Conditions: Chronic Lymphocytic Leukemia
Keywords: Oncology Chronic Lymphocytic Leukemia 17p Deletion TP53 Mutation Relapsed Refractory B-Cell receptor inhibitor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 258
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of venetoclax monotherapy in participants with relapsed/refractory CLL with or without the 17p deletion or TP53 mutation, including those who have received prior treatment with a B-cell receptor inhibitor.

Detailed description:
Following the Screening period, all eligible participants initiate venetoclax on a once daily (QD) dosing schedule. To mitigate the risk for tumor lysis syndrome (TLS), dosing will start with a 5-week dose titration phase.

Participants may receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator assessment), do not have unacceptable toxicity and do not meet any of the criteria for subject discontinuation. In countries where venetoclax is not commercially available, participants who continued to derive benefit after 2 years of treatment may extend their treatment for up to 2 additional years in an extended access phase. Participants in the extended access phase of this study who continue to derive benefit from venetoclax after the 2-year extension and are transferring to the venetoclax extension study, Study M19-388 (NCT03844048), may remain in Extended Access for up to 1 additional year or until the extension study is approved and initiated at the site, whichever is sooner.

Arms:
arm 1: Venetoclax will be administered orally once daily (QD) beginning with a dose-titration phase. The initial venetoclax dose is 20 mg QD. After 1 week of treatment at 20 mg QD, the dose will be escalated to 50 mg QD followed by subsequent increases, each after 1 week, to 100 mg QD, 200 mg QD and the maximum dose of 400 mg QD. Participants may continue to receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator's assessment), do not have unacceptable toxicity, and do not meet any of the criteria for discontinuation.

In countries where venetoclax is not commercially available, participants who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 2 additional years, plus one additional year until the venetoclax extension study was open, determined on a case by case basis.

Interventions: intervention 1: Venetoclax
Intervention descriptions: intervention 1: Tablets for oral administration

Protocol document:
Prot_002.pdf: 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
24 February 2016
Amendment 0.02
25 April 2016
Administrative Change 1 (GLOBAL)
30 June 2016
Amendment 0.02.01 (ROW)
22 May 2017
Amendment 0.02.01.01 (ROW)
23 July 2018
The purpose of this amendment is to:
●
Revise the contact details on the front page of the protocol.
Rationale:  To change the phone number to Sponsor/Emergency Contact Stan 
Fort, MD.
●
Revise Section 5.3.1.1 Study Procedures – Extended Access Phase
Rationale:  To indicate that if a subject in the extended access phase of this 
study continues to derive benefit from Venetoclax after the 2-year extension, 
then per PI's assessment, subjects who are transferring to the venetoclax 
extension study, Study M19-388, may remain in Extended Access for up to 
additional 1 year or until the extension study is approved and initiated at the 
site, whichever is sooner.
●
Update Appendix B – List of signatories.
Rationale:  To replace 
 as the Study Project Manager with 
 
.  To replace 
 as the Sr. Medical Director with 
 
. To remove 
 as the Group Project Director. 
GPD is no longer required for protocