
the suspicious site.  If the biopsy is not feasible due to an inaccessible lesion or if the 
subject has declined to undergo the biopsy, the subject will be excluded from the study.  
Subjects with histological and immunophenotypical confirmation of Richter's 
transformation with a high grade lymphoproliferative disease will be excluded from the 
study.24
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.
Subject must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any screening or study specific procedures.
2.
Subject must be ≥ 18 years of age.
3.
Subject must have diagnosis of CLL that meets published 2008 IWCLL NCI-WG 
criteria.
 


Venetoclax (ABT-199-GDC-0199)
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4.
Subject has relapsed/ refractory disease with an indication for treatment according 
to the 2008 IWCLL NCI-WG criteria.
5.
Subject who has refractory disease or developed recurrence after therapy with 
either Ibrutinib or Idelalisib and meets one of the following:
●
treatment failure with either of the above agents;
●
progression during treatment or after discontinuation of either of the above 
agents.
6.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance score 
of ≤ 2.
7.
Subject must have adequate bone marrow function at Screening as follows:
●
Absolute Neutrophil Count (ANC) ≥ 1000/μL;
○
An exception is for subjects with an ANC < 1000/μL at Screening; when 
bone marrow is heavily infiltrated with underlying disease (approximately 
80% or more), G-CSF may be administered at the discretion of the 
investigator, after Screening and prior to the first dose of venetoclax to 
achieve the ANC eligibility criteria (≥1000/μL).
●
Platelets ≥ 30,000/mm3 (without transfusion support, evidence of mucosal 
bleeding, known history of bleeding episode within 3 months of screening and 
history of bleeding disorder);
●
Hemoglobin ≥ 8.0 g/dL
○
For subjects with AIHA or ITP, hemoglobin of < 8 g/dL and platelet count 
of < 30,000/mm3 without corticosteroid therapy a discussion between the 
investigator and the AbbVie medical monitor must occur.
8.
Subject must have adequate coagulation profile, renal, and hepatic function, per 
laboratory reference range at Screening as follows:
●
aPTT and PT not to exceed 1.5 × the upper limit of normal (ULN).
●
AST and ALT ≤1.5 × the upper normal limit (ULN) of institution's normal 
range.
 


Venetoclax (ABT-199-GDC-0199)
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●
Bilirubin ≤ 1.5 × ULN.  Subjects with AIHA and Gilbert's syndrome may have 
a bilirubin > 1.5 × ULN, per discussion between the investigator and AbbVie 
medical monitor.
●
Creatinine clearance ≥ 50 mL/min using 24-hour measured GFR or estimated 
by modified Cockcroft-Gault equation.
Note:  For subjects that have BMI of > 30 kg/m2, 24-hour measured creatinine 
clearance is required.
CrCl (mL/min) = [(140-age in years) × (weight in kg) × (0.85 if patients is female)]
[72 × (serum creatinine in mg/dL)]
Or, if serum creatinine is µmol/L
CrCl (mL/min) = [(140-age in years) × (weight in kg) × (0.85 if patient is female)]
[0.815 × (serum creatinine in mmol/L)]
9.
For high risk subjects (as defined in Section 6.1.7.1) a pre-approval by the AbbVie 
medical monitor is required prior to enrollment.
10.
Female subjects of childbearing potential and non-sterile male subjects must 
practice at least one of the following methods of birth control with partner(s) 
beginning with initial study drug administration and continuing to 30 days after the 
last dose of study drug:
●
Total abstinence from sexual intercourse as the preferred lifestyle of the 
subject; periodic abstinence is not acceptable;
●
Intrauterine device (IUD);
●
Double-barrier method (contraceptive sponge, diaphragm or cervical cap with 
spermicidal jellies or cream AND a condom);
●
Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months 
prior to study drug administration;
●
Surgically sterile partner(s); acceptable sterility surgeries are:  vasectomy, 
bilateral tubal ligation 3 months prior to screening, bilateral oophorectomy or 
hysterectomy.
 


Venetoclax (ABT-199-GDC-0199)
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39
If hormonal contraceptives are used, the specific contraceptive must have been 
used for at least 3 months prior to study drug administration.  If the subject is 
currently using a hormonal contraceptive, she should also use a barrier method 
during this study from initial study drug administration to 30 days after the last 
dose of study drug.  Any contraception method must be continued for 30 days after 
the last dose of study drug.
11.
Females of childbearing potential (i.e., postmenopausal for at least 1 year with no 
alternative medical reason or surgically sterile) must have negative results for 
pregnancy test performed:
●
At Screening with a serum sample obtained within 14 days prior to the 
first study drug administration, and
●
Prior to dosing with urine sample obtained on Week 1 Day 1, if it has been 
> 7 days since obtaining the serum pregnancy test results.
12.
Male subjects must agree to refrain from sperm donation, from initial study drug 
administration until 90 days after the last dose of study drug.
Rationale for Inclusion Criteria
(1)  In accordance with Harmonized Good Clinical Practice (GCP)
(2 – 7)  To select the subject population
(8 – 9)  For the safety of the subjects
(10 – 12)  The impact of venetoclax on pregnancy is unknown
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Subject has previously received venetoclax.
 


Venetoclax (ABT-199-GDC-0199)
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40
2.
Subject has undergone an allogeneic stem cell transplant within the past 1 year.
3.
Subject has developed Richter's transformation confirmed by biopsy.
4.
Subject has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to 
screening), including autoimmune hemolytic anemia (AIHA) and idiopathic 
thrombocytopenic purpura (ITP) despite low dose corticosteroids.
5.
Subject has tested 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).
6.
Subject has chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring 
treatment.  Note:  Subjects with serologic evidence of prior vaccination to HBV 
(i.e., HBs Ag–, anti-HBs+ and anti-HBc–) and positive anti-HBc from IVIG may 
participate.
7.
Subject has received any of the following within 30 days prior to the first dose of 
study drug with the exception of a BCR PI; 
●
Any anti-cancer therapy including chemotherapy, immunotherapy or 
radiotherapy;
●
Investigational therapy, including targeted small molecule agents (with the 
exception of Ibrutinib and Idelalisib).
8.
Subject has received the following within 7 days prior to the first dose of study 
drug:
●
Steroid therapy with anti-neoplastic intent;
●
Strong and Moderate CYP3A inhibitors (see Appendix C for examples).
9.
Subject has consumed the following within 3 days prior to the first dose of study 
drug:
●
B-cell receptor pathway inhibitor (Ibrutinib or Idelalisib);
●
Grapefruit or grapefruit products;
●
Seville oranges (including marmalade containing Seville oranges);
 


Venetoclax (ABT-199-GDC-0199)
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41
●
Star fruit.
10.
Subject has known contraindication or allergy to both xanthine oxidase inhibitors 
and rasburicase.
11.
Subject has malabsorption syndrome or other condition that precludes enteral route 
of administration.
12.
Subject has a cardiovascular disability status of New York Heart Association Class 
≥ 2.  Class 2 is defined as cardiac disease in which patients are comfortable at rest 
but ordinary physical activity, results in fatigue, palpitations, dyspnea or angina 
pectoris.
13.
Subject has a significant history of cardiovascular, pulmonary, renal, hepatic, 
neurologic, psychiatric, endocrinologic, metabolic or immunologic disease that in 
the opinion of the investigator would adversely affect his/her participation in this 
study or interpretation of study results.  For subjects who have required an 
intervention for any above diseases within the past 6 months a discussion between 
the investigator and the AbbVie medical monitor must occur.
14.
Subject has unresolved toxicities from prior anti-cancer therapy, defined as any 
grade 2 or higher clinically significant non-hematologic toxicity (excluding 
alopecia).
15.
Subject exhibits evidence of other clinically significant uncontrolled condition(s) 
including, but not limited to:
●
Uncontrolled systemic infection (viral, bacterial, or fungal);
●
Febrile neutropenia.
16.
Subject has a history of active malignancy other than CLL within the past 2 years 
prior to study entry, 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;
 


Venetoclax (ABT-199-GDC-0199)
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42
●
Previous malignancy confined and surgically resected (or treated with other 
modalities) with curative intent.
17.
A female subject is pregnant or breast-feeding.
Rationale for Exclusion Criteria
(1 – 9)  To select the appropriate subject population
(10 – 16)  For the safety of the subjects
(17)  The impact of venetoclax on pregnancy is unknown
5.2.3
Prior and Concomitant Therapy
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 
beginning with the Screening visit 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 electronic case report form (eCRF).
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 study treatment with the exception of inhalational steroids 
for the treatment of asthma or COPD, topical steroids and replacement corticosteroid 
therapy for an inherited or acquired deficiency.
In addition, limited corticosteroid treatment (for no more than 14 days with rapid taper) is 
allowed while on study for subjects with clinically significant autoimmune cytopenias, 
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
43
e.g., autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP).  IVIG 
(intravenous immune globulin) is also allowable.  
For additional guidance regarding medications for management of neutropenia and 
management of lymphopenia, refer to Section 6.1.7.3.
The AbbVie medical monitor identified in Section 7.0 should be contacted if there are any 
questions regarding concomitant or prior therapy(ies).
General guidelines regarding excluded and cautionary medications are summarized in 
Table 1.
Table 1.
Excluded and Cautionary Medications/Food Items (See Appendix C 
for Examples of the Medications)
Excluded
Grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or 
starfruit
Excluded During Ramp-Up Phase and Cautionary Afterwards

Strong and Moderate CYP3A Inhibitors 
o
Exclude during ramp-up phase and consider alternative medications.  If subject requires 
use of these medications after the ramp-up phase, use with caution and reduce the 
venetoclax dose 2-fold for moderate inhibitors and 4-fold for strong inhibitors during 
co-administration.  After discontinuation of CYP3A inhibitor, wait for 3 days before 
venetoclax dose is increased back to the initial maintenance/target dose.

Strong and Moderate CYP3A inducers
o
Exclude during ramp-up phase and consider alternative medications.  If subject requires 
use of these medications after the ramp-up phase, use with caution and contact AbbVie 
medical monitor for guidance.
Cautionary

Warfarin

P-gp substrates

BCRP substrates

OATP1B1/1B3 substrates

P-gp inhibitors

BCRP inhibitors
 


Venetoclax (ABT-199-GDC-0199)
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44
Table 2.
Sample of Permitted Medications
Drug or Therapy
Comments
Colony stimulating factors 
e.g., G-CSF, GM-CSF
Permitted; per ASCO guidelines.32  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 can be found in Appendix C.  It is not possible to produce a 100% exhaustive 
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 medical monitor and discuss the investigator's use of 
these medications and the investigator's plans to medically monitor the study subject.
5.3
Efficacy and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
45
Table 3.
Study Activities for Arm A and Arm B
Activity
Scra
Within 
72 Hours 
Prior to
1st Dose
W1
D1
W1
D2
W1
D3
W2
D1
W2
D2
W3
D1
W3
D2
W4
D1
W4
D2
W5
D1
W5
D2
Informed Consent
X
Medical History/Oncology 
History Assessment
X
X
Adverse Event/Concomitant 
Medication Assessment
Xb
Xb
X
X
X
X
X
X
X
X
X
X
X
Physical Examinationc*
X
X
X
X
X
X
Vital Signs*
X
X
X
X
X
X
ECOG Performance Status*
X
X
Pregnancy Testd
X
X
Hematology/Chemistry
X
X
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Coagulation Panel**
X
Urinalysis**
X
Viral Serologies
X
Viral Polymerase Chain 
Reaction
X
12-Lead ECG
X
 


Venetoclax (ABT-199-GDC-0199)
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46
Table 3.
Study Activities for Arm A and Arm B (Continued)
Activity
W8
D1
W12
D1
W16
D1
W20
D1
W24
D1
W36
D1
Every 12 Weeks 
Starting After 
W36
After 1st CR, 
CRi, or PR
FV
30 Day Safety 
Visit
Post-
Treatf
Extended 
Access 
Periodp
Informed Consent
Medical History/ 
Oncology History 
Assessment
Adverse Event/ 
Concomitant Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
X
Physical Examinationc*
X
X
X
X
X
X
X
X
X
X
Vital Signs*
X
X
X
X
X
X
X
X
X
ECOG Performance 
Status*
X
X
X
X
Pregnancy Testd
Hematology/Chemistry**
X
X
X
X
X
X
X
X
X
X
Hematology (Extended 
Access period)q
X
Coagulation Panel**
X
X
X
X
Urinalysis**
X
X
Viral Serologies
Viral Polymerase Chain 
Reaction
12-Lead ECG
X
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
47
Table 3.
Study Activities for Arm A and Arm B (Continued)
Activity
Scra
Within 
72 Hours 
Prior to
1st Dose
W1
D1
W1
D2
W1
D3
W2
D1
W2
D2
W3
D1
W3
D2
W4
D1
W4
D2
W5
D1
W5
D2
Echocardiogram or a Multi 
Gated Acquisition Scan 
(MUGA)g
X
CT or MRI Scanh****
X
PET CT
X
Bone Marrow Aspirate and 
Biopsy
X
Disease Assessmentsi*
X
X
MRD Assessmentj
X
Survival Assessment
Dispense/Collect Venetoclax 
and Subject Calendars/Diaries
X
X
X
X
X
EORTC QLQ C30 and 
EORTC QLQ CLL16k
X
EQ-5D-5L and EQ-5D-VASk
X
 


Venetoclax (ABT-199-GDC-0199)
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48
Table 3.
Study Activities for Arm A and Arm B (Continued)
Activity
W8
D1
W12
D1
W16
D1
W20
D1
W24
D1
W36
D1
Every 12 Weeks 
Starting After 
W36
After 1st CR, 
CRi, or PR
FV
30 Day Safety 
Visit
Post-
Treatf
Extended 
Access 
Periodp
Echocardiogram or a 
Multi Gated 
Acquisition Scan 
(MUGA)g
CT or MRI Scanh****
X
Xl
Xl
X
Xm
Xr
Xl
PET CT
Bone Marrow Aspirate 
and Biopsy
Xn
Disease Assessmentsi*
X
X
X
X
X
X
X
X
X
X
MRD Assessmentj
X
X
Survival Assessment
Xo
X
Dispense/Collect 
Venetoclax and 
Subject 
Calendars/Diaries
X
X
X
X
X
X
X
X
EORTC QLQ C30 and 
EORTC QLQ CLL16k
X
X
X
X
EQ-5D-5L and 
EQ-5D-VASk
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;
**
within 72 hours prior to scheduled visit starting with Week 8 Day 1;
 


Venetoclax (ABT-199-GDC-0199)
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49
Table 3.
Study Activities for Arm A and Arm B (Continued)
*** within 72 hours prior to scheduled visit;
****
within 3 days of the scheduled visit.
a.
Subjects will undergo screening procedures within 28 days prior to the first study drug administration.
b.
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.
c.
A complete physical examination will be performed at Screening and the 30 Day Follow-Up Visit.  A symptom directed physical examination may be performed at every 
other visit.  Refer to Section 5.3.1.1 Physical Examination, for more details.
d.
Urine pregnancy test must be obtained at Week 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy results at Screening.
e.
There is no 72 hour window for these samples.  Refer to Section 6.1.7.1, Prophylaxis and Management of Tumor Lysis Syndrome and Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS).
f.
For subjects who discontinue venetoclax monotherapy but have not had an event of disease progression, post treatment follow-up visits will be performed every 3 months for 
a period of 3 years after the last subject has enrolled in the study until discontinuation from the study due to disease progression requiring alternative therapy or upon a 
subject's refusal of the Post-Treatment visits.
g.
Assessment of ejection fraction will be made at screening at the discretion of the investigator.  Subsequent evaluation of Left Ventricular Ejection Fraction (LVEF) will be 
made as clinically indicated for subjects who develop signs of cardiac compromise.
h.
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 PD criteria), a CT/MRI scan may be performed within 2 weeks to confirm or rule out PD as described in Section 5.3.3.2.
i.
All measurable disease must be documented at screening by laboratory testing, physical examination, CT scans (or MRI if CT is medically contraindicated), and bone marrow 
examinations. For all subsequent disease assessments, only PE and laboratory testing is required unless confirmation of CR is required. If confirmation of CR is required a 
CT/MRI and Bone Marrow will also be completed.
j.
Screening sample will assess individual disease characteristics and the Week 24 sample will measure disease burden.  MRD will be assessed in peripheral blood and bone 
marrow for subjects achieving CR/CRi at the 8 week confirmatory visit.  After Week 24, for subjects that achieve a radiographic PR, MRD will be assessed in peripheral 
blood. MRD for these subjects (radiographic PR/CR/CRi) will continue to be assessed in the peripheral blood at 12 weeks interval visits until 2 consecutive negative MRD 
levels are reported.  A final MRD status will be assessed in bone marrow aspirate once MRD negativity is achieved in two consecutive peripheral blood samples.
k.
The Health Economic and Patient Reported Outcomes questionnaires should be administered and completed prior to any other study procedures being performed at these
visits.  Refer to Section 5.3.8, Health Economic and Patient-Reported Outcome Measures, for further information.  Subjects will be asked to complete a questionnaire 
assessing the information they were provided for the Patient Information Card and the Tumor Lysis Syndrome Patient Information Brochure, at the Week 2 Day 1 visit.
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
50
Table 3.
Study Activities for Arm A and Arm B (Continued)
l.
The Week 24 scan may be performed within 2 weeks before or after the Week 24 scheduled visit provided that it has been at least 8 weeks since the subject's last scan.  
CT/MRI scans should be performed at Week 24 and every 12 weeks thereafter for a period of 1 year from enrollment.  Post-treatment CT or MRI scans are collected only if 
they are performed by the PI's discretion or as part of standard of care.  MRI should be performed if CT with contrast is contraindicated (refer to Section 5.3.1.1).
m.
A CT/MRI scan will be performed after a response of CR/CRi is determined by clinical criteria (PE/labs) for confirmation.  For confirmation of CR, both the CT and/or MRI 
scan and bone marrow are required to be negative.  It is recommended that the CT scan is performed first, and if this does not confirm a CR, then a BM biopsy should not be 
obtained.
n.
For subjects who meet all criteria for CR/CRi (with the exception of a node(s) that is enlarged around 1.5 – 2 cm) may also have a bone marrow performed.  If bone marrow 
was performed to confirm a CR or for any clinical indication close to Week 24, then it should be performed within a week of the Week 24 Day 1 CT/MRI scans.  Subjects 
who have MRD negativity confirmed in peripheral blood on 2 consecutive peripheral blood samples need to have a confirmation by bone marrow.
o.
Survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 3 months for a period of 5 years after the last subject has 
enrolled into the study.
p.
For subjects continuing into the Extended Access period of the trial, visits will include study drug administration, AEs/SAEs and concomitant medication information, 
hemoglobin, hematocrit, absolute neutrophil count, absolute lymphocyte count, platelet counts and white blood cell counts, disease progression and dispensing and collection 
of subject diaries.  All other procedures for disease assessments will be performed as standard of care.
q.
Hematology will include hemoglobin, hematocrit, absolute neutrophil count, absolute lymphocyte count, platelet counts and white blood counts for subjects continuing into 
the Extended Access period of the trial.
r.
CT scan not needed for subjects continuing into the Extended Access period of the trial.
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
51
Table 4.
Study Activities for Expansion Cohort Standard Lead-In
Activity
Scra
Within 72 Hours 
Prior to 1st Dose
W1
D1
W1
D2
W1
D3
W2
D1
W2
D2
W3
D1
W3
D2
W4
D1
W4
D2
W5
D1
W5
D2
Informed Consent
X
Medical History/Oncology History 
Assessment
X
X
Adverse Event/Concomitant 
Medication Assessment
Xb
Xb
X
X
X
X
X
X
X
X
X
X
X
Physical Examinationc*
X
X
X
X
X
X
Vital Signs*
X
X
X
X
X
X
ECOG Performance Status*
X
X
Pregnancy Testd
X
X
Hematology/Chemistry**
X
X
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Coagulation Panel**
X
Urinalysis**
X
Viral Serologies
X
Viral Polymerase Chain Reaction
X
12-Lead ECG
X
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
52
Table 4.
Study Activities for Expansion Cohort Standard Lead-In (Continued)
Activity
W8
D1
W12
D1
W16
D1
W24
D1
W36
D1
Every 12 Weeks 
Starting After 
W36
After 1st
CR, CRi, or 
PR
FV
30 Day 
Safety Visit
Post-Treatf
Extended 
Access 
Periodo
Informed Consent
Medical History/Oncology History Assessment
Adverse Event/Concomitant Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
X
Physical Examinationc*
X
X
X
X
X
X
X
X
X
X
Vital Signs*
X
X
X
X
X
X
X
X
X
ECOG Performance Status*
X
X
X
X
X
Pregnancy Teste
Hematology/Chemistry
X
X
X
X
X
X
X
X
X
X
Hematology (Extended Access period)q
X
Coagulation Panel**
X
X
X
X
Urinalysis**
X
X
Viral Serologies
Viral Polymerase Chain Reaction
12-Lead ECG
X
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
53
Table 4.
Study Activities for Expansion Cohort Standard Lead-In (Continued)
Activity
Scra
Within 72 Hours 
Prior to 1st Dose
W1
D1
W1
D2
W1
D3
W2
D1
W2
D2
W3
D1
W3
D2
W4
D1
W4
D2
W5
D1
W5
D2
Echocardiogram or a Multi Gated 
Acquisition Scan (MUGA)g
X
CT or MRI Scanh****
X
PET CT
X
Bone Marrow Aspirate and Biopsy
X
Disease Assessmentsi*
X
X
MRD Assessmentj
X
Survival Assessment
Dispense/Collect Venetoclax and Subject 
Calendars/Diaries
X
X
X
X
X
EORTC QLQ C30k
X
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
54
Table 4.
Study Activities for Expansion Cohort Standard Lead-In (Continued)
Activity
W8
D1
W12
D1
W16
D1
W24
D1
W36
D1
Every 12 Wks 
Starting After 
W36
After 1st CR, 
CRi, or PR
FV
30 Day 
Safety Visit Post-Treatf
Extended 
Access 
Periodo
Echocardiogram or a Multi Gated Acquisition Scan 
(MUGA)g
CT or MRI Scanh****
X
Xl
Xl
Xq
PET CT
Bone Marrow Aspirate and Biopsy
Xm
Disease Assessmentsi*
X
X
X
X
X
X
X
X
X
MRD Assessmentj
X
X
X
Survival Assessment
Xn
X
Dispense/Collect Venetoclax and Subject 
Calendars/Diaries
X
X
X
X
X
X
X
EORTC QLQ C30k
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;
**
Within 72 hours prior to scheduled visit starting with Week 8 Day 1;
***
Within 72 hours prior to scheduled visit;
****
Within 3 days of the scheduled visit.
a.
Subjects will undergo screening procedures within 28 days prior to the first study drug administration.
b.
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.
c.
A complete physical examination will be performed at Screening and the 30 Day Follow-Up Visit.  A symptom directed physical examination may be performed at every 
other visit.  Refer to Section 5.3.1.1 Physical Examination, for more details.
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
55
Table 4.
Study Activities for Expansion Cohort Standard Lead-In (Continued)
d.
Urine pregnancy test must be obtained at Week 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy results at Screening.
e.
There is no 72 hour window for these samples.  Refer to Section 6.1.7.1, Prophylaxis and Management of Tumor Lysis Syndrome and Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS).
f.
For subjects who discontinue venetoclax monotherapy but have not had an event of disease progression, post treatment follow-up visits will be performed every 3 months for 
a period of 3 years after the last subject has enrolled in the study until discontinuation from the study due to disease progression requiring alternative therapy or upon a 
subject's refusal of the Post-Treatment visits.  
g.
Assessment of ejection fraction will be made at screening at the discretion of the investigator.  Subsequent evaluation of Left Ventricular Ejection Fraction (LVEF) will be 
made as clinically indicated for subjects who develop signs of cardiac compromise.
h.
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 PD criteria), a CT/MRI scan may be performed within 2 weeks to confirm or rule out PD as described in Section 5.3.3.2.
i.
All measurable disease must be documented at screening by laboratory testing, physical examination,  CT scans (or MRI if CT is medically contraindicated), and bone 
marrow examinations. For all subsequent disease assessments, only PE and laboratory testing is required unless confirmation of CR is required. If confirmation of CR is 
required a CT/MRI and Bone Marrow will also be completed.
j.
Screening sample will assess individual disease characteristics and the Week 24 sample will measure disease burden.  MRD will be assessed in peripheral blood and bone 
marrow for subjects achieving CR/CRi at the 8 week confirmatory visit. After Week 24, for subjects that achieve a radiographic PR, MRD will be assessed in peripheral 
blood. MRD for these subjects (radiographic PR/CR/CRi) will continue to be assessed in the peripheral blood at 12 weeks interval visits until 2 consecutive negative MRD 
levels are reported.  A final MRD status will be assessed in bone marrow aspirate once MRD negativity is achieved in two consecutive peripheral blood samples.
k.
The Health Economic and Patient Reported Outcomes questionnaires should be administered and completed prior to any other study procedures being performed at these 
visits.  Refer to Section 5.3.8, Health Economic and Patient-Reported Outcome Measures, for further information.  Subjects will be asked to complete a questionnaire 
assessing the information they were provided for the Patient Information Card and the Tumor Lysis Syndrome Patient Information Brochure, at the Week 2 Day 1 visit.
l.
A CT/MRI scan will be performed after a response of CR/CRi is determined by clinical criteria (PE/labs) for confirmation.  For confirmation of CR, both the CT and/or MRI 
scan and bone marrow are required to be negative.  It is recommended that the CT scan is performed first, and if this does not confirm a CR, then a BM biopsy should not be 
obtained.
m.
For subjects who meet all criteria for CR/CRi (with the exception of a node(s) that is enlarged around 1.5 – 2 cm) may also have a bone marrow performed.  If bone marrow 
was performed to confirm a CR or for any clinical indication close to Week 24, then it should be performed within a week of the Week 24 Day 1 CT/MRI scans.  Subjects 
who have MRD negativity confirmed in peripheral blood on 2 consecutive peripheral blood samples need to have a confirmation by bone marrow.
n.
Survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 3 months for a period of 5 years after the last subject has 
enrolled into the study.
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
56
Table 4.
Study Activities for Expansion Cohort Standard Lead-In (Continued)
o.
For subjects continuing into the Extended Access period of the trial, visits will include study drug administration, AEs/SAEs and concomitant medication information, 
hemoglobin, hematocrit, absolute neutrophil count, absolute lymphocyte count, platelet counts and white blood cell counts, disease progression and dispensing and collection 
of subject diaries.  All other procedures for disease assessments will be performed as standard of care.
p.
Hematology will include hemoglobin, hematocrit, absolute neutrophil count, absolute lymphocyte count, platelet counts and white blood cell counts for subjects continuing 
into the Extended Access period of the trial.
q.
CT scan not needed for subjects continuing into the Extended Access period of the trial.
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
57
Table 5.
Study Activities for Expansion Cohort Modified Lead-In
Activity
Scra
Within 72 Hours 
Prior to 1st Dose
W1
D1
W1
D2
W1
D3
W2
D1
W2
D2
W2
D3
W2
D4
W3
D1
W3
D2
W3
D3
W3
D4
Informed Consent
X
Medical History/Oncology History 
Assessment
X
X
Adverse Event/Concomitant 
Medication Assessment
Xb
Xb
X
X
X
X
X
X
X
X
X
X
X
Physical Examinationc*
X
X
X
X
Vital Signs*
X
X
X
X
ECOG Performance Status*
X
X
Pregnancy Testd
X
X
Hematology/Chemistry**
X
X
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Coagulation Panel**
X
Urinalysis**
X
Viral Serologies
X
Viral Polymerase Chain Reaction
X
12-Lead ECG
X
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
58
Table 5.
Study Activities for Expansion Cohort Modified Lead-In (Continued)
Activity
W8
D1
W12
D1
W16
D1
W24
D1
W36
D1
Every 12 Weeks 
Starting After 
W36
After 1st
CR, CRi, or 
PR
FV
30 Day 
Safety Visit
Post-Treatf
Extended 
Access 
Periodo
Informed Consent
Medical History/Oncology History Assessment
Adverse Event/Concomitant Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
X
Physical Examinationc*
X
X
X
X
X
X
X
X
X
X
Vital Signs*
X
X
X
X
X
X
X
X
X
ECOG Performance Status*
X
X
X
X
X
Pregnancy Teste
Hematology/Chemistry
X
X
X
X
X
X
X
X
X
X
Hematology (Extended Access period)p
X
Coagulation Panel**
X
X
X
X
Urinalysis**
X
X
Viral Serologies
Viral Polymerase Chain Reaction
12-Lead ECG
X
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
59
Table 5.
Study Activities for Expansion Cohort Modified Lead-In (Continued)
Activity
Scra
Within 72 Hours 
Prior to 1st Dose
W1
D1
W1
D2
W1
D3
W2
D1
W2
D2
W2
D3
W2
D4
W3
D1
W3
D2
W3
D3
W3
D4
Echocardiogram or a Multi Gated 
Acquisition Scan (MUGA)g
X
CT or MRI Scanh****
X
PET CT
X
Bone Marrow Aspirate and Biopsy
X
Disease Assessmentsi*
X
MRD Assessmentj
X
Survival Assessment
Dispense/Collect Venetoclax and Subject 
Calendars/Diaries
X
X
X
EORTC QLQ C30k
X
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
60
Table 5.
Study Activities for Expansion Cohort Modified Lead-In (Continued)
Activity
W8
D1
W12
D1
W16
D1
W24
D1
W36
D1
Every 12 Wks 
Starting After 
W36
After 1st CR, 
CRi, or PR
FV
30 Day 
Safety Visit Post-Treatf
Extended 
Access 
Periodo
Echocardiogram or a Multi Gated Acquisition Scan 
(MUGA)g
CT or MRI Scanh****
X
Xl
Xl
Xq
PET CT
Bone Marrow Aspirate and Biopsy
Xm
Disease Assessmentsi*
X
X
X
X
X
X
X
X
X
MRD Assessmentj
X
X
X
Survival Assessment
Xn
X
Dispense/Collect Venetoclax and Subject 
Calendars/Diaries
X
X
X
X
X
X
X
EORTC QLQ C30k
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;
**
Within 72 hours prior to scheduled visit starting with Week 8 Day 1;
***
Within 72 hours prior to scheduled visit;
****
Within 3 days of the scheduled visit.
a.
Subjects will undergo screening procedures within 28 days prior to the first study drug administration.
b.
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.
c.
A complete physical examination will be performed at Screening and the 30 Day Follow-Up Visit.  A symptom directed physical examination may be performed at every 
other visit.  Refer to Section 5.3.1.1 Physical Examination, for more details.
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
61
Table 5.
Study Activities for Expansion Cohort Modified Lead-In (Continued)
d.
Urine pregnancy test must be obtained at Week 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy results at Screening.
e.
There is no 72 hour window for these samples.  Refer to Section 6.1.7.1, Prophylaxis and Management of Tumor Lysis Syndrome and Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS).
f.
For subjects who discontinue venetoclax monotherapy but have not had an event of disease progression, post treatment follow-up visits will be performed every 3 months for 
a period of 3 years after the last subject has enrolled in the study until discontinuation from the study due to disease progression requiring alternative therapy or upon a 
subject's refusal of the Post-Treatment visits.  
g.
Assessment of ejection fraction will be made at screening at the discretion of the investigator.  Subsequent evaluation of Left Ventricular Ejection Fraction (LVEF) will be 
made as clinically indicated for subjects who develop signs of cardiac compromise.
h.
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 PD criteria), a CT/MRI scan may be performed within 2 weeks to confirm or rule out PD as described in Section 5.3.3.2.
i.
All measurable disease must be documented at screening by laboratory testing, physical examination, CT scans (or MRI if CT is medically contraindicated), and bone marrow 
examinations. For all subsequent disease assessments, only PE and laboratory testing is required unless confirmation of CR is required.  If confirmation of CR is required a 
CT/MRI and Bone Marrow will also be completed.
j.
Screening sample will assess individual disease characteristics and the Week 24 sample will measure disease burden.  MRD will be assessed in peripheral blood and bone 
marrow for subjects achieving CR/CRi at the 8 week confirmatory visit.  After Week 24, for subjects that achieve a radiographic PR, MRD will be assessed in peripheral 
blood. MRD for these subjects (radiographic PR/CR/CRi) will continue to be assessed in the peripheral blood at 12 weeks interval visits until 2 consecutive negative MRD 
levels are reported.  A final MRD status will be assessed in bone marrow aspirate once MRD negativity is achieved in two consecutive peripheral blood samples.
k.
The Health Economic and Patient Reported Outcomes questionnaires should be administered and completed prior to any other study procedures being performed at these 
visits.  Refer to Section 5.3.8, Health Economic and Patient-Reported Outcome Measures, for further information.  Subjects will be asked to complete a questionnaire 
assessing the information they were provided for the Patient Information Card and the Tumor Lysis Syndrome Patient Information Brochure, at the Week 2 Day 1 visit.
l.
A CT/MRI scan will be performed after a response of CR/CRi is determined by clinical criteria (PE/labs) for confirmation.  For confirmation of CR, both the CT and/or MRI 
scan and bone marrow are required to be negative.  It is recommended that the CT scan is performed first, and if this does not confirm a CR, then a BM biopsy should not be 
obtained.
m.
For subjects who meet all criteria for CR/CRi (with the exception of a node(s) that is enlarged around 1.5 – 2 cm) may also have a bone marrow performed.  If bone marrow 
was performed to confirm a CR or for any clinical indication close to Week 24, then it should be performed within a week of the Week 24 Day 1 CT/MRI scans.  Subjects 
who have MRD negativity confirmed in peripheral blood on 2 consecutive peripheral blood samples need to have a confirmation by bone marrow.
n.
Survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 3 months for a period of 5 years after the last subject has 
enrolled into the study.
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
62
Table 5.
Study Activities for Expansion Cohort Modified Lead-In (Continued)
o.
For subjects continuing into the Extended Access period of the trial, visits will include study drug administration, AEs/SAEs and concomitant medication information, 
hemoglobin, hematocrit, absolute neutrophil count, absolute lymphocyte count, platelet counts and white blood cell counts, disease progression and dispensing and collection 
of subject diaries.  All other procedures for disease assessments will be performed as standard of care.
p.
Hematology will include hemoglobin, hematocrit, absolute neutrophil count, absolute lymphocyte count, platelet counts and white blood cell counts for subjects continuing 
into the Extended Access period of the trial.
q.
CT scan not needed for subjects continuing into the Extended Access period of the trial.
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
63
Table 6.
Schedule of PK Blood Collection for Venetoclax (and Possible Metabolite[s]) for All Subjects
Study Visit
Week 1 Day 1
Weeks 2, 3, 4 and 5 Day 1
Weeks 8, 12, 16, 24, Day 1
Collection Times
8 hours post dose
8 hours post dose once started at a new dose level
0 hours (pre-dose)
Notes:
The PK collection performed 8 hours post-dose after each increment to a new level of venetoclax may be taken up to 1 hour prior or up to 20 minutes after to allow for 
processing, if necessary.
The date and time (to the nearest minute) of each study drug dose taken and whether or not the dose was taken within 30 minutes after completing breakfast (or the 
subject's first meal of the day) will be recorded on the eCRF for each scheduled venetoclax PK day and for the 2 days prior to every scheduled venetoclax PK day.
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
64
Table 7.
Schedule of Biomarker and Pharmacogenetic Sample Collection for Arm A and Arm B
Sample Collections
Screening
Week 1
Day 1
Week 1
Day 2
Week 2
Day 1
Week 4 
Day 1
Week 24
Day 1
After 1st
CR or CRi
Final Visit 
or Time of 
Relapsek
Comments
Pharmacogenetics 
(Optional)
Xa,f
4 mL Blood
Serum Markers
Xa
Xb
Xb
X
3.5 mL Blood
Blood for CD19 Cell 
Isolation Bcl-2 Family 
Analysis
Xa
X
8 mL Blood
Blood for CLL FISH
Xa
4mL Blood
Blood for Mutation and 
Expression Profiling
X
X
20 mL Blood
Blood for Plasma 
Markers
X
X
X
4 mL Blood
Bone Marrow Aspirate 
for Bcl-2 Protein 
Analysisc
Xa
X
1 mL Bone 
Marrow Aspirate
Bone Marrow Aspirate 
for CD19 Isolationc
Xa
X
4 mL Bone 
Marrow Aspirate
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
65
Table 7.
Schedule of Biomarker and Pharmacogenetic Sample Collection for Arm A and Arm B (Continued)
Sample Collections
Screening
Week 1
Day 1
Week 1
Day 2
Week 2
Day 1
Week 4 
Day 1
Week 24
Day 1
After 1st
CR or CRi
Final Visit 
or Time of 
Relapsek
Comments
Tissue for IHC/FISHc,e
Xa,d,e,g
Xe,g
FFPE Tissue
Peripheral Blood and 
Bone Marrow Aspirate 
for Disease Assessment 
by PCR
Xh
Xh
Xi,j
3 mL Bone 
Marrow Aspirate 
and/or 10 mL 
Blood
Non-tumor DNA Control
Xf
Buccal Swab
a.
Perform once at either Screening or prior to dosing on Week 1 Day 1.
b.
Obtain sample prior to dosing.
c.
Biopsy and aspirate (8 mL) samples should be split from samples obtained for 2008 Modified IWCLL NCI-WG Criteria for Tumor Response assessment whenever possible.  
If additional bone marrow aspirates or biopsies are collected by the site per standard of care, a sample should be provided for this study.  Subjects should not be subjected to 
additional bone marrow sampling only for this purpose.
d.
Archive sample may be used at Screening if obtained within 28 days of starting study drug without intervening treatment and representative of subject's current disease state.
e.
Lymph node collections will be performed for all subjects with Richter's transformation.  Samples should be sent to AbbVie.
f.
If the sample is not collected at either of these visits, the sample can be collected at any visit during the study.
g.
This collection is optional for all Screening and optional at Final Visit or Time of Relapse for subjects that discontinue for reasons other than Richter's transformation.
h.
Only peripheral blood is required for the Screening and Week 24 samples.
i.
Both peripheral blood and bone marrow aspirates should be collected after 1st CR/CRi.  Bone marrow aspirate should be the first sample drawn.
j.
Baseline sample will assess individual disease characteristics and the Week 24 sample will measure disease burden.  MRD will be assessed in peripheral blood and bone 
marrow for subjects achieving CR/CRi at the 8 week confirmatory visit.  After Week 24, for subjects that achieve a radiographic PR, MRD will be assessed in peripheral 
blood. MRD for these subjects (radiographic PR/CR/CRi) will continue to be assessed in the peripheral blood at 12 weeks interval visits until 2 consecutive negative MRD 
levels are reported.  A final MRD status will be assessed in bone marrow aspirate once MRD negativity is achieved in two consecutive peripheral blood samples.
k.
No final visit biomarker specimens are required for subjects continuing in the extended assess period of the trial.
 


Venetoclax (ABT-199-GDC-0199)
M14-032 Protocol Amendment 6
66
Table 8.
Schedule of Biomarker and Pharmacogenetic Sample Collection for Expansion Cohort
Sample Collections
Screening
Week 1
Day 1
Week 1
Day 2
Week 2
Day 1
Week 4 
Day 1
Week 24
Day 1
Week 36
Day 1
After 1st CR 
or CRi
Final Visit 
or Time of 
Relapsek
Comments
Pharmacogenetics (Optional)
Xa,b
4 mL Blood
Serum Markers
Xa
Xc
Xc
X
3.5 mL Blood
Blood for CD19 Cell Isolation 
Bcl-2 Family Analysis
Xa
X
8 mL Blood
Blood for CLL FISH
Xa
4mL Blood
Blood for Mutation and 
Expression Profiling
X
X
20 mL Blood
Blood for Plasma Markers
X
X
X
4 mL Blood
Bone Marrow Aspirate for Bcl-2 
Protein Analysisd
Xa
X
1 mL Bone Marrow 
Aspirate
Bone Marrow Aspirate for CD19 
Isolationd
Xa
X
4 mL Bone Marrow 
Aspirate
Tissue for IHC/FISHc,e
Xa,e,f,g
Xe,g
FFPE Tissue
Peripheral Blood and Bone 
Marrow Aspirate for Disease 
Assessment by PCR
Xh
Xh
Xh
Xi,j
3 mL Bone Marrow 
Aspirate and/or 10 mL 
Blood
Non-tumor DNA Control
Xb
Buccal Swab
a.
Perform once at either Screening or prior to dosing on Week 1 Day 1.
b.
If the sample is not collected at either of these visits, the sample can be collected at any visit during the study.
c.
Obtain sample prior to dosing.
 


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Table 8.
Schedule of Biomarker and Pharmacogenetic Sample Collection for Expansion Cohort (Continued)
d.
Biopsy and aspirate (8 mL) samples should be split from samples obtained for 2008 Modified IWCLL NCI-WG Criteria for Tumor Response assessment whenever possible.  
If additional bone marrow aspirates or biopsies are collected by the site per standard of care, a sample should be provided for this study.  Subjects should not be subjected to 
additional bone marrow sampling only for this purpose.
e.
Lymph node collections will be performed for all subjects with Richter's transformation.  Samples should be sent to AbbVie.
f.
Archive sample may be used at Screening if obtained within 28 days of starting study drug without intervening treatment and representative of subject's current disease state.
g.
This collection is optional for all Screening and optional at Final Visit or Time of Relapse for subjects that discontinue for reasons other than Richter's transformation.
h.
Only peripheral blood is required for the Screening, Week 24 and Week 36 samples.
i.
Both peripheral blood and bone marrow aspirates should be collected after 1st CR/CRi.  Bone marrow aspirate should be the first sample drawn.
j.
Baseline sample will assess individual disease characteristics and the Week 24 and Week 36 samples will measure disease burden.  MRD will be assessed in peripheral blood 
and bone marrow for subjects achieving CR/CRi at the 8 week confirmatory visit.  After Week 36, for subjects that achieve a radiographic PR, MRD will be assessed in 
peripheral blood.  MRD for these subjects (radiographic PR/CR/CRi) will continue to be assessed in the peripheral blood at 12 weeks interval visits until 2 consecutive 
negative MRD levels are reported.  A final MRD status will be assessed in bone marrow aspirate once MRD negativity is achieved in two consecutive peripheral blood 
samples.
k.
No final visit biomarker specimens are required for subjects continuing in the extended assess period of the trial.
 


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5.3.1.1
Study Procedures
All study procedures outlined in Table 4 and Table 6 are discussed in detail in this section, 
with the exception of adverse event information (discussed in Section 6.0).  All study data 
will be recorded on eCRFs with the exception of the pregnancy reporting forms, which 
will be recorded on paper CRFs.
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.  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 Medical 
Monitor 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.  All of the data from 
the screening procedures will be collected into the EDC regardless of subjects' enrollment 
into the study.
Refer to Appendix G for COVID-19-related processes for this section.
Informed Consent
Signed informed consent will be obtained from the subject or the subject's legally 
acceptable representative before any study-specific procedures are undertaken or before 
any prohibited medications are withheld from the subject in order to participate in this 
study.  Informed consent is also required for pharmacogenetic (PG) sampling and a 
portion of the pharmacodynamic (PD) sample collections.  Details about how informed 
consent will be obtained and documented are provided in Section 9.3.
 


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Medical History
The following will be collected during the Screening Visit:
●
Complete medical history, including documentation of any clinically 
significant medical condition
●
History of tobacco and alcohol use
Detailed Oncology History:
The following will be collected during the Screening Visit:
●
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)
●
Detailed prior and concomitant medication usage including dates of usage and 
dosing information for all medications and supplements taken
On Week 1 Day 1, any changes observed from the Screening assessments (prior to 
dosing) will be recorded in the subject's medical history.
Adverse Event and Concomitant Medication Assessment
Medication (prescription or over-the-counter, including vitamins and herbal supplements) 
will be recorded beginning with the Screening Visit through the end of the study.
At each visit, including the Final Visit and the 30-Day Safety Follow-Up Visit, the 
subject's medical history will be reviewed and any changes from baseline will be recorded 
on the adverse event eCRF.
 


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Physical Examination
A complete physical examination, including height, will be performed at Screening and 
at the 30-Day Follow-Up Visit.  The complete PE should include an evaluation of head, 
eyes, ears, nose, and throat (HEENT); cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems.
Clinically significant changes from baseline that are unrelated to disease will be 
documented in the source documentation and eCRFs as Adverse Events.
A symptom directed physical examination may be performed at all other visits (other 
than Screening and 30 Day Follow-Up visit) and should be limited to systems of primary 
relevance-that is, cardiovascular, respiratory and/or those associated with symptoms.
Physical Examination (Disease Assessment)
All Physical Examinations (complete or symptom-directed) should also 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.  Refer to Section 5.3.3.1 for additional information pertaining to methods of 
measurement.
If during physical examination, signs or symptoms suggestive of Richter's Syndrome are 
observed, further assessments (i.e., nodes, biopsy, PET scan) should be considered to 
exclude or confirm the transformation.
All physical examinations may be performed within 72 hours before or after the scheduled 
visit starting with Week 8 Day 1.
Vital Signs
For all subjects, body temperature (oral or tympanic), weight, blood pressure and pulse 
will be measured at:
 


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●
Screening
●
Week 1 Day 1
●
Week 2 Day 1
●
Week 3 Day 1
●
Week 4 Day 1
●
Week 5 Day 1 
●
Week 8 Day 1
●
Week 12 Day 1
●
Week 16 Day 1
●
Week 24 Day 1
●
Week 36 Day 1 and every 12 weeks thereafter (e.g., Weeks 48, 60, 72, etc.)
●
Final Visit
●
30-Day Safety Follow-Up Visit
●
Post Treatment Follow-Up Visit
Note:  Vital signs may be performed within 72 hours before or after the 
scheduled visit starting with Week 8 Day 1.
Blood pressure and pulse rate will be measured after the subject has been sitting for at 
least 5 minutes on days when study drug is administered in the clinic.
ECOG Performance Status
For all subjects, the ECOG performance status25 will be performed as follows:
●
Screening
●
Week 1 Day 1
●
Week 24 Day 1 
●
Week 36 Day 1 and every 12 weeks thereafter (e.g., Weeks 48, 60, 72, etc.)
●
Final Visit
●
30-Day Safety Follow-Up Visit
 


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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:
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.
Clinical Laboratory Tests
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 after receipt from the 
local laboratory.  The central laboratory will be utilized for special diagnostic testing only 
(refer to Table 9, and Section 5.3.1.2, Section 5.3.1.3 and Section 5.3.2.3).
Pregnancy Test
For all female subjects of childbearing potential, pregnancy testing must be performed as 
follows:
●
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.
Pregnancy test results must be reviewed and determined to be negative prior to dosing.  
Subjects considered not of childbearing potential must be documented as being surgically 
sterile or postmenopausal for at least 2 years.
 


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Hematology and Chemistry
For all subjects, chemistry and hematology samples will be collected at the following time 
points.
●
Screening
●
Baseline within 72 hours of dosing for W1 to W5
●
Week 1 Days 1, 2 and 3
●
Weeks 2, 3, 4, 5 Days 1 and 2
●
Week 8 Day 1
●
Week 12 Day 1
●
Week 16 Day 1
●
Week 24 Day 1
●
Week 36 Day 1 and every 12 weeks thereafter (e.g., Weeks 48, 60, 72, etc.)
●
Approximately 8 weeks after the CR, CRi or PR criteria for tumor response are 
first met
●
Final Visit
●
30-Day Safety Follow-Up Visit
●
Post Treatment Follow-Up Visit
●
As needed throughout study
Note:  Chemistry and hematology samples may be collected within 72 hours 
prior to the scheduled visit starting with Week 8 Day 1.  There is no 72 hour 
window permitted for the chemistry and hematology samples collected Week 1 
Day 1 through Week 5 Day 1.
Refer to Table 9 for a special sample handling procedure that must be followed to avoid 
ex vivo uric acid degradation in the presence of rasburicase for samples analyzed locally.
For chemistry and hematology laboratories performed during Weeks 1 – 5 (lead-in 
period), refer to Section 6.1.7.1, Prophylaxis and Management of Tumor Lysis Syndrome, 
and Appendix D, Recommendations for Initial Management of Electrolyte Abnormalities 
and Prevention of Tumor Lysis Syndrome (TLS), for specific requirements.
 


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Additional monitoring as needed based on risk assessment by the investigator and 
discussion with the AbbVie medical monitor.
Coagulation Panel
For all subjects, PT/aPTT samples will be collected at the following time points:
●
Screening
●
Week 12 Day 1
●
Week 24 Day 1
●
Final Visit
●
Post Treatment
Note:  Coagulation panel may be collected within 72 hours prior to the 
scheduled visit.
Urinalysis
For all subjects, urinalysis samples will be collected at:
●
Screening
●
Week 24 Day 1
●
Final Visit
Note:  Urinalysis may be collected within 72 hours prior to the scheduled visit.
Viral Polymerase Chain Reaction (PCR)
Approximately 4 mL of blood will be collected by venipuncture into an appropriately 
labeled tube at the following time points:
●
Screening
●
As needed throughout study
 


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Viral polymerase chain reaction (PCR) samples are to be collected and sent to the central 
laboratory for archiving and will only be analyzed if needed due to manifestations of 
possible infections during the treatment period.
Viral Serologies
●
Viral serologies to identify hepatitis B (HBsAg, anti-HBs, total anti-HBc, IgM 
anti-HBc), hepatitis C (HCV) antibody or RNA, cytomegalovirus, varicella 
zoster virus, herpes simplex virus, and Epstein-Barr virus will be collected at 
Screening
Samples for viral serologies are to be collected and sent to the central laboratory for 
archiving and will only be analyzed if needed for any manifestations of possible infections 
during the treatment period.
 


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Table 9.
Clinical Laboratory Tests for All Subjects
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Absolute Neutrophilc Count
Bands
Absolute Lymphocyte Count
Monocytes
Platelet count (estimate not 
acceptable)
Reticulocyte counta
Blood Urea Nitrogen (BUN)
Creatinine Clearance
Creatinineb
Total bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic 
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acidc
Total protein
Glucose
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate/CO2
G6PD assayd
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Coagulation
Viral Analysis
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
Viral Polymerase Chain 
Reaction (PCR)e
Viral Serologies
a.
To be performed at screening and Week 36.
b.
Creatinine clearance should be assessed using Cockcroft-Gault equation or a 24-hour urine collection.
c.
For samples analyzed locally, at room temperature, rasburicase causes enzymatic degradation of the uric acid in 
blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings.  The 
following special sample handling procedure must be followed to avoid ex vivo uric acid degradation.  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.
d.
Prior to rasburicase administration per protocol, test to be performed per label.
e.
Viral polymerase chain reaction (PCR) samples are to be collected and sent to the central laboratory for archiving 
and will only be analyzed if needed due to manifestations of possible infections during the treatment period.
12-Lead Electrocardiogram
For all subjects, a 12-lead resting ECG will be obtained at the following:
●
Screening
 


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●
Final Visit
●
As clinically indicated
The ECG results will be used by the investigator for subject safety assessments, including 
adverse event determination and management and termination of subjects from the study.  
ECG results will be summarized as follows:
●
normal ECG
●
abnormal ECG – not clinically significant
●
abnormal ECG – clinically significant
●
unable to evaluate
Any ECG report that is both abnormal and clinically significant will be faxed to the 
Oncology Safety Management Team via the contact information provided in Section 6.1.5
within 5 business days of obtaining the results.  The QT interval measurement will be 
documented in the eCRF only if a "prolonged QT" is observed.  Correction by the 
Fridericia formula (QTcF) is preferred; however, correction by other methods may be 
acceptable based on discussion with the AbbVie medical monitor.  The original ECG 
tracing will be retained in the subject's records at the study site.
Assessment of Left Ventricular Ejection Fraction (LVEF)
Assessment of ejection fraction will be made at screening by either two-dimensional 
echocardiogram or a Multi Gated Acquisition Scan (MUGA) at the discretion of the 
investigator.  Subsequent evaluation of LVEF will be made as clinically indicated for 
subjects who develop signs of cardiac compromise.
Disease Assessments
For all subjects, clinical response will be assessed by the investigator based on analysis of 
clinical laboratory tests (hematology laboratory values) and physical examination.  In 
addition, upon achieving a clinical response of (CR/CRi), a CT scan of involved anatomic 
regions (or MRI if CT is medically contraindicated) and bone marrow aspirate and biopsy 
 


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will be performed for confirmation.  Subjects will be evaluated against the 2008 Modified 
IWCLL NCI-WG Criteria for Tumor Response including CT imaging (or MRI).
Disease Assessment will be performed at the following visits:

Screening

Week 5 Day 1 (or Day 1 of initiation of 400 mg dose)

Week 8 Day 1

Week 12 Day 1

Week 16 Day 1

Week 24 Day 1

Week 36 Day 1 and every 12 weeks thereafter (e.g., Weeks 48, 60, 72, etc.) until 
disease progression, death, discontinuation from the study or study completion.

Approximately 8 weeks after the CR/CRi criteria is first met (if applicable)

Final Visit

Post Treatment Follow-Up Visits
Response criteria definitions are outlined in Section 5.3.3.1.
Note:  Disease assessments may be performed 72 hours before or after, starting with 
Week 8 Day 1.
Radiographic Imaging
A PET and CT scan with contrast must be performed within 28 days prior to study drug 
administration for all subjects.  CT must be of diagnostic quality with contrast to serve as 
a baseline for future comparisons.  CT scans (with contrast) including neck, chest, 
abdomen, and pelvis will be performed to assess response to treatment.  MRI of the 
abdomen and pelvis with a non-contrast CT scan of the neck and chest may be used 
instead in subjects for whom CT scan with contrast is contraindicated (i.e., subjects with 
contrast allergy and impaired renal clearance).  Subjects should have the same imaging 
modality performed throughout the study for consistency and direct comparison.  
 


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Interpretation of the PET-CT scans for all subjects including screen failures will be 
collected in the EDC.
When CR/CRi is determined by clinical criteria at any time during the study, a CT/MRI 
scan must be performed for confirmation (refer to Table 10).  If the CT/MRI scan 
confirms a CR, then a BM biopsy is also required.  For confirmation of CR, both the 
CT/MRI scan and bone marrow are required to be negative.   
When PR is determined by clinical criteria by changes in disease assessment they must be 
confirmed by a repeat clinical assessment at least 8 weeks after the clinical criteria for 
response are first met. 
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 PD criteria, a CT/MRI scan must be performed within 
2 weeks to confirm or rule out PD, as described in Section 5.3.3.2 according to Modified 
IWCLL NCI-WG Criteria for Tumor Response.
Clinical data and radiographic scans will be interpreted according to 2008 Modified 
IWCLL NCI-WG Criteria for Tumor Response (refer to Table 10).  In addition to being 
reviewed by the investigator and/or site staff, an independent review will be performed to 
assess tumor response and disease progression.  The independent review facility will 
provide instructions regarding the preparation and shipment of the data.  Interpretations 
from the independent review will not be sent to the site.  Subject treatment management 
will be based on review by the local investigator and/or site staff.  Local assessments will 
be used for endpoints.
If a subject has study drug interrupted for more than 3 days (i.e., adverse event), the site 
must contact the AbbVie study team or AbbVie medical monitor to adjust the subject's 
visit schedule, procedures and/or dosing on a case by case basis.  CT/MRI scans will be 
performed within 3 days of the following visits:
 


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Arm A and Arm B Subjects:
●
Screening (PET/CT with contrast of neck, chest, abdomen and pelvis)
●
An MRI of the abdomen and pelvis with a non-contrast CT scan of the neck 
and chest may be used instead in subjects for whom CT scan with contrast is 
contraindicated
●
Week 8
●
Week 24
●
Every 12 weeks after Week 24 for a period of 1 year from enrollment
●
Final Visit* (if the most recent scan is ≥ 8 weeks prior to this visit)
○
*CT scan not needed at Final Visit for subjects entering the Extended 
Access period.
Expansion Cohort Subjects:
●
Screening (PET/CT with contrast of neck, chest, abdomen and pelvis)
●
An MRI of the abdomen and pelvis with a non-contrast CT scan of the neck 
and chest may be used instead in subjects for whom CT scan with contrast is 
contraindicated
●
Week 12
●
Week 36
●
Final Visit* (if the most recent scan is ≥ 8 weeks prior to this visit)
○
*CT scan not needed at Final Visit for subjects entering the Extended 
Access period.
Bone Marrow Aspirate and Biopsy
A bone marrow aspirate and biopsy will be done at the following timepoints:
●
Screening (within 28 days prior to the first dose of study drug).  The bone 
marrow aspirate and biopsy should be performed after all other eligibility 
criteria have been met, unless otherwise obtained through standard of care.  
 


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●
Upon meeting all clinical/laboratory criteria for CR/CRi and having a 
confirmatory CT/MRI scan that meets the criteria for CR/CRi (with the 
exception of a node(s) that is enlarged around 1.5 – 2 cm.
●
Upon having MRD negativity confirmed in peripheral blood on 2 consecutive 
samples.
Bone marrow aspirates and biopsies, immunohistochemical analysis and cytogenetics 
performed as standard of care throughout the study should be captured in EDC.  All bone 
marrow aspirate and biopsy reports (done as standard of care or per protocol) with 
complete immunohistochemical analysis and cytogenetics must be faxed to the AbbVie 
primary contact listed in Section 7.0 or designee.  All reports must be fully de-identified 
prior to sending to AbbVie.
Bone marrow aspirates and biopsies for biomarker assessments should be split from this 
sample whenever possible and when deemed feasible by the investigator.  If the subject 
wishes to participate in the optional biomarker testing, a separate consent form will need 
to be signed.
The order of collections from the bone marrow aspirate and biopsy should be 1) clinical 
assessment, 2) MRD assessment and, 3) biomarker assessment.
Minimal Residual Disease (MRD) Assessment
MRD28 will be assessed in peripheral blood and/or bone marrow aspirate using a 
recommended methodology (flow cytometry, PCR, and/or sequencing) to define CLL 
event for all subjects at:
●
Screening for baseline assessment (peripheral blood and bone marrow aspirate)
●
Week 24 (Peripheral Blood, All Subjects)
●
Week 36 (peripheral blood Expansion Cohort subjects only)
●
Upon achieving CR/CRi (peripheral blood and bone marrow) at the 8 week 
confirmatory visit.  After Week 24 (Week 36 for Expansion Cohort subjects),
for subjects that achieve a radiographic PR, MRD will be assessed in 
 


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peripheral blood only. For subjects who meet all laboratory criteria for CR 
with the exception of a node(s) that are enlarged around 1.5 – 2 cm should also 
have MRD assessed (peripheral blood and bone marrow aspirate).  
●
MRD for subjects achieving a radiographic PR/CR/CRi will continue to have 
MRD assessed in the peripheral blood at 12 weeks intervals until 
two consecutive negative MRD levels are reported.
●
Once MRD negativity is achieved and confirmed in peripheral blood (by 
two consecutive peripheral blood samples), a bone marrow aspirate specimen 
will be collected for analysis and confirmation of MRD negativity.
Note:  The bone marrow aspirate for MRD assessments (flow cytometry, PCR 
and/or sequencing) should be the first samples collected.  Only peripheral 
blood is required for the baseline MRD assessment by PCR.
Dispense/Collect Venetoclax and Subject Calendars/Diaries
For all subjects, subject calendars/diaries will be provided.  Subjects will be instructed to 
bring their calendars/diaries back to the site to be reviewed at:
●
Week 1 Day 1
●
Week 2 Day 1
●
Week 3 Day 1
●
Week 4 Day 1
●
Week 5 Day 1
●
Week 8 Day 1 
●
Week 12 Day 1
●
Week 16 Day 1
●
Week 24 Day 1
●
Week 36 Day 1 and every 12 weeks thereafter (e.g., Weeks 48, 60, 72, etc.)
●
Extended Access Period:  Every 12 weeks (+/– 7 days)
Subjects will be instructed to record the date and time each dose of study drug is taken, 
(indicating if any doses of study drug are missed) and whether or not doses were taken 
 


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within 30 minutes after completing breakfast or the subject's first meal of the day.  The 
date and time (to the nearest minute) of each dose taken and whether or not the dose was 
taken within 30 minutes after completing breakfast or the subject's first meal of the day 
will be recorded on the eCRF on the scheduled venetoclax PK days and for the 2 days 
prior to every scheduled venetoclax PK day.
Subjects will also be instructed to record adverse events and concomitant medications in 
the subject calendars/diaries.
The calendars/diaries are to be reviewed at each visit and relevant pages are to be 
photocopied by study staff.  At the end of the subject's participation in the study, the 
calendars/diaries are to be returned to the site and appropriately filed with the subject's 
source documents for this study.
Health Economic and Patient Reported Outcome Measures 
The EORTC QLQ-C30 and EORTC QLQ CLL16 (a measure of health related quality of 
life), and the EQ-5D-5L and EQ-5D-VAS (measure of general health status) are the 
measures of quality of life as they pertain to symptomology and treatment that will be 
assessed in the study. 
Arm A and Arm B Subjects
The EORTC QLQ-C30 and EORTC QLQ CLL16 assessment will take place at:
●
Week 1 Day 1
●
Week 24 Day 1 and every 12 weeks thereafter
●
Final Visit
●
Post Treatment Follow-Up Visits
The EQ-5D-5L and EQ-5D-VAS assessments will take place at:
●
Week 1 Day 1
●
Week 24 Day 1 and every 12 weeks thereafter
 


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●
Final Visit
Expansion Cohort Subjects:
The EORTC QLQ-C30 assessment will take place at:
●
Week 1 Day 1
●
Week 24 Day 1 
●
Week 36 Day 1 and every 12 weeks thereafter
●
Final Visit
●
Post Treatment Follow-Up Visits
The Health Economic and Patient Reported Outcomes questionnaires should be 
administered and completed prior to any other study procedures being performed at these 
visits.  Refer to Section 5.3.8, Health Economic and Patient-Reported Outcome Measures, 
for further information.
Subjects will be asked to complete a questionnaire assessing the information they were 
provided for the Patient Information Card and the Tumor Lysis Syndrome Patient 
Information Brochure, at the Week 2 Day 1 visit.
Post-Treatment Follow-Up Visit(s)
Subjects who discontinue venetoclax monotherapy, and have not had an event of disease 
progression, will remain on study for Post Treatment Follow-Up Visits.  During Post 
Treatment Follow-Up, the following assessments will be performed every 3 months until 
discontinuation from the study (e.g., disease progression, alternative therapy is required, 
or a subject's refusal of the Post-Treatment visits) for a period of 3 years after the last 
subject has enrolled on the study:
●
Adverse Event/Concomitant Medication Assessment
●
Physical Examination
●
Vital Signs
 


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●
Hematology and Chemistry
●
Coagulation
●
Disease Assessments
●
The EORTC QLQ-C30 and EORTC QLQ CLL16 Assessment (only the 
EORTC QLQ C30 will be utilized in the Expansion Cohort)
●
CT or MRI scans are not required during Post Treatment Follow-Up, however 
if collected by the site as standard of care, the data must be recorded in EDC
Note:  Effective with protocol Amendment 5, subjects being followed in Post-Treatment 
as of 08Nov2018 will switch to being assessed per the Survival Assessments below.  No 
new subjects will enter the Post-Treatment period.
Survival Assessment(s)
Survival information (i.e., the date and cause of death, post treatment cancer therapies, 
disease status etc.) will be collected via clinic visits, telephone calls, or through public 
records at approximately 3-month intervals (+/– 7 days) after the last study visit for a 
period of 5 years after the last subject has enrolled on the study.
Extended Access
For subjects continuing into the Extended Access period of the trial, venetoclax will be 
dispensed at the Final Visit, followed by Extended Access visits every 12 weeks
(+/– 7 days) until disease progression, or until a subject chooses to receive commercial 
supply of VENCLEXTA.  Extended Access visits will include:
●
AE/SAE/ConMed assessment
●
Study drug reconciliation and dispensing
●
Hemoglobin, hematocrit, absolute neutrophil count, absolute lymphocyte 
count,  platelet counts and white blood cell counts
●
Dispense/Collect subject diaries
All other procedures for disease assessments will be performed as standard of care.
 


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Richter's Transformation and Second Primary Malignancies Assessment
Richter's transformation and second primary malignancies information (i.e., confirmation 
if the subject developed Richter's transformation and/or second primary malignancies and 
any post study treatment for CLL, etc.) will be collected via clinic visits or telephone calls 
at 3 month intervals after the last study visit for a period of up to 5 years after the last 
subject has been enrolled, for those subjects who have consented for this follow-up 
procedure.
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 and AbbVie medical monitor before a 
subject can be administered study drug.  Subjects will not be enrolled in the study if 
laboratory or other screening results are unacceptable.
Confinement
All high risk subjects will be hospitalized for TLS prophylaxis and observation prior to 
their first dose of venetoclax at 20 mg and at 50 mg.  Additionally, subjects who continue 
to meet the criteria for high risk of TLS will be hospitalized for prophylaxis and 
monitoring at each subsequent dose increment.
Subjects in the Medium Risk category who have creatinine clearance of < 80 mL/min 
and/or higher tumor burden (i.e., ALC > 100 × 109/L or multiple bulky nodes) may be 
handled as high risk subjects per investigator discretion for the first dose of venetoclax at 
20 mg and 50 mg.
Meals and Dietary Requirements
Each dose of venetoclax will be taken with approximately 240 mL of water within 
30 minutes after the completion of breakfast or the subject's first meal of the day.  
Subjects may not consume:
 


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●
Grapefruit or grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or Star fruit within the 3-day period prior to the 
first study drug administration and until the last day of treatment is completed 
due to possible CYP3A mediated metabolic interaction.
5.3.1.2
Blood Samples for Pharmacogenetic Analysis (Optional)
One 4 mL whole blood sample for DNA isolation will be collected at Screening or prior 
to first dose of study drug on Week 1 Day 1 from each subject who consents to provide 
samples for pharmacogenetic analysis.  If the sample is not collected at either of these 
visits, it may be collected at any visit during the study.  The procedure for obtaining and 
documenting informed consent is discussed in Section 9.3.
Whole blood will be collected by standard phlebotomy techniques as described below:
●
Collect approximately 4 mL of blood into an appropriately labeled EDTA 
tube.
●
Immediately invert the collection tube 8 to 10 times to reduce the likelihood of 
clot formation.
●
Store samples at –20°C or colder within 30 minutes of the blood draw until 
shipped/transported to AbbVie on dry ice sufficient to last during 
shipment/transport.
Samples will be shipped frozen to central laboratory.  The central laboratory or AbbVie 
will maintain the samples for DNA extraction and long-term storage.  Samples should not 
be allowed to thaw prior to arrival at the central laboratory.  Arrangements will be made 
with AbbVie for the shipment of samples to:
 


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Attn:  AbbVie Sample Receiving
D-R43F, Bldg. AP13A, Rm. 2310
c/o:  Delivery Services
1150 S. Northpoint Blvd.
Waukegan, IL  60085
Phone:
(847) 937-0889
Fax:
(847) 938-9898
E-mail:
sample.receiving@abbvie.com
The sample collection tubes will minimally be labeled with "PG-DNA blood," the drug 
number, protocol number, subject number and the study day.  AbbVie or designee will 
store the DNA samples in a secure space with adequate measures to protect 
confidentiality.  The samples will be retained while research on venetoclax (or drugs of 
this class) continues but no longer than 20 years or per country requirement.
5.3.1.3
Collection and Handling of Biomarker Testing
Mandatory Collections
Serum Markers
Approximately 3.5 mL of blood will be collected by venipuncture into an appropriately 
labeled 3.5 mL SST (gold top) tube from all subjects at the following time points:
●
Screening or Week 1 Day 1 pre-dose
●
Week 1 Day 2
●
Week 4 Day 1
●
Final Visit/Time of Relapse
Serum Marker samples will be processed and shipped to the central laboratory from the 
site per the current laboratory manual.
Blood for CLL FISH
Approximately 4 mL of blood will be collected by venipuncture into a heparin vacutainer 
from subjects with unknown 17p deletion status at the following time point:
 


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●
Screening or Week 1 Day 1 pre-dose
Blood for CD19 Cell Isolation Bcl-2 Family Analysis
Approximately 8 mL of blood will be collected by venipuncture into an ACD vacutainer 
from all subjects at the following time points:
●
Screening or Week 1 Day 1 pre-dose
●
Final Visit/Time of Relapse
Blood for CD19 Isolation Bcl-2 Family Analysis samples will be processed and shipped 
to the central laboratory from the site per the current laboratory manual.
Blood for Mutation and Expression Profiling 
Approximately 20 mL of blood will be collected by venipuncture into ACD vacutainers 
from all subjects at the following time points:
●
Week 1 Day 1 pre-dose
●
Week 2 Day 1 pre-dose
Bone Marrow Aspirate for Bcl-2 Protein Analysis
Approximately 1 mL of bone marrow aspirate will be collected and placed into a sodium 
heparin vacutainer.  Bone marrow aspirate must be split for this analysis from samples 
obtained for 2008 Modified IWCLL NCI-WG Criteria for Tumor Response whenever 
feasible, but should not require the subject to undergo a second bone marrow collection if 
sample is insufficient.  Samples should be collected at the following time points:
●
Screening or Week 1 Day 1 pre-dose
●
Final Visit/Time of Relapse
Bone Marrow Aspirate Bcl-2 Protein Analysis samples will be processed and shipped 
directly to the central laboratory from the site per the current laboratory manual.
 


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Bone Marrow Aspirate for CD19 Isolation
Approximately 4 mL of bone marrow aspirate each will be collected and placed into a 
ACD vacutainer.  Bone marrow aspirate must be split for this analysis from samples 
obtained for 2008 Modified IWCLL NCI-WG Criteria for Tumor Response whenever 
feasible, but should not require the subject to undergo a second bone marrow collection if 
sample is insufficient.  Samples should be collected at the following time points:
●
Screening or Week 1 Day 1 pre-dose
●
Final Visit/Time of Relapse
Bone Marrow Aspirate for CD19 Isolation samples will be processed and shipped to the 
central laboratory from the site per the current laboratory manual.
Peripheral Blood and Bone Marrow Aspirate for Disease Assessment by PCR
Approximately 10 mL of blood will be collected in a sodium heparin vacutainer and 
Approximately 3 mL of bone marrow aspirate will be collected and placed into a sodium 
heparin vacutainer.  Bone marrow aspirate must be split for this analysis from samples 
obtained for 2008 Modified IWCLL NCI-WG Criteria for Tumor Response whenever 
feasible, but should not require the subject to undergo a second bone marrow collection if 
sample is insufficient.  Samples should be collected at the following time points:
●
Screening or Week 1 Day 1 pre-dose (Peripheral Blood only)
●
Week 24 (Peripheral Blood only, All Subjects)
●
Week 36 (Peripheral Blood Expansion Cohort subjects only)
●
After the 1st CR (Peripheral Blood and Bone Marrow Aspirate)*
*
Specimens will continue to be collected for these subjects in the peripheral 
blood only at the 12 weeks interval visits until 2 negative MRD levels are 
reported.  A final specimen will be assessed in bone marrow aspirate once 
MRD negativity (as indicated by Flow cytometry) is achieved in 
two consecutive peripheral blood samples.
 


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The Peripheral Blood and Bone Marrow Aspirate for MRD assessment by PCR samples 
will be processed and shipped directly to the central laboratory from the site per the 
current laboratory manual.
Non-Tumor DNA for Mutational Profiling (Control Specimen)
A buccal swab will be collected at the following time point:
●
Screening (preferred) or prior to the first dose of study drug 
Note, if the sample is not collected at either visit.  It can be collected at any 
subsequent visit.
Tissue for IHC and FISH
Optional for all subjects:
Screening or Week 1 Day 1 pre-dose
Subjects who undergo Richter's transformation while taking venetoclax will require a 
mandatory biopsy from the new lesion (when deemed feasible by the investigator).  If the 
subject discontinues for any other reason, the collection is optional.
Final Visit/Time of Relapse (when feasible)
Either archived diagnostic formalin fixed paraffin embedded (FFPE) tissue blocks and/or 
formalin fixed core needle biopsy should be completed at Screening for all subjects who 
provide consent.  A formalin-fixed core needle biopsy should be completed at the Final 
Visit or time of disease progression for all subjects who have consented.  Tissue specimen 
for IHC and FISH testing should be split from samples obtained for 2008 Modified 
IWCLL NCI-WG Criteria for Tumor Response whenever possible.  If feasible, it is 
preferred that tissue specimens from both locations be submitted for analysis from 
subjects with lymph node and bone marrow involvement.
 


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Formalin Fixed, Paraffin Embedded Samples (Archived Tissues are Acceptable at 
Screening Only)
Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and/or nucleic 
acid analysis, for example, quantitative polymerase chain reaction (qPCR), or micro RNA 
quantitation may be performed on tissue slides from archived, diagnostic, formalin fixed, 
paraffin embedded FFPE tissue blocks from all subjects who consent in the study.
The tissue may be processed according to the institutional standard procedures or per the 
most current version of the Laboratory Manual for this study.  If a procedure other than 
what is described in the most current version of the Laboratory Manual for this study is 
used, a description of the procedure should be provided to AbbVie.
Core Needle Biopsy – Formalin Fixed (Prior to Therapy if FFPE Block is Not 
Available or if Investigator Prefers; and at Time of Disease Progression)
Formalin-fixed core needle biopsies will be obtained prior to therapy and at time of 
disease progression, when feasible, for all subjects in the study who consent and who have 
readily accessible tumor tissue.  Biopsies will be performed after consent, prior to study 
drug administration and after the subject has progressed on therapy.  Lymph node 
collections will be performed for all subjects with Richter's transformation.
The needle biopsy should be at least 18 gauge in diameter and at least 1 cm in length.  It is 
estimated that there will be between 2 to 5 million cells from each biopsy.  The biopsy 
may be processed according to the institutional standard procedures or per the most 
current version of the Laboratory Manual for this study.  If a procedure other than what is 
described in the most current version of the Laboratory Manual for this study is used, a 
description of the procedure should be provided to AbbVie.
Recollection of biopsy samples prior to the first dose of venetoclax may occur as 
necessary due to technical failures such as inadequate sampling in screening.
Tissue for IHC and FISH should be shipped to the central laboratory from the site per the 
current laboratory manual.
 


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5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples (3 mL) for venetoclax (and possible metabolite[s]) assay will be collected 
in K2EDTA containing tubes by venipuncture in appropriately labeled tubes at the times 
listed in Table 6.
A total of approximately 11 blood samples (approximately 33 mL) will be collected.  The 
PK collection performed 8 hours post dose after each dose increment, may be taken up to 
1 hour before or up to 20 minutes after, to allow for processing if necessary.
The date and time of each blood sample collection will be recorded to the nearest minute 
on the eCRF.  The date and time (to the nearest minute) of each venetoclax dose and 
whether or not the venetoclax dose was taken within 30 minutes after the completion of 
breakfast (or subject's first meal of the day) will be recorded on the scheduled venetoclax
PK days and for the 2 days prior to every scheduled venetoclax PK day.  Sites will ensure 
that all information is captured through source documents (site or subject calendar/diary 
provided by AbbVie).
5.3.2.2
Handling/Processing of Samples
Blood and plasma samples must be protected from direct sunlight during collection, 
processing and storage.  Immediately after collection, the blood samples for venetoclax 
will be inverted 8 to 10 times to ensure good mixing of the blood and anticoagulant, and 
will be placed in an ice bath.  Within 1 hour of blood draw, the blood samples will be 
centrifuged using a refrigerated centrifuge (2° to 8°C) to separate the plasma at 1100 to 
1600 × g for approximately 10 to 15 minutes.  The plasma samples will be transferred 
using plastic pipettes into a 2 mL Greiner tube labeled with the drug number name, assay 
type, type of sample (plasma), the protocol number, the subject number, the study week 
and day, and the planned time of sampling relative to dosing and then frozen at –20°C or 
colder.  The entire process should be completed within 2 hours of draw.  Samples should 
be maintained at –20°C or colder until shipped to the central laboratory.
 


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5.3.2.3
Disposition of Samples
The frozen plasma samples for venetoclax (and possible metabolite[s]) assay will be 
packed in dry ice sufficient to last during transport and shipped from the study site to the 
central laboratory according to instructions included in the Laboratory Manual for this 
study.  An inventory of the samples included will accompany the package.  The central 
laboratory will be responsible for shipping the plasma samples to AbbVie or designated 
laboratory for testing.
5.3.2.4
Measurement Methods
Plasma concentrations of venetoclax will be determined by the Drug Analysis Department 
at AbbVie using a validated method.  Other potential metabolites of venetoclax may be 
analyzed with either a validated or non-validated assay.
5.3.3
Efficacy Variables
The primary objective of this study is to evaluate the efficacy and safety of venetoclax 
monotherapy in subjects with Chronic Lymphocytic Leukemia (CLL) relapsed after or 
refractory to treatment with B-cell Receptor Signaling Pathway Inhibitors.  Efficacy will 
be measured by overall response rate (ORR).
The secondary objectives are to evaluate the duration of response (DOR), time to 
progression (TTP) progression free survival (PFS), and overall survival (OS).
Additional exploratory objectives will be evaluated.  Minimal residual disease (MRD) is 
assessed in the peripheral blood and bone marrow (BM) by flow cytometry, PCR and/or 
sequencing.  Health Economic and Patient-Reported Outcome Measures will include the 
EORTC QLQ-C30 and EORTC QLQ CLL16 (a measure of health related quality of life 
specific to CLL) and the EQ-5D-5L (measure of general health status) including 
EQ-5D-VAS.  For Expansion Cohort subjects, only the EORTC QLQ-C30 will be 
performed.
Analyses of these endpoints are described in Section 8.0.
 


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5.3.3.1
Primary Variables
For disease assessments, response will be assessed by the investigator based on analysis 
of clinical laboratory tests (hematology laboratory values), complete physical 
examination, CT scan of involved anatomic regions (or MRI if CT is medically 
contraindicated), bone marrow aspirate and biopsy.  Subjects will be evaluated against the 
2008 Modified IWCLL NCI-WG Criteria for Tumor Response27 with the addition of CT 
imaging (or MRI).
At Screening, all measurable disease must be documented by laboratory testing 
(hematologic status), physical examination, PET/CT and bone marrow.  All baseline 
evaluations should be performed no more than 4 weeks before the beginning of the 
treatment.  All the other tumor assessments after baseline should be performed within 
7 days after the scheduled visit.  During the study, subjects will have a disease assessment 
at Screening, Week 5 Day 1 (or Day 1 of initiation of 400 mg dose) and beyond by a 
physical examination and laboratory testing.  When a CR/CRi response is determined by 
clinical criteria at any time during the study, a CT scan or MRI must be performed within 
8 weeks for confirmation.  For determination of CR, both the CT/MRI scan and bone 
marrow are required to be negative.  If the scans confirm a CR, then a BM biopsy is 
required for confirmation of the CR.
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 PD criteria, then additional assessments including 
contrast enhanced CT scan (or MRI) and/or bone marrow must be performed within 
2 weeks to confirm or rule out PD.
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.
 


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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.
Details on the analysis of peripheral blood required to assess response are provided in 
Section 5.3.1.1, Study Procedures.
A full physical examination should be performed to assess the extent of disease 
involvement.  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 extranodal).  Target nodal lesions must be abnormal (> 1.5 cm in 
LDi at baseline), clearly measurable and suitable for consistent, reproducible 
measurement in at least two perpendicular dimensions.  Target extranodal 
lesions must be > 1 cm in two perpendicular diameters at baseline.
●
Non-Target Lesions:  A maximum of 10 non-target lesions can be selected.  
Non-target nodal lesions must be abnormal (> 1.5 cm in LDi at baseline).  
Non-target extranodal lesions must be > 1 cm in two perpendicular diameters.  
Nodal and extranodal 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.  Magnetic Resonance 
Imaging (MRI) may be used if CT is medically contraindicated (e.g., severe contrast 
allergy).  If MRIs are used instead of CT scans, MRIs should be used consistently 
 


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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.
In addition to being reviewed by the investigator and/or site staff, an independent review 
will be performed to assess tumor response and disease progression.  Clinical data and 
radiographic scans will be interpreted according to 2008 Modified IWCLL NCI-WG 
Criteria for Tumor Response (refer to Table 10).  The independent review facility will 
provide instructions regarding the preparation and shipment of the imaging data.  
Interpretations from the independent review for individual subjects will not be sent to the 
site.  Subject treatment management will be based on review by the local investigator 
and/or site staff.
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
●
No hepatomegaly or splenomegaly by physical examination (as determined by 
measurement below the relevant costal margin)
 


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●
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 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 size 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 10.
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
Other Considerations
New Lesions
None
None
Appearance of new 
palpable lymph nodes 
(> 1.5 cm in longest 
diameter) or any new 
extra nodal lesion 
(regardless of size) or 
transformation to a more 
aggressive histology, 
e.g., Richter Syndromed
None
 


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Table 10.
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 SD
CLL = chronic lymphocytic leukemia; LN = lymph nodes; N/A = Not applicable; SPD = sum of the products of 
diameters; CRi = complete remission with incomplete marrow recovery
a.
CR also requires the lack 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.
The goal of confirmation of overall response is to avoid overestimating responses.  In 
cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome that the response(s) is (are) not confirmed.
 


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To be assigned a status of PR changes in tumor measurements must be confirmed by 
repeat assessments.  These must be performed at least 8 weeks after the clinical criteria 
for response are first met.
5.3.3.2
Secondary Variables
Disease progression according to 2008 Modified IWCLL NCI-WG Criteria for Tumor 
Response is characterized by at least one of the following:
●
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.
5.3.4
Safety Variables
The following safety evaluations will be performed during the study:  adverse event 
monitoring, vital signs, physical examination, 12-lead ECG, and laboratory assessments.
5.3.5
Pharmacokinetic Variables
Plasma concentration of venetoclax will be tabulated.  Values for the PK parameters of 
venetoclax, including the apparent clearance (CL/F), and the apparent volume of 
 


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distribution (V/F), may be determined using a population PK approach.  Additional 
parameters may be calculated if useful in the interpretation of the data.
5.3.6
Pharmacogenetic Variables
DNA samples may be analyzed for genetic factors contributing to the subject's response to 
venetoclax in terms of pharmacokinetics, efficacy and safety.  Such genetic factors may 
include, for example, drug metabolizing enzymes, drug transport proteins, CLL 
prognostic markers and Bcl-2 family members.  Some genes currently insufficiently 
characterized or unknown may be understood to be important at the time of analysis.  
These samples may be analyzed as part of a multicenter, multi-study project to identify 
genetic factors involved in the response to study drugs.  The samples may also be used for 
the development of diagnostic tests related to venetoclax (or drugs of this class).  The 
results of pharmacogenetic analyses may not be reported with the study summary.
5.3.7
Biomarker Variables
Several putative biomarkers of efficacy and response may be evaluated in this protocol 
with the goal of defining the relationship between various disease markers and disease 
status.  Biospecimens collected during the course of this study will be banked and used in 
the future to investigate new scientific questions related to this study.  The samples may 
also be used for diagnostic test development.  AbbVie (or a designated laboratory) will 
store the samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on venetoclax (or drugs of 
this class) continues but no longer than 20 years.
Examination of the plasma and serum components of subjects on this venetoclax clinical 
trial may reveal patterns of cell-free nucleic acids, proteins/peptides or metabolites that 
may be further evaluated in future clinical studies to determine any prognostic value and 
any correlation with clinical response.  Plasma and serum samples may also be analyzed 
for predictive or drug-responsive markers.  In the event that any plasma and serum 
samples are unused, remaining samples will be banked for use in diagnostic test 
development efforts.
 


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DNA methylation regulates gene expression (inactivates certain genes and their normal 
role); aberrant methylation of specific genes is associated with cancer development and 
poor clinical outcome.  Genes with variable methylation status that are known to have 
prognostic implications may be assessed in the trial.  These analyses may examine 
putative stratification markers for correlation for efficacy.
Genetic amplification, chromosomal loss and/or mutational/methylation status of various 
genes represent genetic lesions potentially associated with subject outcome.  Nucleic 
acids, protein expression, and/or mutational/methylation analysis may be conducted on 
CLL cells isolated from blood, tissue from tumor samples and/or DNA/RNA extracted 
from serum from subjects participating in this study to assess modifications in genes 
(e.g., which may include but will not be limited to the Bcl-2 family, p53, notch and other 
genes associated with resistance to B-cell receptor targeted agents such as BTK and 
PLCγ), which may prove to be informative.  Additionally, comprehensive sequencing of 
CLL cells isolated from the blood or bone marrow aspirate may also be performed.  The 
sequencing may be used to identify the mutation status of genes associated with CLL as 
well as sequencing of the tumor associated immunoglobulin gene as a method to monitor 
disease burden.  FISH may be conducted on tissue from tumor samples and/or CLL cells 
from subjects participating in this study to assess amplifications and translocations in the 
Bcl-2 gene and other alteration in genes associated with CLL, which may prove to be 
informative.  The potential relationship between amplification/loss/mutation/methylation 
of these genes and the clinical outcome in these subjects may be examined as a subject 
stratification tool.  Biospecimens collected during the course of this study may be banked 
and used in the future to investigate new scientific questions related to this study.
5.3.8
Health Economic and Patient-Reported Outcome Measures
The EORTC QLQ-C30 consists of a Global Health Status/QoL scale, a Financial 
Difficulties scale, five Functional scales (Cognitive Functioning, Social Functioning, 
Physical Functioning, Emotional Functioning, and Role Functioning), and eight Symptom 
scales/items (Fatigue, Insomnia, Appetite Loss, Pain, Constipation, Diarrhea, Dyspnea, 
 


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and Nausea and Vomiting).  For Expansion Cohort subjects, only the EORTC QLQ-C30
will be performed.
Each of these domains will be calculated as per the EORTC scoring manual, and 
summarized (mean, std. dev., median) at each assessment; in addition mean change in 
each of these values (final assessment versus baseline) will be calculated to identify any 
statistically significant differences versus baseline.
The five EORTC QLQ CLL16 domains (Fatigue, Treatment Side Effects and Disease 
Symptoms, Infection, Social Activities, Future Health Worries) will be summarized 
(mean, std. dev., median) at each assessment; in addition mean change in each of these 
values (final assessment versus baseline) will be calculated to identify any statistically 
significant differences versus baseline.29
EQ-5D-5L and EQ-5D-VAS
The EuroQol 5 Dimensions (EQ-5D-5L) is a generic preference instrument that has been 
validated in numerous populations.  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 EQ-5D-5L also contains a visual analog scale 
(VAS) to assess the subject's overall health.30
Each of the five dimensions of the EQ-5D-5L, the Visual Analog Scale (VAS) and overall 
utility score will be calculated using the EuroQol scoring manual, and summarized (mean, 
std. dev., median) at each assessment; in addition mean change in each of these values 
(final assessment versus baseline) will be calculated to identify any statistically significant 
differences versus baseline.30
 


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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 at any time.  In addition, the 
investigator will discontinue a subject from the study 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;
●
The subject's response to therapy is unsatisfactory, as evidenced by 
progression of disease while on study drug;
●
The subject requires radiotherapy, cancer-related surgery as a result of tumor 
progression, or alternate anti-neoplastic agents during the study period;
●
Noncompliance with the protocol.
Subjects with disease progression may continue to receive study treatment when, in the 
opinion of the investigator, it is in the subject's best interest to stay on the study drug.  
Disease progression will be captured in EDC per iWCLL NCI-WG criteria as described in 
Section 5.3.3.2 of the protocol.  The subject will be monitored per study procedures 
described in Section 5.3.1.1 or more often if the investigator considers it necessary.
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.
Refer to Appendix G for COVID-19-related processes for this section.
Post Treatment Follow-Up Visits
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 visits will be performed every 3 months until discontinuation from 
the study (e.g., disease progression, alternative therapy is required, or a subject's refusal of 
 


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the Post-Treatment visits) for a period of 3 years after the last subject has enrolled on the 
study.
Final Visit
Upon discontinuation from the study, the reason(s) for discontinuation will be recorded in 
EDC and a Final Visit will be performed.  The Final Visit procedures as listed in Table 4
and Table 6 should be performed as soon as possible after discontinuation from the study.
At the Final Visit, the subject's calendars/diaries are to be returned to the site and 
appropriately filed with the subject's source documents.
30 Day Safety Follow-Up Visit
A Safety Follow-Up Visit should be performed for all subjects approximately 30 days 
following discontinuation of study drug and then as clinically appropriate for safety 
assessment.  The subject will be followed until a satisfactory clinical resolution of the 
adverse event is achieved.
A Safety Follow-Up Visit does not need to be performed for subjects who had a Final 
Visit conducted > 30 days after discontinuation of study drug and did not require 
additional adverse event follow-up.  If the subject refuses or is unable to attend the Safety 
Follow-Up Visit, this should be noted in the subject's source documentation.
Survival Follow-Up
Survival information (i.e., the date and cause of death, post-treatment cancer therapies, 
etc.) will be collected via telephone calls and/or clinical visits at 3-month intervals after 
the last study visit for a period of 5 years after the last subject has enrolled on the study.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the study, the administration of study drug must be 
discontinued immediately.  The investigator must report a pregnancy within 1 working 
 


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day of the site being aware to one of the AbbVie representatives listed in Section 6.1.5 or 
Section 7.0.
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
Each dose of venetoclax will be taken with approximately 240 mL of water within 
30 minutes after the completion of breakfast or the subject's first meal of the day.
In cases of vomiting, if vomiting occurs within 15 minutes of taking the dose and all 
tablets are intact, another dose may be given.  Otherwise, no replacement dose is to be 
given.  In cases where a dose is missed or forgotten, the subject should take the dose as 
soon as possible, ensuring the dose is taken within 8 hours of the missed dose with food.  
Otherwise, the dose should not be taken.
Refer to Appendix G for COVID-19-related processes for this section.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 11.
 


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Table 11.
Identity of Investigational Product
Study Drug
Trademark
Formulation
Route of Administration
Manufacturer
Venetoclax
N/A
10 mg Tablet
Oral
AbbVie
Venetoclax
N/A
50 mg Tablet
Oral
AbbVie
Venetoclax
N/A
100 mg Tablet
Oral
AbbVie
5.5.2.1
Packaging and Labeling
The venetoclax tablets will be packaged in high density polyethylene (HDPE) plastic 
bottles or blister packs to accommodate the study design.  Each container will be labeled 
per local regulatory requirements.
Blister Packs will contain study drug for one week plus one extra day.  Subjects will be 
instructed to take the extra day's dose (noted with an "X" on the Blister Pack) only if 
directed by the investigator.
5.5.2.2
Storage and Disposition of Study Drugs
The investigational product supplied in this study is for investigational use only, and are 
to be used only within this study.  All clinical supplies must be maintained under adequate 
security and stored under conditions specified on the label.
The tablets must be stored at 15° to 25°C (59° to 77°F).
5.5.3
Method of Assigning Subjects to Treatment Groups
There is no randomization schedule for this study.  Subjects will be assigned at Screening, 
a unique consecutive subject number.  All subjects will be enrolled using an IxRS.  Before 
the study is initiated, each site will be provided with the IxRS user instructions, which 
provides direction on how to use the IxRS 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 
 


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sponsor, will be responsible for assignment of all unique subject numbers at Screening
and dose assignments if the subject is not a screen failure.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the dose for this study is discussed in Section 5.6.4.  Each dose of venetoclax
will be taken with approximately 240 mL of water.  All subjects will be trained to 
self-administer venetoclax orally QD within 30 minutes after the completion of breakfast 
or the subject's first meal of the day.
5.5.5
Blinding
This is an open-label, two 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 study drug to the subject.  Compliance below 
80% will require counseling of the subject by study site personnel.
5.5.7
Drug Accountability
Documentation of the receipt of supplies will be supported by a signed and dated Proof of 
Receipt or similar shipping document in IxRS.  A current (running) and accurate 
 


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inventory of study drug will be kept by the site and will include lot number, Proof of 
Receipt number(s), container numbers, blister pack numbers, and the date on which study 
drug is administered to the subject.
An overall accountability of study drug will be performed in IxRS and verified by AbbVie 
or the designated monitor(s) throughout the study and at the study site closeout visit.  
Upon completion or termination of the study, 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 at the site.  Empty 
containers will be destroyed at the site.  Labels must remain attached to the containers.
5.6
Discussion and Justification of Study Design
Antiapoptotic BCL-2 family members are associated with tumor initiation, disease 
progression, and drug resistance, and thus are compelling targets for antitumor therapy.  
Venetoclax is a novel orally bioavailable small molecule BCL-2 family protein inhibitor 
that binds with high affinity to Bcl-2 and with lower affinity to other Bcl-2 family 
proteins BCL-xL and BCL-w.  The mechanism of action of venetoclax is independent of 
the BCR signaling and TP53 pathway.  Briefly, venetoclax inhibits BCL-2 allowing the 
release of BIM, which includes oligomerization of pro-apoptotic molecules such as BAK 
and BAX which triggers rapid apoptosis independent of TP53 and BCR pathways.
Preliminary data indicate that ongoing venetoclax first-in-human Study M12-175 had a 
strong efficacy signal in oncology subjects.  In the CLL Arm A, 47 of 52 (90.2%) 
evaluable subjects achieved a best response of complete response (CR), CR with 
incomplete bone marrow recovery (CRi), or partial response (PR):  12 (21%) subjects 
experienced CR/CRi, and 36 (63%) subjects experienced PR (of which 30 were 
confirmed).  Subjects with high-risk CLL had a response rate of 82% in del (17p) and 
78% in fludarabine-refractory disease.  Three of the 4 high-risk disease subjects who 
achieved CR/CRi had no detectable MRD.  One subject with SLL after disease 
progression on Idelalisib had PR on venetoclax for 11 months prior to developing PD.
 


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5.6.1
Discussion of Study Design and Choice of Control Groups
There are no control groups in this study.
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.
5.6.3
Suitability of Subject Population
Subjects with relapsed or refractory CLL will be selected to participate in this study.  
Subjects must have relapsed or be refractory to Ibrutinib or Idelalisib containing regimen.
5.6.4
Selection of Doses in the Study
The dose of 400 mg was selected on the basis of the data in relapsed/refractory CLL/SLL 
subjects from the ongoing venetoclax first-in-human Study M12-175.  A time-to-response 
model and a logistic-regression model were developed using data from Study M12-175 to 
understand the relationship between the response outcome and the final target venetoclax
dose.  Both models found that a faster response was achieved with a higher final target 
dose.  Further analysis focused on comparing 400 mg and 600 mg as the final target dose 
showed a minimum difference on the overall response rate (i.e., percentage of subjects 
with partial response or better).  With doses below 400 mg QD, however, a longer (and 
clinically unfavorable) duration will be needed to achieve the same response rate.  Since 
there is no strong difference between 400 mg and 600 mg as the final dose, the 400 mg 
dose was selected as the minimum effective dose.
To mitigate the risk for TLS, a lead-in period of 5 weeks will be employed to escalate 
venetoclax dose to the final treatment dose of 400 mg.  All high risk subjects will be 
admitted to the hospital and begin the lead-in period with an initial dose of 20 mg 
venetoclax on Week 1 Day 1 and first dose of 50 mg on Week 2 Day 1.  Low risk subjects 
and medium risk subjects with Cr Cl ≥ 80 mL/min will begin lead-in-period as 
outpatients.  If no significant findings suggestive of clinical or lab TLS occur within 
 


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24 hours, the same dose will be continued until Day 7 in the outpatient setting.  A dose of 
50 mg venetoclax will be administered on Week 2 Day 1.  After a week at 50 mg, weekly 
dose increments will be implemented as follows:  100 mg →200 mg →400 mg (or 
additional lead-in steps to designated 400 mg dose) as tolerated.  Expansion Cohort 
subjects with bulky disease that are non-responders either by clinical or radiographic 
Disease Assessment between Week 6 to Week 12 or subjects who show signs of clinical 
progression after completing the ramp up to 400 mg may be permitted to escalate 
venetoclax to a 600 mg dose.
The maximum dose in this study is 400 mg, however currently the established maximum 
clinical dose of venetoclax is not to exceed 1200 mg/day for a duration not to exceed 
48 months based on genotoxicity studies.
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.  Medical complaints are further detailed in the Adverse Events Section.  For 
adverse events, please refer to Sections 6.1 through 6.1.7.4.
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.
 


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All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient 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 6.1.7 regarding toxicity 
management]) and/or if the investigator considers them to be adverse events.
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 
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 adverse event is defined as any adverse event 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 study drug administration.
 


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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.  For deaths related to disease progression 
(coded to malignant neoplasm progression), the date and cause of death will be recorded 
on the appropriate case report form, however, the event will be considered expected for 
the purpose of determining expedited reporting requirements to regulatory authorities.  If 
the cause of death is unknown at the time of reporting, "unexplained death" should be 
recorded on the eCRF.  If the cause of death later becomes available "unexplained death"
should be replaced by the established cause of death.
Hospitalization of a subject to allow observation and management (e.g., for IV hydration) 
for the purpose of TLS prophylaxis will not be captured as a serious adverse event (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.).
Certain adverse events are anticipated to occur in the study population (CLL) at some 
frequency independent of drug exposure.  These are discussed here as Adverse Events 
commonly associated with CLL or progression of CLL.  Such events include known 
consequences of the underlying disease or condition under investigation (e.g., symptoms, 
 


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disease progression) and events unlikely to be related to the underlying 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 E.
These adverse events may occur alone or in various combinations and are considered 
expected for reporting purposes.
Although exempted from expedited reporting to Health Authorities and IRBs as 
individual cases, if an event commonly associated with CLL or progression of CLL meets 
seriousness criteria (as defined in Section 6.1.1.2) it must be reported to AbbVie within 
24 hours of the site being made aware of the serious adverse event.  For deaths related to 
disease progression (coded to malignant neoplasm progression), the date and cause of 
death will be recorded on the appropriate case report form, but the event will not be 
expedited as an individual case safety report (ICSR) to regulatory authorities.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4.0).27  If a reported adverse event increases in severity, the initial adverse event 
should be given final outcome date and a new adverse event must be reported to reflect
the change in severity.  The dates on the AE's cannot overlap.  For all reported serious 
adverse events that increase in severity, the supplemental eCRFs also need to be updated 
to reflect any changes due to the increase in severity.  For adverse events not captured by 
the Common Terminology Criteria, 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).
 


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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
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
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
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 a 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 serious 
adverse event.
6.1.4
Adverse Event Collection Period
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.
In addition, all adverse events reported from the time of study drug administration until 
30 days following discontinuation of study drug administration have elapsed will be 
collected, whether solicited or spontaneously reported by the subject.
 


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Serious and nonserious adverse events occurring after the study-specific informed consent 
is signed but prior to the initial dose of venetoclax will be collected only if they are 
considered by the Investigator to be causally related to the study-required procedures.
Adverse event information will be collected as shown in Figure 3.
Figure 3.
Adverse Event Collection
*Protocol-related 
SAEs & Nonserious 
AEs
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported




Study-
specific 
Consent 
Signed
Study 
Drug 
Start
Study Drug 
Stopped
30 Days After
After Study 
Drug Stopped
*
Only if considered by the Investigator to be causally related to study required procedures.
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance and Oncology Safety Management within 24 hours of the site being 
made aware of the serious adverse event.
Refer to Appendix G for COVID-19-related processes for this section.
 




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Escalation Hotline where your call will be re-directed to a designated backup AbbVie 
SDP.
Phone:  +1-973-784-6402
6.1.6
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 discontinuing study drug.  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.
Male subjects should be informed that contraceptive measures should be taken by their 
female partners.  If the subject's partner should become pregnant during the study, this 
should also be reported and data may be collected.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of 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.
 


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6.1.7
Toxicity Management
6.1.7.1
Prophylaxis and Management of Tumor Lysis Syndrome 
(TLS)
There is a potential for tumor lysis syndrome in subjects, affected by hematologic 
malignancies especially in those with bulky disease, elevated pretreatment lactate 
dehydrogenase (LDH) levels, elevated leukocyte count, renal dysfunction, and 
dehydration.
In response to the events of TLS reported in the Phase 1 studies in subjects with diagnosis 
of relapsed or refractory CLL treated with venetoclax monotherapy or in combination 
with an anti-CD20 antibody, an extensive review of the safety data was performed across 
all CLL trials in January of 2013.  These clinical data suggest that size of baseline lymph 
nodes is a risk factor for TLS, with larger lymph nodes resulting in increased risk.  In 
addition, creatinine clearance of ≤ 80 mL/min at Screening was identified as a risk factor 
for TLS.  Data analyses have resulted in development of three risk categories, listed 
below.  Risk category for an individual patient is determined upon study entry.
A detailed description of risk factors for developing tumor lysis following treatment with 
venetoclax is available in the current Investigator's Brochure.
A "TLS Prophylaxis and Monitoring Checklist" will be completed throughout the lead-in 
period to ensure proper TLS prophylaxis measures.
Refer to table in Appendix F for laboratory and clinical TLS.
For TLS prophylaxis, all subjects enrolling into the study will be classified into 3 risk 
categories based on the tumor burden prior to venetoclax administration.  The tumor 
burden assessed by the nodal disease and absolute lymphocyte count at Screening will be 
used to define each category as described below:
 


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6.1.7.1.1
Risk Categories for Developing TLS
TLS Risk Category
Criteria
Low
All measurable lymph nodes with the largest diameter 
< 5 cm AND ALC < 25 × 109/L
Medium
Any measurable lymph node with the largest diameter 
≥5 cm and < 10 cm OR ALC ≥ 25 × 109/L
High
Any measurable lymph node with the largest diameter 
≥10 cm
OR
ALC ≥ 25 × 109/L AND any measurable lymph node 
with the largest diameter ≥ 5 cm but < 10 cm
6.1.7.1.2
TLS Prophylaxis Guidelines
The section below describes the management of subjects throughout dosing based on their 
risk factors for developing TLS identified upon study entry.
First Dose of Venetoclax at 20 mg and at 50 mg
TLS prophylaxis must be initiated in all subjects irrespective of their TLS risk category 
prior to the first dose of venetoclax at 20 mg and at 50 mg.  
●
An oral agent to reduce the uric acid level (e.g., allopurinol) to be initiated at 
least 72 hours prior to dosing.  Treatment may need to be continued for up to 
5 weeks based on the ongoing risk of TLS development.  Subjects allergic to 
allopurinol must use another uric acid reducer.
●
Oral hydration consisting of fluid intake of 1.5 to 2 L per day starting at least 
48 hours prior to the start of treatment for all subjects prior to first dose, at all 
subsequent dose increment steps and continued for at least 24 hours after 
dosing until all of the chemistry laboratory values remain within ULN.  Oral 
hydration is recommended beyond 24 hours post-dose for subjects who 
demonstrate any laboratory changes.
 


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●
Serum chemistry and hematology laboratory samples (low risk and medium 
risk subjects to be treated in the outpatient setting) must be drawn anytime 
within 72 hours prior to first dose.  For subjects who will receive outpatient 
dosing, the 0 hour pre-dose chemistry and hematology lab results may be used 
for dosing decisions on Day 1 of each week during the lead-in period.  For 
subjects who will be hospitalized and will receive inpatient dosing, the 
chemistry and hematology labs must be drawn upon admission the night 
before first dose of venetoclax.  All electrolyte values should be reviewed and 
not demonstrate any clinically significant abnormalities prior to the first dose 
of venetoclax in order to keep the treatment on schedule.
●
If clinically significant laboratory abnormalities are observed in this baseline 
laboratory assessment, the first dose of venetoclax must be delayed until 
resolution and initiate TLS management per the protocol Appendix D, 
Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome (TLS) must be initiated.  If aggressive 
correction of electrolytes was performed, the initial dose of venetoclax can 
only be given when electrolytes have been stable without any further treatment 
for at least 24 hours.  If needed, subjects may continue to receive additional 
prophylactic treatment prior to the initiation of dosing.
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS 
risk category as follows:
Subjects in Low Risk Category
Subjects in the Low Risk category may begin the lead-in period in the outpatient setting if 
there is no indication to hospitalize.
●
For subjects who are unable to maintain adequate oral hydration, IV hydration 
of 1.5 to 2 L is recommended in the outpatient setting on D1 of the 20 mg and 
50 mg dose to assure the full amount of hydration is achieved.  For subjects in 
whom volume overload is considered a significant risk, hospitalization should 
be considered.
 


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●
Chemistry and hematology laboratory tests are to be performed within 
72 hours before the first dose of venetoclax.  These laboratory values must be 
reviewed by the investigator.  The investigator's decision to proceed with the 
initiation of venetoclax treatment may be based on these laboratory values.
●
Chemistry laboratory tests must be performed STAT at 0 hour (pre-dose, 
within 4 hours before venetoclax administration), 8, and 24* hours post-dose 
after the first dose of venetoclax at 20 mg and at 50 mg.  These laboratory 
values must be reviewed in real time by the investigator.  Results from 0 hour 
(pre-dose) laboratory values will be collected and used as baseline to assess 
potential electrolyte abnormalities occurring post venetoclax administration.  
Results from STAT 0 hour (pre-dose) laboratory values are not required to be 
available prior to initiating venetoclax treatment.  Subjects must remain at the 
hospital, or clinic, until the 8 hour laboratory values have been reviewed by the 
investigator.
●
The Day 2 dose of venetoclax should not be administered until the 24 hour 
post-dose chemistry laboratory values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient setting.
●
If any significant laboratory changes are observed within the first 24 hours 
after the first dose, refer to Appendix D (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]) for procedures to follow.  These laboratory values must be 
reviewed in real time by the investigator.
○
Additional laboratory assessments may be performed per investigator 
discretion.
●
Hematology laboratory tests must be performed 24* hours post-dose after the 
first dose of venetoclax at 20 mg and at 50 mg.
*
All 24 hour post-dose laboratory assessments may be taken within a 2 hour 
window if necessary.
 


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Subjects in Medium Risk Category
●
Subjects in the Medium Risk category who have creatinine clearance 
≥80 mL/min may receive their initial doses of venetoclax at 20 and 50 mg in 
the outpatient setting.
●
Subjects in the Medium Risk category who have creatinine clearance of 
< 80 mL/min and/or higher tumor burden (i.e., ALC > 100 × 109/L or multiple 
bulky nodes) may be handled as high risk subjects per investigator discretion 
for the first dose of venetoclax at 20 mg and 50 mg (Refer to section for high 
risk subjects below).
●
Subjects will receive IV hydration of 1.5 to 2 L in the outpatient setting on 
Day 1 of the 20 mg and 50 mg dose in addition to oral hydration as outlined 
above.  For subjects in whom volume overload is considered a significant risk, 
hospitalization should be considered.
●
Chemistry and hematology laboratory tests are to be performed within 
72 hours before the first dose of venetoclax.  These laboratory values must be 
reviewed by the investigator.  The investigator's decision to proceed with the 
initiation of venetoclax treatment may be based on these laboratory values.
●
Chemistry laboratory tests must be performed STAT at 0 hour (pre-dose, 
within 4 hours before venetoclax administration), 8, and 24* hours after the 
first dose of venetoclax at 20 mg and at 50 mg.  These laboratory values must 
be reviewed in real time by the investigator.  Results from 0 hour (pre-dose) 
laboratory values will be collected and used as baseline to assess potential 
electrolyte abnormalities occurring post venetoclax administration.  Results 
from STAT 0 hour (pre-dose) laboratory values are not required to be available 
prior to initiating venetoclax treatment.  Subjects must remain at the hospital, 
or clinic, until the 8 hour laboratory values have been reviewed by the 
investigator.
●
The Day 2 dose of venetoclax should not be administered until the 24 hour 
post-dose chemistry laboratory values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient setting. 
 


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●
If any significant laboratory changes are observed within the first 24 hours 
after the first dose, refer to Appendix D, (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]) for procedures to follow.  
○
Additional laboratory assessments may be performed per investigator 
discretion. 
●
Hematology laboratory tests must be performed 24* hours post-dose after the 
first dose of venetoclax at 20 mg and at 50 mg.
*
All 24 hours post-dose laboratory assessments may be taken within a 
2 hour window if necessary.
Subjects in High Risk Category
High-risk subjects will be hospitalized to receive their initial doses of 20 and 50 mg of 
venetoclax.  Hospitalization and monitoring will start the night before administration of 
the first dose of 20 mg and 50 mg of venetoclax and will be continued until the 24 hour 
post-dose chemistry laboratory values are reviewed by the investigator.
●
Chemistry and hematology laboratory tests are to be performed upon 
admission the night before the first dose of venetoclax.  The investigator's 
decision to proceed with venetoclax treatment initiation will be based on these 
laboratory values.  
●
Nephrology (or other acute dialysis service) consultation should be considered 
upon admission per institutional standards at investigators' discretion to ensure 
emergency dialysis is available and the appropriate staff is aware and prepared 
to handle any necessary intervention for TLS.  Telemetry should also be 
considered.
●
IV hydration must be started the night before the first dose of 20 mg and 
first dose of 50 mg, with a target of approximately 1.5 – 2 L/day, or as 
clinically appropriate, and continued for at least 24 hours after dosing.
 


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●
Rasburicase must be administered prior to the first dose of venetoclax (per 
regional standards or institutional guidelines) for subjects with elevated uric 
acid level at baseline (> ULN) or > Cairo-Bishop threshold of 476 mol/L) as 
prophylaxis.  For subjects with a contraindication to rasburicase 
(i.e., glucose-6-phosphate dehydrogenase [G6PD] deficiency), the TLS 
risk-mitigation plan must be reviewed with AbbVie medical monitor prior to 
initiating treatment.
●
Chemistry laboratory tests must be performed STAT at 0 (pre-dose, within 
4 hours before venetoclax administration), 4, 8, 12 and 24* hours after the 
first dose of venetoclax at 20 mg and 50 mg.  These laboratory values must be 
reviewed in real time by the investigator.  Results from 0 hour (pre-dose) 
laboratory values will be collected and used as baseline to assess potential 
electrolyte abnormalities occurring post venetoclax administration.  Results 
from 0 hour (pre-dose) laboratory values are not required to be available prior 
to initiating venetoclax treatment.
●
If any significant laboratory changes are observed within the first 24 hours 
after initiation of dosing, refer to Appendix D, (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]), for additional laboratory assessments and management 
guidelines.  If aggressive correction of electrolytes abnormalities was 
performed, the next dose of venetoclax can only be given when electrolytes 
have been stable without any further treatment for at least 24 hours.
●
Hematology laboratory tests will be performed pre-dose (within 4 hours before 
venetoclax administration), and 24* hours after the first dose of venetoclax at 
20 mg and 50 mg.
●
The Day 2 dose should not be administered until the 24 hour post-dose 
laboratory values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient setting.
*
All 24 hours laboratory assessments may be taken within 2 hour window if 
necessary.
 


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Dose Escalation of Venetoclax to 100 mg, 200 mg, and 400 mg
All subjects, irrespective of their risk category, must receive the following TLS 
prophylaxis measures prior to subsequent dose increases of venetoclax:
●
Continue administration of an oral uric acid reducer as indicated above.
●
Oral hydration consisting of fluid intake of approximately 1.5 to 2 L/day 
starting at least 48 hours days prior to each dose increment.  IV hydration is 
encouraged at subsequent dose increases for subjects who are unable to 
maintain such oral hydration.  IV hydration will be in the outpatient setting on 
the day of dose increment.  For subjects in whom volume overload is 
considered a significant risk, hospitalization should be considered.
●
Chemistry and Hematology laboratory tests for all subjects treated in the 
outpatient setting must be performed within 72 hours and results must be 
reviewed by the investigator prior to each dose escalation.  For subjects 
demonstrating any clinically significant laboratory abnormalities, additional 
prophylactic treatment should be administered prior to dosing (see 
Appendix D; Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]).  If 
aggressive correction of electrolytes was performed, the next dose of 
venetoclax can only be given when electrolytes have been stable without any 
further treatment for at least 24 hours.
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS 
risk category as follows:
Subjects Low Risk Category
●
Subjects in the Low Risk category will receive subsequent dose escalations 
(100, 200 and 400 mg) as outpatients.
 


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●
Chemistry laboratory tests will be performed at STAT at 0 hour (pre-dose, 
within 4 hours before venetoclax administration), 8 and 24* hours after dose 
administration.  Hematology laboratory tests must be performed STAT at 
0 hour (pre-dose, within 4 hours before venetoclax administration) and 24* 
hours post-dose.  These laboratory values must be reviewed in real time by the 
investigator.  Results from 0 hour (pre-dose) laboratory values will be 
collected and used as baseline to assess potential electrolyte abnormalities 
occurring post venetoclax administration.  Results from 0 hour (pre-dose) 
laboratory values are not required to be available prior to administering 
venetoclax treatment unless these results are used for dosing decisions.
*
All 24 hours laboratory assessments may be taken within 2 hour window if 
necessary.
●
Subjects must remain at the hospital, or clinic, until the 8 hour laboratory 
values have been reviewed by the investigator.
●
The Day 2 dose should not be administered until the 24 hours post-dose 
chemistry laboratory values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient setting.  
○
Additional laboratory assessments may be performed per investigator 
discretion.
Subjects in Medium Risk Category
●
Subjects in the Medium Risk category who have creatinine clearance 
≥80 mL/min may receive their subsequent dose escalations in the outpatient 
setting.
●
Subjects with creatinine clearance < 80 mL/min and/or higher tumor burden 
(i.e., ALC > 100 × 109/L or multiple bulky nodes) may be hospitalized per 
investigator's discretion.  Hospitalization will begin the evening prior to 
administering venetoclax and will continue for 24 hours after dose 
administration.
●
For subjects who receive their subsequent dose escalations in the outpatient 
setting, Chemistry laboratory tests will be performed 0 (pre-dose, within 
 


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4 hours before venetoclax administration), 8 and 24* hours post dose 
administration.  Hematology laboratory tests must be performed STAT at 
0 hour (pre-dose, within 4 hours before venetoclax administration) and 24* 
hours post-dose.  These laboratory values must be reviewed in real time by the 
investigator.  Results from 0 hour (pre-dose) laboratory values will be 
collected and used as baseline to assess potential electrolyte abnormalities 
occurring post venetoclax administration.  Results from 0 hour (pre-dose) 
laboratory values are not required to be available prior to initiating venetoclax
treatment unless these results are used for dosing decisions.
○
Subjects must remain at the hospital, or clinic, until the 8 hour laboratory 
values have been reviewed by the investigator.
○
The Day 2 dose should not be administered until the 24 hours post-dose 
chemistry laboratory values are reviewed by the investigator.
○
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient 
setting.
○
Additional laboratory assessments may be performed per investigator 
discretion.
●
For subjects who are hospitalized during subsequent dose escalations, 
Chemistry and Hematology laboratory tests will be performed upon admission.  
Chemistry tests will be performed STAT at 0 hour (pre-dose, within 4 hours 
before venetoclax administration), 4, 8, 12 and 24 hours post dose.  These 
laboratory values must be reviewed in real time by the investigator.  Results 
from 0 hour (pre-dose) laboratory values will be collected and used as baseline 
to assess potential electrolyte abnormalities occurring post venetoclax
administration.  
○
IV hydration should be started with a target of approximately 1.5 – 2 L per 
day or as clinically appropriate for subjects who are hospitalized.
○
Nephrology (or acute dialysis service) consultation may be considered on 
admission (based on investigator discretion) for hospitalized subjects.
○
Hematology laboratory tests will be performed 24 hours post-dose.
○
The 24-hour post-dose laboratory results must be reviewed by the 
investigator prior to the subject leaving the hospital. 
 


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○
The Day 2 dose should not be administered until the 24 hours post-dose 
chemistry laboratory values are reviewed by the investigator.
○
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient 
setting.
●
Additional laboratory assessments may be performed per investigator 
discretion.
*
All 24 hours laboratory assessments may be taken within 2 hour window if 
necessary.
Subjects in High Risk Category
●
High risk subjects may receive the subsequent dose increases as outpatients.  
Subjects with creatinine clearance < 80 mL/min and/or higher tumor burden 
(i.e., ALC > 100 × 109/L or multiple bulky nodes) may be hospitalized per 
investigator discretion.  Hospitalization will begin the night prior to 
administration of venetoclax and continue for 24 hours after dose 
administration.
●
For subjects who are hospitalized during subsequent dose escalations, 
Chemistry and Hematology laboratory tests will be performed upon admission.  
Chemistry tests will be performed STAT at 0 hour (pre-dose, within 4 hours 
before venetoclax administration), 4, 8, 12 and 24 hours post-dose.  These 
laboratory values must be reviewed in real time by the investigator.  Results 
from 0 hour (pre-dose) laboratory values will be collected and used as baseline 
to assess potential electrolyte abnormalities occurring post venetoclax
administration.
○
IV hydration should be started with a target of approximately 1.5 – 2 L per 
day or as clinically appropriate for subjects who are hospitalized.
○
Nephrology (or acute dialysis service) consultation may be considered on 
admission (based on investigator discretion) for hospitalized subjects.
○
Hematology laboratory tests will be performed 24 hours post-dose.
○
The 24-hour post-dose laboratory results must be reviewed by the 
investigator prior to the subject leaving the hospital.
 


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●
For subjects who are not hospitalized, Chemistry laboratory tests will be 
performed at 0 hours (pre-dose, within 4 hours before venetoclax
administration), 8 and 24 hours post dose administration.  Hematology
laboratory tests must be performed STAT at 0 hour (pre-dose, within 4 hours 
before venetoclax administration) and 24* hours post-dose.  These laboratory 
values must be reviewed in real time by the investigator.  Results from 0 hour 
(pre-dose) laboratory values will be collected and used as baseline to assess 
potential electrolyte abnormalities occurring post venetoclax administration.  
Results from 0 hour (pre-dose) laboratory values are not required to be 
available prior to initiating venetoclax treatment.
○
Intravenous hydration of approximately 1.5 to 2 L or as clinically 
appropriate will be given in the outpatient setting.
○
Subjects must remain at the hospital, or clinic, until the 8 hour laboratory 
values have been reviewed by the investigator.
●
The Day 2 dose should not be administered until the 24 hours post-dose 
chemistry laboratory values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient setting.
●
Additional laboratory assessments may be performed per investigator 
discretion.
Re-Assessment of Risk Category for Subjects with Lymph Nodes < 10 cm:
Subjects classified in the high-risk TLS category at Screening due to an absolute 
lymphocyte count ≥ 25 × 109/L AND a measurable lymph node with the largest diameter 
≥ 5 cm but less than 10 cm by radiologic assessment may have a re-evaluation of their 
TLS risk category based on their most recent ALC for dose escalations after 50 mg.  
Based on those results, one of the following two options may be implemented:
●
If the subject's ALC decreases to 25 × 109/L, the subject may be 
re-categorized as medium-risk for TLS and follow the TLS management
guidelines for the medium-risk category for subsequent dose escalations of 
venetoclax during the Lead-In Period.
 


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●
If the subject's ALC remains ≥ 25 × 109/L, the subject will remain in the 
high-risk TLS category and continue to follow TLS management guidelines 
for high-risk subjects for subsequent dose escalations of venetoclax during the 
Lead-In Period.
Re-assessment of the subject's TLS risk category can occur prior to each subsequent dose 
escalation.
Expansion Cohort:  Modified Dose Ramp-Up for Select High Risk Subjects Only
First Dose of Venetoclax at 20 mg and Dose Escalation 
Subjects who have signs of clinical progression at Screening and who are categorized as 
high-risk for TLS may participate in a Modified Lead-In Period allowing them to more 
rapidly escalate to higher doses of venetoclax.
A discussion between the investigator and the AbbVie medical monitor must occur 
before beginning the modified lead-in period. 
●
Hospitalization is required for these subjects starting the night before the initial 
dose of venetoclax and for a minimum of 24 hours after any dose escalation.  
All of the TLS prophylaxis measures described in Section 6.1.7.1.2 for the 
high risk category must be implemented before the first dose of venetoclax.
●
Chemistry and hematology laboratory tests to be performed upon admission to 
the hospital the night before first dose of venetoclax.  The investigator's 
decision to proceed with venetoclax treatment initiation will be based on these 
laboratory values.
●
Nephrology (or other acute dialysis service) consultation should be considered 
upon admission per institutional standards at investigators' discretion to ensure 
emergency dialysis is available and the appropriate staff is aware and prepared 
to handle any necessary intervention for TLS.  Telemetry should also be 
considered.
●
IV hydration must be started the night before the first dose of 20 mg with a 
target of approximately 1.5 – 2 L/day, or as clinically appropriate, and 
 


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continued for at least 24 hours after administration of the 100 mg dose of 
venetoclax.
●
Rasburicase must be administered prior to the first dose of venetoclax (per 
regional standards or institutional guidelines) for subjects with elevated uric 
acid level at baseline (> ULN) or > Cairo-Bishop threshold of 476 µmol/L) as 
prophylaxis.  For subjects with a contraindication to rasburicase (i.e., glucose 
6 phosphate dehydrogenase [G6PD] deficiency), the TLS risk mitigation plan 
must be reviewed with AbbVie medical monitor.
●
Chemistry and Hematology laboratory tests will be performed upon admission 
and daily at 0 hour.  Chemistry tests will be performed STAT at 0 hour 
(pre-dose, within 4 hours before venetoclax administration), 4, 8, 12 and 
24 hours post dose.  These laboratory values must be reviewed in real time by 
the investigator.  Results from 0 hour (pre-dose) laboratory values will be 
collected and used as baseline to assess potential electrolyte abnormalities 
occurring post venetoclax administration.  
●
The first dose of 20 mg venetoclax will be administered on Week 1 Day 1.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours then dose increments will be implemented as follows: 
○
50 mg (Week 1 Day 2 and Week 1 Day 3).
○
100 mg (Week 1 Day 4 – Week 1 Day 7) Subjects will remain in the 
hospital for at least 24 hours after reaching the 100 mg dose.
○
200 mg (Week 2 Day 1 – Week 2 Day 7) Subjects will remain in the 
hospital for at least 24 hours after reaching the 200 mg dose.
○
400 mg (Week 3 Day 1) Subjects will remain in the hospital for at least 
24 hours after reaching the 400 mg dose.
If there is indication of lab or clinical TLS the study drug dose will be interrupted until 
resolution of all findings.  If a subject has study drug interrupted for more than 3 days 
(i.e., adverse event), the site will contact the AbbVie study team or AbbVie medical 
monitor to adjust the subject's visit schedule, procedures and/or dosing on a case by case 
basis.  TLS management will be implemented as appropriate (per Appendix F).  If 
aggressive correction of electrolytes was performed, the subsequent dose of venetoclax 
 


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can only be given when electrolytes have been stable without any further treatment for at 
least 24 hours. 
Additional laboratory assessments may be performed per investigator discretion
●
The Week 2 Day 2 dose should not be administered until the 24 hours 
post-dose chemistry laboratory values are reviewed by the investigator. 
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours after the Week 2 Day 2 dose, the same dose will be continued in the 
outpatient setting.
●
TLS Chemistry labs will be performed at Week 2 Day 3 and Week 2 Day 4 
after reaching the 200 mg dose in the outpatient setting.
●
Week 3 Day 2 dose should not be administered until the 24 hours post-dose 
chemistry laboratory values are reviewed by the investigator. 
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours after Week 3 Day 2 dose, the same dose will be continued in the 
outpatient setting.
●
TLS Chemistry labs must be performed at Week 3 Day 3 and Week 3 
Day 4 after reaching the 400 mg dose in the outpatient setting.
Subjects with bulky disease who are non-responders either by clinical or radiographic 
Disease Assessment between Week 6 to Week 12 or subjects who show signs of clinical 
progression after completing the ramp up to 400 mg who are permitted to escalate 
venetoclax to 600 mg dose must be hospitalized and follow all of the high risk TLS 
prophylaxis guidelines below:
●
Venetoclax dose escalation to 600 mg may occur once approved by AbbVie 
Medical Monitor.  Subjects will remain in the hospital for at least 24 hours 
after reaching the 600 mg dose.
●
Chemistry and Hematology laboratory tests will be performed upon admission 
and daily at 0 hour.  Chemistry tests will be performed STAT at 0 hour 
(pre-dose, within 4 hours before venetoclax administration), 4, 8, 12 and 
24 hours post dose.  These laboratory values must be reviewed in real time by 
 


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the investigator.  Results from 0 hour (pre-dose) laboratory values will be 
collected and used as baseline to assess potential electrolyte abnormalities 
occurring post venetoclax administration.  
●
IV hydration should be started with a target of approximately 1.5 – 2 L per day 
or as clinically appropriate upon admission to the hospital and continued for at 
least 24 hours after the administration of the escalated dose.
●
Nephrology (or acute dialysis service) consultation may be considered on 
admission (based on investigator discretion). 
●
Chemistry and Hematology laboratory tests will be performed 24 hours 
post-dose.
●
The 24-hour post-dose laboratory results must be reviewed by the investigator 
prior to the subject receiving the dose on W13 D2 and leaving the hospital. 
●
The Day 2 dose should not be administered until the 24 hours post-dose 
chemistry laboratory values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued in the outpatient setting.
●
Additional laboratory assessments may be performed per investigator 
discretion.
●
TLS Chemistry labs must be performed on Day 3, Day 4 and Day 5 after 
reaching the 600 mg dose in the outpatient setting.
Any subject, who at any dose level develops clinically significant electrolyte 
abnormalities must have their subsequent venetoclax dose interrupted until the electrolyte 
abnormalities resolve.  Electrolyte changes should undergo aggressive management and 
further monitoring as per Appendix D, Recommendations for Initial Management of 
Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS).  If aggressive 
correction of electrolytes was performed, the next dose of venetoclax can only be given 
when electrolytes have been stable without any further treatment for at least 24 hours.  
The subject may resume dosing based on a risk assessment (including tumor burden 
status), as determined by the investigator.  All subjects must receive the intended dose for 
at least 7 consecutive days before increasing to the next higher dose.
 


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6.1.7.2
Management of Neutropenia
Based on clinical observations with the 1st generation Bcl-2 inhibitor, navitoclax and in 
vitro colony-forming assays to assess Bcl-2-selective inhibitor effects on granulocyte 
precursors, it is possible that subjects treated with venetoclax might experience 
neutropenia.  Subjects with a history of neutropenia, who have received multiple prior 
therapies and/or have significant bone marrow involvement, may be at particular high 
risk. If determined to be clinically indicated by the treating physician in compliance with 
ASCO guidelines,32 G-CSF may be administered during dosing of venetoclax.  The use of 
G-CSF support is strongly recommended for subjects with Grade 4 neutropenia (ANC 
< 500/μL).  If the subject presents with febrile neutropenia or Grade 4 neutropenia for 
more than one week despite the use of optimal G-CSF support, venetoclax dosing should 
be interrupted until ANC recovery to > 500/μL.  Venetoclax may then be re-initiated at a 
lower dose as defined in the following table.  Subjects not responding to G-CSF despite 
venetoclax interruption should undergo further evaluation to determine the etiology of the 
neutropenia.  If study drug administration is interrupted (i.e., adverse event), the site will 
contact the AbbVie study team or AbbVie Medical Monitor to adjust the subject's visit 
schedule, procedures and/or dosing on a case by case basis.
Table 12.
Dose Reduction Guidelines for Management of Neutropenia
Venetoclax Dose
Reduced Dose
600 mg
400 mg
400 mg
200 mg
200 mg
100 mg
100 mg 
50 mg
50 mg
Re-challenge at 20 mga
a.
Subjects who do not tolerate 50 mg will discontinue venetoclax, but remain on study for Post Treatment Follow-Up 
Visits to assess for progression.
6.1.7.3
Management of Lymphopenia
There is a potential for clinically significant lymphopenia in this study.  If clinically 
indicated, anti-infective prophylaxis should be implemented at the investigator's 
 


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discretion, including appropriate prophylaxis for viral, fungal, bacterial or Pneumocystis 
infections.  Potential for drug-drug interactions should be considered.  Most anti-fungals 
are excluded and other commonly used agents may be cautionary or prohibited due to 
drug-drug interactions.  Please refer to Table 1 and Appendix C for a description of 
excluded and cautionary medications/food items.
6.1.7.4
Management of Decrease in Spermatogenesis
Based on findings in a preclinical study, there is a potential for decreased 
spermatogenesis.  Male subjects should consider sperm banking before treatment with 
venetoclax if they are considering preservation of fertility.
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 CRO Clinical Monitor or the following 
AbbVie Clinical Monitor(s):
 




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8.0
Statistical Methods and Determination of Sample 
Size 
8.1
Statistical and Analytical Plans
Unless otherwise noted, statistical analyses will be two-sided using alpha = 0.05 
(one-sided alpha = 0.025 where applicable).
The primary and secondary efficacy analyses will be performed on all subjects enrolled 
unless otherwise specified.  The date of enrollment is defined as the date that the IxRS 
provided a subject number.
Safety analyses will be performed on all subjects who receive at least one dose of 
venetoclax.
Detailed analysis descriptions will be provided in a separate statistical analysis plan.
8.1.1
Baseline Characteristics
All baseline summary statistics will be based on characteristics prior to the initiation of 
study drug.  Unless otherwise stated, baseline for a given variable will be defined as the 
last value for that variable obtained prior to the first dose of study drug.
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 errors, 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.
 


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8.1.2
Efficacy Endpoints Per Investigator Assessment
8.1.2.1
Primary Efficacy Endpoints
The primary efficacy endpoint will be overall response rate (ORR) – the proportion of
subjects with an overall response (per the investigator assessment) will be calculated for 
all subjects 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 ORR.
The assessment of ORR will be performed independently for Arm A, Arm B and the 
Expansion Cohort.  In the Expansion Cohort assessment of ORR will be performed 
independently for ibrutinib failure and idelalisib failure subjects.  Subjects who have not 
had a confirmed response prior to the data "cutoff" date defined in Section 8.1.3 will be 
considered to be non-responders.
8.1.2.2
Secondary Efficacy Endpoints
Key secondary efficacy endpoints will include duration of response, time to progression, 
progression-free survival, and overall survival.
Duration of response will be defined as the number of days from the date of first response 
(CR 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 response will be analyzed by 
Kaplan-Meier methodology using data for all enrolled subjects.  Median duration of 
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 
 


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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 patients 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 
assessment.  Data for patients 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.
 


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8.1.3
Efficacy Endpoints Per Independent Review Committee
An Independent Review Committee (IRC) will evaluate disease progression and response.  
The following efficacy endpoints, described in Section 8.1.2, will be summarized based 
on this IRC review:  overall response rate, duration of response, time to progression, and 
progression-free survival.
8.1.4
Timing of Efficacy Endpoints and Safety Evaluations
The date when 60 subjects in the Expansion Cohort have completed their Week 36 disease 
assessment, or after all enrolled subjects have discontinued venetoclax, whichever is 
earlier, will be defined as the data "cutoff" date for the efficacy analyses.  Efficacy and 
safety data up to and including this date will be collected.  Exact data cutoff date for the 
efficacy analysis will be detailed in a statistical analysis plan (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 from the date of the last subject enrolled in study.  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.
8.1.5
Pharmacokinetics
An analysis may be performed using a nonlinear mixed-effect population modeling 
approach with NONMEM software to describe the disposition of venetoclax, to identify 
significant covariates and explore relationship between pharmacokinetics and 
pharmacodynamics by combining data from this study with other venetoclax clinical 
studies.  Additional analyses may be performed if useful in the interpretation of the data.
 


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8.1.6
Additional Exploratory Efficacy Analyses
Time to next anti-CLL treatment will be defined as the number of days from the date of 
the first dose of venetoclax to the date of first dose of new non-protocol anti-lymphoma 
therapy (NPT) or death from any cause.  For subjects who did not take NPT, the data will 
be censored at the last known date to be free of NPT.  TTNT will be analyzed by 
Kaplan-Meier methodology using data for all enrolled subjects.  Median TTNT time will 
be calculated and 95% confidence interval for median TTNT time will be presented.
The rate of MRD negativity in subjects will be an exploratory endpoint.  This rate will be 
defined as the proportion of subjects who had MRD negativity status.  Ninety-five percent 
(95%) confidence intervals based on the binomial distribution will be provided.
Health Economic and Patient Reported Outcome measures will include the EORTC 
QLQ-C30 and QLQ CLL16 (a measure of health related quality of life specific to CLL) 
and the EQ-5D-5L (measure of general health status) and EQ-5D-VAS.  Descriptive 
statistics will be calculated for the EORTC QLQ-C30 and EORTC QLQ CLL16, the 
EQ-5D-5L utility score, and the EQ-5D-VAS score including mean change from baseline 
to each assessment as well as the final visit.  Additionally, the EORTC QLQ-C30 and 
EORTC QLQ CLL16 will be administered through post-treatment.  The results obtained 
for each instrument will be explored for trends and summarized as appropriate.
Alternative statistical analyses may be performed if deemed as necessary and helpful in 
understanding the drug effect.
8.1.7
Safety
The safety of venetoclax will be assessed by evaluation study drug exposure, adverse 
events, serious adverse events, all deaths, as well as changes in laboratory values and vital 
sign parameters.
Safety analyses will be performed for all subjects who take at least one dose of study 
drug.
 


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8.1.7.1
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 MedDRA dictionary.  In addition, 
the percentage of subjects experiencing an adverse event at a NCI CTCAE Version 4.0 
toxicity grade, and relationship to study drug will be provided.
8.1.7.2
Serious Adverse Events
Serious adverse events will be summarized using the same methods as Adverse Events 
described above.
8.1.7.3
Deaths
The number of subject deaths will be summarized (1) for deaths occurring within 30 days 
of the last dose of study drug, (2) for deaths occurring more than 30 days of the last dose 
of study drug, and (3) for all deaths in this study regardless of the number of days after the 
last dose of study drug.
8.1.7.4
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline will be analyzed for each scheduled post-baseline visit and for the 
final visit for blood chemistry and hematology parameters, as well as urinalysis and vital 
sign parameters.  If more than one measurement exists for a subject on a particular day, 
then an arithmetic average will be calculated.  This average will be considered to be that 
subject's measurement for that day.  Post-baseline measurements more than 30 days after 
the last dose of study drug will not be included.  Subjects that do not have a baseline 
measurement or do not have any post-baseline measurements will not be included.
 


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8.1.7.5
Analyses of Laboratory Data Using NCI CTCAE
Where applicable, blood chemistry, hematology and lymphocyte enumeration 
determinations will be categorized according to NCI CTCAE version 4.0 grades or higher, 
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.  An 
exception will be used for those subjects enrolled with a baseline value of neutrophils less 
than 1,000/μL requiring G-CSF support to meet entry criteria.  For these subjects, the last 
value pre-G-CSF administration will be the baseline.  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
There is no planned hypotheses testing on the primary endpoint overall response rate 
(ORR).  ORR will be presented by a point estimate and its corresponding 95% confidence 
interval.  A sample size of 20 subjects would ensure that the distance of true rate will be 
within 23% of the observed rate with 95% confidence and a sample size of 60 subjects 
would ensure that the distance of true rate will be within 14% of the observed rate with 
95% confidence.
 


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Table 13.
Sample Size Calculation
Number of Subjects (N)
Distance of True Rate from Observed Rate
20
23%
40
17%
60
14%
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 
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 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.
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.
Refer to Appendix G for COVID-19-related processes for this section.
 


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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 A.
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 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.
Pharmacogenetic analysis will only be performed if the subject has voluntarily signed and 
dated a separate pharmacogenetic informed consent, approved by an IRB/IEC, after the 
nature of the testing has been explained and the subject has had an opportunity to ask 
questions.  The separate pharmacogenetic informed consent must be signed before the 
pharmacogenetic testing is performed.  If the subject does not consent to the 
pharmacogenetic testing, it will not impact the subject's participation in the study.
 


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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, subjects' diaries 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(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 
 


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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.
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 
investigator 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.
Refer to Appendix G for COVID-19-related processes for this section.
11.0
Data Quality Assurance
Prior to enrolling any subject in the study, a Site Initiation Visit will be held with AbbVie 
personnel (and/or their representatives), the investigators, and the appropriate site 
personnel.  This meeting will include a detailed discussion and review of the protocol and 
essential documents, performance of study procedures, eCRF completion, and specimen 
collection methods.  The personnel at the study site will be trained on the study 
procedures, when applicable, by an AbbVie monitor or designee.
The AbbVie monitor or designee will monitor the study site throughout the study.  A 
source document review will be performed against entries on the eCRFs and a quality 
assurance check will be performed to ensure that the investigator is complying with the 
protocol and regulations.  In addition, ongoing review of the data will be conducted by a 
physician or representative at AbbVie.
 


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Data entered into eCRFs will be electronically transferred to AbbVie and imported into 
the database using validated software throughout the study.  Computer logic checks will 
be run to identify such items as inconsistent study dates.  Any necessary corrections will 
be made to the eCRF.
Routine hematology, serum chemistry and serology, and urinalysis will be conducted 
using the local laboratory.
A review of all laboratory results will be conducted by a physician and clinical review 
team at AbbVie, the AbbVie monitors (or their representatives), the investigator, and 
other appropriate personnel from AbbVie.
12.0
Use of Information
All information concerning venetoclax and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
venetoclax.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical investigators, other pharmaceutical companies, and to governmental agencies.  To 
allow for the use of the information derived from this clinical study and to ensure 
complete and thorough analysis, the investigator is obligated to provide AbbVie with 
complete test results and all data developed in this study and to provide direct access to 
source data/documents for study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
 


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The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name and subject number.  This list will be 
maintained at the study site with other study records under adequate security and 
restricted access and will not be retrieved by AbbVie.
Any pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature and the results will not be suitable for clinical decision making 
or patient management.  Hence, neither the investigator, the subject, nor the subject's 
physician (if different from the investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic 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.  Aggregate pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  Pharmacogenetic information will be published or presented only in a way 
that does not identify any individual subject.
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 retain any records related to the study according to local 
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 
 


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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.
 


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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: 
A Phase 2 Open-Label Study of the Efficacy and Safety of ABT-199 
(GDC-0199) in Chronic Lymphocytic Leukemia Subjects with 
Relapse or Refractory to B-Cell Receptor Signaling Pathway 
Inhibitor Therapy
Protocol Date:
15 December 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
Reference List
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Willis S, Day CL, Hinds MG, et al.  The Bcl-2-regulated apoptotic pathway.  J Cell 
Sci.  2003;116(Pt 20):4053-6.
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Cory S, Adams JM.  The Bcl-2 family:  regulators of the cellular life-or-death 
switch.  Nature Rev Cancer.  2002;2(9):647-56.
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Borner C.  The Bcl-2 protein family:  sensors and checkpoints for life-or-death 
decisions.  Mol Immunol.  2003;39(11):615-47.
4.
Cory S, Huang DC, Adams JM.  The Bcl-2 family:  roles in cell survival and 
oncogenesis.  Oncogene.  2003;22(53):8590-607.
5.
Cimmino A, Calin GA, Fabbri M, et al.  miR-15 and miR-16 induce apoptosis by 
targeting BCL2.  Proc Natl Acad Sci USA.  2005;102(39):13944-9.
6.
Calin GA, Cimmino A, Fabbri M, et al.  MiR-15a and miR-16-1 cluster functions 
in human leukemia.  Proc Natl Acad Sci USA.  2008;105(13):5166-71.
7.
Souers AJ, Leverson JD, Boghaert ER, et al.  ABT-199, a potent and selective 
BCL-2 inhibitor, achieves antitumor activity while sparing platelets.  Nat Med.  
2013;19(2):202-8.
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Del Gaizo Moore V, Schlis KD, Sallan SE, et al.  BCL-2 dependence and ABT-737 
sensitivity in acute lymphoblastic leukemia.  Blood.  2008;111(4):2300-9.
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Yan W, Huang JX, Lax AS, et al.  Overexpression of Bcl-W in the testis disrupts 
spermatogenesis:  revelation of a role of BCL-W in male germ cell cycle control.  
Mol Endocrinol.  2003;17(9):1868-79.
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Sugiyama N, Obinata M, Matsui Y.  Bcl-2 inhibits apoptosis of spermatogonia and 
growth of spermatogonial stem cells in a cell-intrinsic manner.  Mol Reprod Dev.  
2001;58(1):30-8.
11.
Oldereid NB, Angelis PD, Wiger R, et al.  Expression of Bcl-2 family proteins and 
spontaneous apoptosis in normal human testis.  Mol Hum Reprod.  
2001;7(5):403-8.
 


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Yamamura K, Kamada S, Ito S, et al.  Accelerated disappearance of melanocytes in 
bcl-2-deficient mice.  Cancer Res.  1996;56(15):3546-50.
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Wilson H, O'Connor A, Czuczman S, et al.  Phase 1/2a study of navitoclax 
(ABT-263) in relapsed or refractory lymphoid malignancies.  Haematologica.  
2010;95 Suppl 2:116-7.  Abstract 0292.
14.
AbbVie.  ABT-199 Investigator's Brochure Edition 12.  14 January 2020.
15.
Jaglowski S, Jones JA.  Choosing first-line therapy for chronic lymphocytic 
leukemia.  Expert Rev Anticancer Ther.  2011;11(9):1379-90.
16.
Zwiebel JA, Cheson BD.  Chronic lymphocytic leukemia:  staging and prognostic 
factors.  Semin Oncol.  1998;25(1):42-59.
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American Cancer Society: Cancer Facts and Figures 2013.  Atlanta, GA:  
American Cancer Society, 2013.
18.
Sant M, Allemani C, Tereanu C, et al.  Incidence of hematologic malignancies in 
Europe by morphologic subtype:  results of the HAEMACARE project.  Blood.  
2010;116(19);3724-34.  Erratum in:  Blood.  2011;117(12):3477.
19.
Jemal A, Clegg LX, Ward E, et al.  Annual report to the nation on the status of 
cancer, 1975-2001, with a special feature regarding survival.  Cancer.  
2004;101(1):3-27.
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Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in 
chronic lymphocytic leukemia.  N Engl J Med.  2000;343(26):1910-6.
21.
Oppezzo P, Dighiero G.  "Role of the B-cell receptor and the microenvironment in 
chronic lymphocytic leukemia." Blood Cancer J.  2013;3:e149.
22.
Chang BY, Furman RR, Zapatka M, et al.  Use of tumor genomic profiling to 
reveal mechanisms of resistance to the BTK inhibitor ibrutinib in chronic 
lymphocytic leukemia (CLL).  J Clin Oncol.  2013;31(15 Suppl):7014.
23.
Herishanu Y, Katz B-Z, 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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24.
Bodet-Milin C, Kraeber-Bodéré F, Moreau P, et al.  Investigation of FDG-PET/CT 
imaging to guide biopsies in the detection of histological transformation of indolent 
lymphoma.  Haematologica.  2008;93(3):471-2.
25.
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.
26.
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(12):5446-56.
27.
National Cancer Institute.  Common Terminology Criteria for Adverse Events 
(CTCAE), v4.0, NCI, NIH, DHHS.  28 May 2009.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
Accessed on:  09 September 2010.
28.
Böttcher S, Ritgen M, Fischer K, et al.  Minimal residual disease quantification is 
an independent predictor of progression-free and overall survival in chronic 
lymphocytic leukemia:  a multivariate analysis from the randomized GCLLSG 
CLL8 trial.  J Clin Oncol.  2012;30(9):980-8.
29.
EORTC quality of life.  EORTC QLQ-C30 and EORTC QLQ CLL16.  Available 
from:  http://groups.eortc.be/qol.
30.
EQ-5D measure of health outcome.  EQ-5D-5L and EQ-5D-VAS.  Available from:  
http://www.euroqol.org.
31.
Coiffier B, Altman A, Pui CH, et al.  Guidelines for the management of pediatric 
and adult tumor lysis syndrome:  an evidence-based review.  J Clin Oncol.  
2008;26(16):2767-78.
32.
Smith TJ, Khatcheressian J, Lyman GH, et al.  2006 update of recommendations 
for the use of white blood cell growth factors:  an evidence-based clinical practice 
guideline.  J Clin Oncol.  2006;24(19):3187-205.
 


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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
Study Project Manager
Clinical
Head of Statistics
Statistics
Senior Consultant, Clinical Supply
Global Drug Supply Management
Senior Medical Director
Clinical
Director
Clinical Pharmacokinetics
Senior Scientist III
Discovery
Principle Bioanalytical Investigator
Bioanalysis
 


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Appendix C.
Sample List of Excluded and Cautionary Medications
Excluded During Ramp-Up Phase and Cautionary Afterwards:  (Additional Guidance Noted):
Strong CYP3A inducers – avasimibe, carbamazepine, enzalutamine, mitotane, phenytoin, rifampin, 
St. John's wort
Moderate CYP3A inducers^ – bosentan, efavirenz, etravirine, modafinil, nafcillin
Strong CYP3A inhibitors† – Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, 
elvitegravir/ritonavir, idelalisib,* indinavir, itraconazole, ketoconazole, mibefradil, lopinavir/ritonavir, 
nefazodone, nelfinavir, paritaprevir/ritonavir combinations, ritonavir, posaconazole, saquinavir, 
telaprevir, telithromycin, tipranavir/ritonavir, troleandomycin, voriconazole
Moderate CYP3A inhibitors†† – Amprenavir, aprepitant, atazanavir, cimetidine, ciprofloxacin, clotrimazole, 
crizotinib,* cyclosporine,* darunavir/ritonavir, diltiazem,1 dronedarone, erythromycin, fluconazole, fluvoxamine, 
fosamprenavir, imatinib,* isavuconazole, tofisopam, verapamil
Cautionary
Coumarins (vitamin K antagonists):
  Warfarin (Coumadin)**
  phenprocoumon (Marcumar)**
P-gp substrates
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus,* fexofenadine, lapatinib,* 
loperamide, maraviroc, nilotinib,* ranolazine, saxagliptin, sirolimus,* sitagliptin, talinolol, tolvaptan, 
topotecan*
BCRP substrates
Methotrexate,* mitoxantrone,* irrinotecan,* lapatinib,* rosuvastatin, sulfasalazine, topotecan*
OATP1B1/1B3 substrates
Asunaprevir,  atrasentan, atorvastatin, certivastatin, docetaxel, ezetimibe, fluvastatin, glyburide, 
nateglinide, paclitaxel, rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, telmisartan, 
valsartan, olmesartan
P-gp inhibitors
Amiodarone, captopril, carvedilol, , felodipine, propafenone, quercetin, ronalzine, ticagrelor
BCRP inhibitors
Geftinib*, curcumin
Note that this is not an exhaustive list.  For an updated list, see the following link:  
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm08049
9 htm
In addition to the medications listed in this table, subjects receiving venetoclax should not consume grapefruit, 
grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruits.
*
These are anticancer agents; contact AbbVie medical monitor before use.
**
Closely monitor international normalized ratio (INR).
^
If subject requires use of these medications, use with caution and contact AbbVie Primary TA MD or designee for 
guidance.
 


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†
If subject requires use of these medications, use with caution and reduce the venetoclax dose at least by 4-fold.  
After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose is increased back to the target 
dose.
††
If subject requires use of these medications, use with caution and reduce the venetoclax dose at least by 2-fold.  
After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose is increased back to the target 
dose.
1
Moderate CYP3A inhibitor per venetoclax FDA USPI.
 


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Appendix D.
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS)
Section 1:  First Dose of Venetoclax or Dose Escalation
●
Within the first 24 hours after either the first dose or dose escalation, if any 
laboratory criteria below are met, the patient should be hospitalized for 
monitoring and the investigator notified.  No additional venetoclax doses 
should be administered until resolution.  A rapidly rising serum potassium is a 
medical emergency.
●
Nephrology (or other acute dialysis service) must be consulted/contacted (per 
institutional standards to ensure emergency dialysis is available) upon 
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 least 
1 mL/kg/hr rounded to the nearest 10 mL (target 150 to 200 mL/hr; not 
< 50 mL/hr).  Modification of fluid rate should also be considered for 
individuals with specific medical needs.
●
Rasburicase must be administered/considered per regional standards or 
institutional guidelines for subjects with rapidly rising uric acid level.
●
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.
 


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In addition to the recommendations in the table below, for patients receiving the first dose 
of venetoclax:
●
For potassium increase ≥ 0.5 mmol/L from baseline, or any value 
> 5.0 mmol/L, recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour STAT and follow first guideline.
●
For phosphorus increase of > 0.5 mg/dL AND > 4.5 mg/dL, administer 
phosphate binder and recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour STAT.
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.
If potassium < ULN 1 hour later, repeat potassium, phosphorus, uric 
acid, calcium and creatinine 1, 2 and 4 hours, if no other evidence of 
tumor lysis.
 


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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.
If rasburicase is used, sodium bicarbonate 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).
If rasburicase is used, sodium bicarbonate should not be used as this 
may exacerbate calcium phosphate precipitation.
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT.
Uric acid ≥ 10 mg/dL
(595 µmol/L)
OR
Uric acid ≥ 8.0 mg/dL 
(476 µmol/L) with 25% 
increase and creatinine 
increase ≥ 0.3 mg/dL 
(≥0.027 mmol/L) from 
pre-dose level
Administer rasburicase (dose based on local guidelines and/or 
institutional standards).
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.
If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, phosphorus, uric 
acid, calcium and creatinine 2 and 4 hours, later, if no other evidence of 
tumor lysis.
 


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Abnormality
Management Recommendations
Hypocalcemia
Calcium ≤ 7.0 mg/dL 
(1.75 mmol/L)
AND
Patient 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 hour STAT.
If calcium normalized 1 hour later, repeat potassium, phosphorus, uric 
acid, calcium and creatinine 2 and 4 hours, later, if no other evidence of 
tumor lysis.
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 hour STAT.
If phosphorus < 5.0 mg/dL 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium and creatinine 2 and 4 hours, later, if no other 
evidence of tumor lysis.
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.
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 patient is hospitalized, no additional venetoclax doses should be administered 
until resolution.
 


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●
For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or 
any level > upper limit of normal.
○
Refer to the management guidelines for electrolyte changes observed 
within the first 24 hours after either the first dose or dose escalation (see 
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 E.
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)
Secondary 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
 


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


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Appendix F.
Definitions of Laboratory and Clinical Tumor Lysis Syndrome
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 falure 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 definited as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 µmol per 
liter) or a period of oliguia lasting 6 hours or more.  By definition, if acute kidney injury is present, the patient has 
clinical tumor lysis syndrome.  Data about acute kidney injurt from Levin at al.
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.
Summary of COVID-19 Processes
Section
Title
Language Added
3.2
Benefits and 
Risks
Considering the coronavirus (COVID-19) pandemic, the benefit and risk 
to subjects participating in this study has been re-evaluated.  Subjects 
receiving venetoclax may be at an increased risk for COVID-19 infection 
or experience serious illness if infected.  Management of these adverse 
events will be made on a case-by-case basis with consideration of 
benefit/risk.  However, based on the population and disease being 
studied and the anticipation that COVID-19 related risks are not 
expected to differ substantially between study subjects and the broader 
population of subjects receiving treatment for CLL, no change to the 
benefit/risk balance for subjects in this study is expected.
5.2.3
Prior and 
Concomitant 
Therapy
A vaccine for COVID-19, though not yet available at the time of 
protocol amendment version 6.0, may be allowed when available after 
documented communication with the AbbVie TA MD.
5.3.1.1
Study 
Procedures
During the COVID-19 pandemic, it has been necessary to employ 
mitigation strategies to enable the investigator to ensure patient safety 
and continuity of care.  Acceptable mitigation strategies are identified 
below and throughout the protocol.
Study visits may be impacted due to the COVID-19 pandemic.  This may 
include changes such as phone or virtual visits, visits at alternative 
locations, or changes in the visit frequency and timing of study 
procedures, among others.  Additional details are provided in the 
subsequent section.  Every effort should be made to ensure the safety of 
subjects and site staff, while maintaining the integrity of the study.  If 
visits cannot be conducted onsite due to travel restrictions or other 
pandemic-related reasons, follow the updates below on how to proceed.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, if it is not possible for all study 
procedures to be performed as specified due to travel restrictions or other 
reasons, the following modifications are allowed:

Some study visits and/or activities may be performed by 
phone/virtually.

Some study visits and/or activities may be performed by a local 
clinic/hospital/laboratory.  All procedures performed at local 
facilities must be performed by appropriately qualified personnel.

Study visits and/or activities should be performed as scheduled 
whenever possible.  If it is not possible to do so due to the 
pandemic, the following modifications are allowed:
o
If an activity is missed during a virtual visit, perform the 
activity at the earliest feasible opportunity.
o
NOTE:  If a subject tests positive for COVID-19 or if there is 
 


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Section
Title
Language Added
strong suspicion of COVID-19 (based on symptoms, travel 
history, or close contact with a case), the investigator should 
evaluate the benefit/risk of venetoclax being interrupted until 
the infection has resolved or has been ruled out.  There are no 
time limits for venetoclax interruption as long as no permanent 
study discontinuation criteria have been met.  The investigator 
should contact the AbbVie TA MD prior to reintroducing 
venetoclax in research participants previously diagnosed with 
COVID-19.  See also Section 5.4.1, Discontinuation of 
Individual Subjects, for additional detail.
Informed Consent
Due to the COVID-19 pandemic, it is possible that additional protocol 
modifications not outlined in this protocol may become necessary.  If 
this situation arises, in addition to the study informed consent, additional 
verbal consent may be obtained prior to these adaptations or substantial 
changes in study conduct in accordance with local regulations.
Clinical Laboratory Testing

If travel restrictions or other changes in local regulations in light of 
the COVID-19 pandemic prevent the subject from having blood 
drawn for laboratory testing at the study site, if possible, arrange for 
subjects to have laboratory work done at a local lab, hospital, or 
other facility.  Local lab results should be obtained along with 
reference ranges and kept within the subjects' source documentation.  
Local lab results should be reviewed by the investigator as soon as 
possible and before venetoclax is administered.

If laboratory samples cannot be obtained, study drug administration 
may be continued provided the investigator has reviewed all prior 
laboratory results and confirms and discusses with the subject that 
there is no safety concern for the subject to continue use of the study 
drug in the absence of current labs.  The subject should be 
scheduled for laboratory draws as soon as feasible.
5.4.1
Discontinuation 
of Individual 
Subjects
COVID-19 Pandemic-Related Acceptable Protocol Modification
The investigator should contact the sponsor medical contact before 
discontinuing a subject from the study for a reason other than "planned 
per protocol," to ensure all acceptable mitigation steps have been 
explored.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
During the Study Drug Dosing Period, a subject with confirmed (viral 
test positive) or suspected COVID-19 infection can only be dosed with 
study drug if the following COVID-19 viral clearance criteria are met:

Symptomatic subjects:  At least 2 negative viral tests in a row, 
≥24 hours apart after at least 10 days have passed since recovery, 
defined as resolution of fever without use of antipyretics and 
 


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Section
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Language Added
improvement in respiratory symptoms (e.g., cough, shortness of 
breath)

Asymptomatic subjects:  At least 2 negative viral tests in a row, 
≥24 hours apart after at least 10 days have passed since prior 
positive result (note:  subjects who develop symptoms will follow 
guidance above for symptomatic subjects)
Delays in study drug dosing due to the above COVID-19 testing 
guidance for subjects must be discussed with the AbbVie medical 
contact, along with the possibility of premature discontinuation from the 
study drug dosing period.  Frequency or timing of COVID-19 testing and 
intervals between testing for the above viral clearance criteria may be 
adjusted to account for epidemiologic trends, updated information 
regarding infectivity, and local/institutional guidelines.
5.5.1
Treatments 
Administered
Direct-to-patient (DTP) Shipment of Study Drug
If a subject is unable to come to the study site to pick up their study drug 
due to COVID-19, a direct-to-patient (DTP) study drug shipment can be 
made from the study site to the subject if allowed by local regulations.  
AbbVie will submit any required notifications to the regulatory authority 
as applicable.
Study drug may be shipped from the study site directly to the study 
subject's home if all the following criteria are met:

Direct-to-patient (DTP) shipment of study drug is allowed by local 
regulations and the relevant ethics committee

Study drug can be administered by the subject (or subject's 
caregiver) at home

Subject agrees to have the study drug shipped directly to their home
o
Shipments may also include other study supplies (e.g., drug 
dosing diaries).  Instructions will be provided by AbbVie as to 
how a study site can initiate a DTP shipment using Marken, a 
global vendor selected by AbbVie to provide this service when 
necessary.  Shipments of study drugs from the study site to a 
subject's home will be appropriately temperature controlled 
(qualified shipper or temperature monitoring) within the labeled 
storage conditions.  Signature is required upon delivery; due to 
COVID-19 related social distancing, this may be provided by 
the courier after delivery.  Documentation of the shipment is to 
be retained by the clinical site.

AbbVie will not receive subject identifying information related to 
these shipments, as the site will work directly with the courier.
The study site is responsible for meeting IRB/IEC reporting 
requirements related to DTP shipments of study drug, and for obtaining 
consent to provide delivery information to the courier and documenting 
 


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Language Added
this consent in source documents.
6.1.5
Adverse Event 
Reporting
Adverse Event Reporting
Supplemental study case report forms should be completed in the event 
of COVID-19 related missed/virtual visits, study drug interruptions or 
discontinuations, or adverse events (including capture of specific 
signs/symptoms of infection and testing results).
COVID-19 infections should be captured as adverse events.  If the event 
meets the criteria for a serious adverse event (SAE), then follow the SAE 
reporting directions per the protocol and above.  The following 
COVID-19 related supplemental eCRFs should be completed (for both 
serious and non-serious events):

COVID-19 Supplemental Signs/Symptoms

COVID-19 Status Form
If a subject has a confirmed or suspected COVID-19 infection and study 
drug was interrupted, the investigator should contact the sponsor 
emergency medical contact listed above before reintroducing study drug.
7.0
Protocol 
Deviations
Protocol deviations may include modifications due to COVID-19.
9.1
Independent 
Ethics 
Committee 
(IEC) or 
Institutional 
Review Board 
(IRB)
In the event of a state of emergency due to the COVID-19 pandemic 
leading to difficulties in performing protocol-specific procedures, 
AbbVie will engage with study site personnel in efforts to ensure the 
safety of subjects, maintain protocol compliance, and minimize risks to 
the integrity of the study while trying to best manage subject continuity 
of care.  This may include alternative methods for assessments (e.g., 
phone contacts or virtual site visits), alternative locations for data 
collection (e.g., use of a local lab instead of a central lab), and shipping 
investigational product and/or supplies direct to subjects to ensure 
continuity of treatment where allowed.  Refer to Section 5.3.1.1 and 
Section 5.5.1 for additional details.  In all cases, these alternative 
measures must be allowed by local regulations and permitted by 
IRB/IEC.  Investigators should notify AbbVie if any urgent safety 
measures are taken to protect the subjects against any immediate hazard.
11.0
Source 
Documents and 
Case Report 
Form 
Completion
During the COVID-19 pandemic, remote monitoring of data may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the 
study site.
 

SAP_001.pdf: 
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Version 5.0 – 09 Nov 2018
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1.0
Title Page
Statistical Analysis Plan
Study M14-032
A Phase 2 Open-Label Study of the Efficacy and 
Safety of ABT-199 (GDC-0199) in Chronic 
Lymphocytic Leukemia Subjects with Relapse or 
Refractory to B-Cell Receptor Signaling Pathway 
Inhibitor Therapy
Date:  09 Nov 2018
Version 5.0
 
NCT02141282


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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
Sample Size............................................................................................ 6
4.3
Interim Analysis..................................................................................... 6
4.4
Efficacy Analyses and Safety Evaluations .............................................. 7
5.0
Analysis Populations .............................................................8
5.1
Definition for Analysis Populations ........................................................ 8
5.2
Variables Used for Stratification of Randomization ................................ 9
6.0
Analysis Conventions ............................................................9
7.0
Subject Disposition..............................................................10
8.0
Demographics, Baseline Characteristics, Medical 
History, and Previous Concomitant Medications..............10
8.1
General Consideration.......................................................................... 10
8.2
Demographic and Baseline Characteristics ........................................... 11
8.3
Medical History.................................................................................... 12
8.4
Previous Treatment and Concomitant Medications ............................... 12
9.0
Venetoclax Exposure and Compliance...............................13
10.0
Efficacy Analysis .................................................................14
10.1
General Considerations......................................................................... 14
10.2
Efficacy Analyses per Investigators' Review......................................... 14
10.2.1
Primary Efficacy Analyses ................................................................... 14
10.2.2
Secondary Efficacy Analyses ............................................................... 14
10.3
Efficacy Analyses per Independent Review Committee ........................ 16
10.4
Additional Exploratory Efficacy Analyses............................................ 16
10.5
Subgroup Analyses of Efficacy............................................................. 18
10.6
Handling of Multiplicity....................................................................... 19
11.0
Safety Analysis.....................................................................19
11.1
Analysis of Treatment-Emergent Adverse Events................................. 19
 


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11.2
Deaths .................................................................................................. 21
11.3
Analysis of Laboratory and Vital Signs Data ........................................ 21
11.3.1
Analyses of Shift from Baseline in Clinical Laboratory Data................ 21
11.3.2
Assessment of Potentially Clinically Significant Vital Signs 
Values .................................................................................................. 23
12.0
Pharmacokinetic Analyses..................................................24
13.0
Summary of Changes ..........................................................24
14.0
References............................................................................24
List of Tables
Table 1.
Sample Size Calculation......................................................................... 6
Table 2.
Summary of Interim Analyses with Cutoff Dates and Data 
Included ................................................................................................. 7
Table 3.
Time Windows for Quality of Life ....................................................... 10
Table 4.
Adverse Events of Special Interest........................................................ 21
Table 5.
Howard Criteria for TLS ...................................................................... 23
Table 6.
Criteria for Potentially Clinically Significant Laboratory Values –
Vital Signs Variables............................................................................ 24
List of Figures
Figure 1.
Dosing Schematic................................................................................... 6
List of Appendices
Appendix A.
List of Abbreviations............................................................................ 25
 


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3.0
Introduction
This statistical analysis plan (SAP) describes the fifth interim statistical analyses for 
venetoclax (ABT-199/GDC-0199) Protocol M14-032 Amendment 4 dated 
13 September 2016.  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 (SAS 
Institute Inc., Cary, NC 27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
Primary Objective:
The primary objective of this study is to evaluate the efficacy and safety of venetoclax 
monotherapy in subjects with chronic lymphocytic leukemia (CLL) relapsed after or 
refractory to treatment with B-cell receptor signaling pathway inhibitors.  Efficacy will be 
measured by overall response rate (ORR).
Secondary Objectives:
The secondary objectives are to evaluate the duration of overall response, time to 
progression (TTP), progression free survival (PFS), event free survival (EFS), time to first 
response, and overall survival (OS).
Exploratory Objectives:
●
Time to next anti-CLL treatment (TTNT)
●
Minimal residual disease (MRD) will be assessed in the peripheral blood and 
bone marrow (BM) by flow cytometry and PCR 
●
Health Economic and Patient-Reported Outcome Measures will include the 
EORTC QLQ-C30 and EORTC QLQ CLL16 (a measure of health-related 
 


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quality of life specific to CLL) and the EQ-5D-5L (measure of general health 
status) including EQ-5D-VAS.
Study Design and Plan
This is an open-label, non-randomized, two arm, and multicenter study to determine the 
efficacy and safety of venetoclax monotherapy in subjects with CLL relapsed/refractory to 
treatment with B-cell receptor signaling pathway inhibitors and is sponsored by AbbVie 
in collaboration with Genentech/Roche.
This study is designed to enroll approximately 120 subjects, who have CLL that is 
refractory to treatment with ibrutinib and/or idelalisib, has relapsed on treatment or 
experienced progression after discontinuation of either one of these agents.
Two arms and an expansion cohort will be implemented to enroll as follows: 
●
Arm A with approximately 40 subjects that have ibrutinib-resistant with 
relapsed or refractory CLL.
●
Arm B with approximately 20 subjects that have idelalisib-resistant with
relapsed or refractory CLL.
●
Expansion Cohort with approximately 60 subjects that have either 
ibrutinib-resistant or idelalisib-resistant with relapsed or refractory CLL.
Subjects who have received both agents and any additional interim therapy 
will be enrolled into the corresponding arm based on their most recent 
treatment.
Subjects in this study will be enrolled at approximately 15 research sites.
The study was designed to enroll approximately 120 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.
 


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Dosing Schedule Overview
Venetoclax was administered orally once daily (QD), continuously.  To mitigate the risk 
for tumor lysis syndrome (TLS), a lead-in period (up to 5 weeks) was employed to 
evaluate a step wise dose escalation as specified in the protocol, and Figure 1.
Figure 1.
Dosing Schematic
4.2
Sample Size
There are no planned hypotheses testing on the primary endpoint overall response rate 
(ORR).  ORR will be presented by a point estimate and its corresponding 95% confidence 
interval.  A sample size of 20 subjects ensures that the distance of true rate will be within 
23% of the observed rate with 95% confidence and a sample size of 60 subjects ensures 
that the distance of true rate will be within 14% of the observed rate with 95% confidence.
Table 1.
Sample Size Calculation
Number of Subjects (N)
Distance of True Rate from Observed Rate
20
23%
40
17%
60
14%
4.3
Interim Analysis
To support regulatory submission of venetoclax with indication of relapsed/refractory 
CLL, the interim analyses were conducted with the corresponding data cutoff dates 
illustrated in Table 2. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.4
Efficacy Analyses and Safety Evaluations
Table 2.
Summary of Interim Analyses with Cutoff Dates and Data Included
Analysis Number/
Database Version
Cutoff Date
Efficacy Data Included
Safety Data 
Included
1/M14032E
30 April 2015
Subjects with Investigator assessed 
response/progression data: N = 28.
Subjects with IRC assessed 
response/progression data: N = 0.
All subjects:
N = 28.
2/M14032O
10 June 2016
Subjects with Investigator assessed 
response/progression data: N = 64.
Subjects with IRC assessed 
response/progression data: N = 64.
All subjects: 
N = 109.
3/M14032Q
31 January 2017
Subjects with Investigator assessed 
response/progression data: N = 127.
Subjects with IRC assessed 
response/progression data: N = 64.
All subject: 
N = 127.
4/M14032T
31 January 2017
Subjects with Investigator assessed 
response/progression data: N = 127.
Subjects with IRC assessed 
response/progression data: N = 97.
All subjects: 
N = 127.
5/M14032AA
26 July 2017
Subjects with Investigator assessed 
response/progression data: N = 127.
Subjects with IRC assessed 
response/progression data: N = 127.
All subjects: 
N = 127.
6/M14032AE
30 March 2018
Subjects with Investigator assessed 
response/progression data:  N = 127.
Subjects with IRC assessed 
response/progression data:  N = 127.
All subjects: 
N = 127.
Database versions for previous and current interim CSRs are summarized below:
●
M14032E for the 1st interim CSR (R&D/14/1069), which was used for 
venetoclax Submission in U.S.
●
M14032O for the 2nd interim CSR (R&D/16/0802), which was used for 
venetoclax Submission in Russia and Switzerland.
●
M14032Q for the 3rd interim CSR (R&D/17/0383), which was used for 
venetoclax Submission in Canada.
 


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●
M14032T for the 4th interim CSR (R&D/17/0573), which was used for 
venetoclax supplemental Submission in U.S.
●
M14032AA for the 5th interim CSR (R&D/17/1058), which was used for 
venetoclax Commitment in EU.
●
M14032AE for the 6th interim CSR (R&D/18/0885), which will be used for 
venetoclax Post Marketing Commitment for FDA using updated IRC data as 
of 30 March 2018.
All data specified in Table 2 from dosed subjects up to the corresponding cutoff date will 
be included in the corresponding interim analysis.  Efficacy and safety analyses will be 
performed for the subjects in the Main and Expansion Cohort.  Efficacy and safety data up 
to and including the cutoff date will be collected.  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 from the date of the last subject enrolled in study.  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.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
Efficacy and safety analyses will be performed for all subjects in the Main and Expansion 
Cohort who received at least one dose of venetoclax.  Subjects in the Expansion Cohort 
will be categorized to either Arm A Expansion or Arm B Expansion based on their last 
received BCRi regimens.  Both efficacy and safety analyses will be performed for 
ibrutinib and idelalisib failure subjects with the following 9 groups:  Arm A, Arm B, Main 
Cohort Total, Arm A Expansion, Arm B Expansion, Expansion Cohort Total, Arm A 
Total, Arm B Total, and All Subjects.
 


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5.2
Variables Used for Stratification of Randomization
There is no randomization for this trial.
6.0
Analysis Conventions
Definition of 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 
laboratory variables will be defined as:
●
For subject hospitalized for TLS prophylaxis, the baseline value will be the lab 
value taken at hospital admission prior to the subject receiving hydration for 
TLS prophylaxis (the day prior to the first dose of venetoclax).
For subject not hospitalized for TLS prophylaxis, the baseline value will be the 0 hour lab 
draw prior to the first dose of study drug on Day 1.
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.
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 
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).
 


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Definition of Analysis Windows
For quality of life, the time window is specified in Table 3.
Table 3.
Time Windows for Quality of Life
Scheduled Visit
Nominal Day
Time Window (Study Rx Day Range)
Week 1 Day 1
Baseline
See the baseline definition
Week 24 Day 1
162
[149, 176]
Week 36 Day 1
246
[233, 288]
Every 12 Weeks from 
Week 36 Day 1
Rx day of Week X Day 1
[Rx day of Week (X) Day 1 – 6 weeks to Rx 
day of Week (X) Day 1 + 6 weeks]
Final Observation
Last value within 30 days of last dose of 
Venetoclax
Note:
EQ-5D-5L and EQ-5D-VAS will be assessed at Week 1 Day 1, Week 24 Day 1, every 12 weeks starting with 
Week 36, and at the Final Visit.  EORTC QLQ-C30 and EORTC QLQ-CLL16 will be assessed at Week 1 
Day 1, Week 24 Day 1, every 12 weeks starting with Week 36, at the Final Visit.
7.0
Subject Disposition
The number and percentage of subjects will be summarized for each of the following 
categories, for overall and by country:
●
Subjects enrolled into the study.
●
Subjects who discontinued the study – overall and for each reported primary 
reason.
●
Subjects who discontinued venetoclax – overall and for each reported primary 
reason.
8.0
Demographics, Baseline Characteristics, Medical 
History, and Previous Concomitant Medications
8.1
General Consideration
All demographic, baseline characteristics, medical history, prior and concomitant 
medication summaries will be performed on the analysis sets specified in Section 8.2.
 


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8.2
Demographic and Baseline Characteristics
All baseline summary statistics and analyses are based on characteristic prior to the 
first dose of venetoclax.  The following demographic and baseline characteristics will be 
summarized:
●
Age
●
Gender
●
Race
●
Region (US, EU, ROW)
●
Tobacco use
●
Alcohol use
●
ECOG performance status
●
LDH
●
Prior number of oncology therapies
●
17p deletion status
●
Rai staging at diagnosis
●
Binet staging at diagnosis
●
IGVH status
●
ZAP-70
●
CD-38
●
Beta 2-microglobulin
●
TP53 mutation
●
11q
●
13q
●
12q trisomy
●
ALC (< 25 × 109/L, ≥ 25 × 109/L)
●
ALC (< 100 × 109/L, ≥ 100 × 109/L)
●
Nodal size (≥ 5 cm, < 5 cm)
●
Nodal size (≥ 10 cm, < 10 cm)
 


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●
TLS risk category (low, medium, or high)
The distributions of the continuous demographic and baseline variables will be 
summarized with the number of non-missing observations, mean, standard deviation, and 
median, as well as the minimum and maximum values.
For the categorical variables, the frequency and percentages of subjects within each 
outcome will be summarized.  The number of subjects with missing information will also 
be summarized.
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 zero, 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 (1 day to ≤ 35 days), > 5 weeks to 8 weeks (> 35 days to 56 days), > 8 weeks to 
12 weeks (> 56 days to 84 days), > 12 weeks to 16 weeks (> 84 days to 112 days), 
> 16 weeks to 20 weeks (> 112 days to 140 days), > 20 weeks to 24 weeks (> 140 days to 
168 days), > 24 weeks to 28 weeks (> 168 days to 196 days), > 28 weeks to 32 weeks 
(> 196 days to 224 days), > 32 weeks to 36 weeks (> 224 days to 252 days), > 36 weeks 
to 48 weeks (> 252 days to 336 days), > 48 weeks to 60 weeks (> 336 days to 420 days), 
and > 60 weeks (> 420 days).
The compliance based on investigator opinion for each subject will be provided in the 
listing.
 


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10.0
Efficacy Analysis
10.1
General Considerations
No statistical testing will be performed for the efficacy endpoints.  Further details on the 
analysis sets used will be specified in efficacy analyses described below.
10.2
Efficacy Analyses per Investigators' Review 
10.2.1
Primary Efficacy Analyses
The primary efficacy endpoint will be overall response rate (ORR) – the proportion of 
subjects with an overall response (per the investigator assessment) will be calculated for 
all subjects based on 2008 Modified IWCLL NCI-WG criteria.
In addition, the ninety-five percent (95%) confidence interval based on binomial 
distribution (Clopper-Pearson exact method) will be constructed for the calculated ORR.
The assessment of ORR will be performed for subjects in the Main Cohort (by Arm A and 
Arm B) and the Expansion Cohort (by Arm A Expansion and Arm B Expansion as 
defined in Section 5.1) separately, and combined (by Main Cohort Total, Expansion 
Cohort Total, Arm A total, Arm B total, and all subjects).  Subjects who have not had a 
confirmed response prior to the data "cutoff" date defined in Section 4.4 will be 
considered to be non-responders.
10.2.2
Secondary Efficacy Analyses
Key secondary efficacy endpoints will include duration of overall response, time to 
progression, progression-free survival, and overall survival.
Duration of overall response will be defined as the number of days from the date of 
first response (CR 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 first dose.  Duration of overall response will be analyzed by 
 


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Kaplan Meier methodology using data for all 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 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 patients 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 dosing plus 1 day.  TTP will be analyzed by Kaplan-
Meier methodology using data for all dosed subjects.  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 
assessment.  Data for patients 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 dosing plus 1 day.  PFS will be analyzed by Kaplan-
Meier methodology using data for all dosed subjects.  Median time PFS will be calculated 
and 95% confidence interval for median time PFS will be presented.
Event-free survival (EFS) is defined as the number of days from the date of first dose to 
the date of earliest confirmation of disease progression, death, or start of a new anti-
leukemic therapy.  If the specified event (disease progression, death, start of a new anti-
leukemic treatment) does not occur, patients will be censored at the date of last disease 
 


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assessment.  Data for subjects without any disease assessments performed after the 
baseline visit will be censored at the date of first dose plus 1 day.  EFS will be analyzed 
by Kaplan-Meier methodology.  EFS will be calculated and 95% confidence interval for 
median EFS will be presented.
Time to first response will be defined as the number of days from the date of first dose to 
the date of the first sign of response (CR, CRi, nPR, or PR) given the subject has had a 
confirmed CR, CRi, nPR, or PR per the 2008 Modified IWCLL NCI-WG criteria.  The 
first response can be an assessment by physical exam as long as the results are later 
confirmed per the 2008 Modified IWCLL NCI-WG criteria.  For subjects who never 
experience a response, the subject's data will not be included in the analysis.  Descriptive 
statistics (mean, standard deviation, median, and range) and the 95% confidence interval 
of the mean 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 dosed 
subjects.  Median time survival will be estimated and 95% confidence interval for the 
median time survival will be presented.
10.3
Efficacy Analyses per Independent Review Committee
An Independent Review Committee (IRC) will evaluate disease progression and response.  
The following efficacy endpoints, described in details in Section 10.2, overall response 
rate, duration of response, time to progression, and progression-free survival based on this 
IRC review, will be analyzed.
10.4
Additional Exploratory Efficacy Analyses
Additional efficacy endpoints to be analyzed for the Main and Expansion Cohort subjects 
are time to next anti-leukemia treatment, MRD response rate, and Health Economic and 
Patient Reported Outcome measures.
 


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Time to next anti-leukemia treatment will be defined as the number of days from the date 
of the first dose to the date of first dose of any non-protocol anti-leukemia therapy (NPT) 
or death from any cause.  For subjects who did not take NPT, the data will be censored at 
the last known date to be free of NPT.  TTNT will be analyzed by Kaplan-Meier 
methodology.  Median TTNT time will be calculated and 95% confidence interval for 
median TTNT time will be presented.
The rate of MRD response in subjects will be defined as the proportion of subjects who 
had MRD negative status.  All dosed patients will be included in the calculation of MRD 
response rate, indeterminate or missing samples will be considered MRD positive for the 
calculation.  Ninety-five percent (95%) confidence intervals based on the binomial 
distribution (Clopper-Pearson exact method) will be provided.
Health Economic and Patient Reported Outcome measures will include the EORTC QLQ-
C30, QLQ-CLL16 (a measure of health related quality of life specific to CLL), and the 
EQ-5D-5L (measure of general health status) and EQ-5D-VAS.
The EORTC QLQ-C30 consists of a Global Health Status/QoL scale, 
five Functional scales (Cognitive Functioning, Social Functioning, Physical Functioning, 
Emotional Functioning, and Role Functioning), and nine Symptom scales/items (Fatigue, 
Insomnia, Appetite Loss, Pain, Constipation, Diarrhea, Dyspnea, Financial Difficulties, 
and Nausea and Vomiting).
Each of these scales will be calculated as per the EORTC scoring manual, and 
summarized (mean, standard deviation, median) at each assessment; in addition mean 
change in each of these values (final assessment versus baseline) will be calculated to 
identify any statistically significant differences versus baseline.
The five 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 mean change in 
 


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each of these values (final assessment versus baseline) will be calculated to identify any 
statistically significant differences versus baseline.
The EORTC QLQ-C30 and EORTC QLQ-CLL16 will also be administered through post 
treatment.  To explore the trend of time, a repeated measures analysis will be performed 
for the scheduled times of measurement without imputation of missing values.
The EuroQol 5 Dimensions (EQ-5D-5L) is a generic preference instrument that has been 
validated in numerous populations.  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 EQ-5D-5L also contains a visual analog scale 
(VAS) to assess the subject's overall health.
For each of the five dimensions of the EQ-5D-5L, the number and percentage of subjects 
at each level will be summarized at each assessment.  The Visual Analog Scale (VAS) 
will also be summarized (mean, standard deviation, median) at each assessment; in 
addition mean change in VAS values (final assessment versus baseline) will be calculated 
to identify any statistically significant differences versus baseline.
10.5
Subgroup Analyses of Efficacy
ORR will be assessed by the following subgroups:
●
Age (< 65 years versus ≥ 65 years, < 75 years versus ≥ 75 years)
●
Gender (Male, Female)
●
Race (White, Black, Asian, and other)
●
ECOG performance status (0, 1, 2)
●
Prior number of oncology therapies (1, 2, 3, 4, ≥ 5)
●
Prior number of BCRi regimens (< 2, ≥ 2)
●
Fludarabine refractory (yes, no)
●
Prior chemoimmunotherapy (yes, no)
 


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●
17p deletion (Deleted, Not deleted)
●
TP53 mutation status (Yes, No)
●
TP53 mutation and/or 17p del (yes, no)
●
Rai staging at diagnosis (Stage 0, Stage 1, Stage 2, Stage 3 or Stage 4)
●
Binet staging at diagnosis (Stage A, Stage B, or Stage C)
●
ALC (< 25 × 109/L, ≥ 25 × 109/L)
●
ALC (< 100 × 109/L, ≥ 100 × 109/L)
●
Nodal size (≥ 5 cm, < 5 cm)
●
Nodal size (≥ 10 cm, < 10 cm)
ORR and their 95% CIs will be reported for each level of subgroups in a forest plot.  
DOR, PFS, EFS, TTP, OS, and TTNT will also be assessed by 17p deletion, TP53
mutation status, and TP53 mutation and/or 17p deletion.
10.6
Handling of Multiplicity
There will be no multiplicity adjustments performed.
11.0
Safety Analysis
Safety assessments will only include subjects who have received at least one dose of 
venetoclax in the Main Cohort (by Arm A and Arm B) and the Expansion Cohort (by 
Arm A Expansion and Arm B Expansion), and total (Main Cohort Total, Expansion 
Cohort Total, Arm A Total, Arm B Total, and all subjects).
11.1
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 
 


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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).
Adverse event data will be summarized and presented using primary MedDRA system 
organ classes (SOCs) and preferred terms (PTs) according to the MedDRA coding 
dictionary version 17.1 or higher.
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be summarized for the following adverse event summaries:
●
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, 4, or 5 adverse 
events.
●
Any treatment-emergent NCI toxicity (CTCAE V4.0) grade 3 or 4 adverse 
event.
●
Adverse events broken down by NCI toxicity grade (Severity).
●
Any treatment-emergent serious adverse event.
●
Any treatment-emergent adverse event leading to discontinuation of 
venetoclax.
●
Any treatment-emergent adverse event leading to discontinuation of 
venetoclax due to progression.
●
Any treatment-emergent adverse event leading to discontinuation of 
venetoclax not due to progression.
●
Any treatment-emergent adverse event leading to venetoclax interruption.
●
Any treatment-emergent adverse event leading to venetoclax reduction.
●
Any treatment-emergent adverse event leading to death.
In addition, adverse events of special interest will be summarized.  The list of adverse 
events of special interest that will be presented is shown in Table 4.
 


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Table 4.
Adverse Events of Special Interest
Adverse Event of Special Interest/Lab 
Abnormality
Search Criteria
Tumor Lysis Syndrome (AE)
Tumor Lysis Syndrome (Howard Criteria)
SMQ – "Tumor Lysis Syndrome" (narrow); ≥ 2 of 
the following metabolic abnormalities within 
24 hours of each other (applicable to post-dose lab 
values only):  Uric Acid > 476 μmol/L or 
8.0 mg/dL; Potassium > 6.0 mmol/L; Inorganic 
Phosphorus > 1.5 mmol/L or 4.5 mg/dl; Calcium 
< 1.75 mmol/L or 7.0 mg/dl
Grade ≥ 3 neutropenia
PT terms – "neutropenia," "neutrophil count 
decreased," "febrile neutropenia," 
"agranulocytosis," "neutropenic infection," and 
"neutropenic sepsis"
Grade ≥ 3 infection, including opportunistic 
infections
SOC of "infections and infestations"
Second primary malignancy 
SMQ – "malignant tumours" (narrow) and 
"myelodysplastic syndromes" (narrow)
Drug-Induced Liver Injury
PT Term – Drug induced liver injury;
Grade ≥ 3 thrombocytopenia
PT terms – "thrombocytopenia" and "platelet count 
decreased"
ALT = alanine aminotransferase; AST = aspartate aminotransferase; PT = preferred term; SMQ = Standardised 
MedDRA Query; SOC = system organ class; ULN = upper limit of normal
11.2
Deaths
The number of deaths will be summarized (1) for deaths occurring while the subject is 
still receiving venetoclax in this study, (2) for deaths occurring off treatment within 
30 days after the last dose of venetoclax.
11.3
Analysis of Laboratory and Vital Signs Data
The value for baseline used in laboratory and vital sign analyses is defined in Section 6.0. 
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 
 


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(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.
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.  An exception will be used for those subjects enrolled 
with a baseline value of neutrophils less than 1000/μL requiring G-CSF support to meet 
entry criteria.  For these subjects, the last value pre-G-CSF administration will be the 
baseline.
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 
final observations of grade 0, grade 1, grade 2, grade 3, or grade 4.
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.
 


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Laboratory Search Strategy for TLS
To determine if subjects' laboratory values qualify for TLS, the Howard criteria1 will be 
used.  The Howard criteria for TLS comprise of ≥ 2 of the following electrolyte 
abnormalities within 24 hours of each other and are specified in Table 5.
Table 5.
Howard Criteria for TLS
Element
Value
Uric Acid
< 476 μmol/L or 8 mg/dL
Potassium
< 6.0 mmol/L or 6 mEq/L
Inorganic Phosphorus
< 1.5 mmol/L
Calcium
< 1.75 mmol/L
The following summaries of laboratory TLS as assessed by Howard criteria will be 
provided:
●
Number and percentage of subjects meeting the Howard criteria for laboratory 
TLS (at least two values meeting the criteria in Table 5, occurring within 
24 hours of each other). 
●
Listing of all the lab test values for each subject meeting the Howard criteria 
for laboratory TLS.
11.3.2
Assessment of Potentially Clinically Significant Vital Signs 
Values
For selected vital signs variables, a listing of all observations collected will be generated 
for subjects that had at least one post-baseline observation meeting pre-defined criteria for 
potentially clinically significant values.  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 variable.
Pre-defined criteria for potentially clinically significant vital signs values are given in 
Table 6 below based on CTCAE criteria:
 


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Table 6.
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
12.0
Pharmacokinetic Analyses
Plasma concentrations of venetoclax and possible metabolites(s) will be listed for each 
subject by scheduled visit.  Summary statistics will also be computed for each scheduled 
visit.
13.0
Summary of Changes
For the 6th interim clinical study report, the following changes have been implemented 
into the current statistical analysis plan V5, compared with SAP V4:
●
The cutoff date 30 March 2018 for Interim CSR #6 was added in Table 2 for 
updated Investigator and IRC assessed data.
14.0
References
1.
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  
2011;364(19):1844-54.
 


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Appendix A.
List of Abbreviations 
AE
Adverse Event
BM
Bone Marrow
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
G-CSF
Granulocyte-colony stimulating factor
IWCLL
International Workshop for Chronic Lymphocytic Leukemia
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Minimal Residual Disease
NCI
National Cancer Institute
NCI-WG
National Cancer Institute-Working Group
NPT
Non-protocol Anti-leukemia Therapy
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
TTNT
Time to next anti-CLL treatment
TTP
Time to Progression
ULN
Upper Limit of Normal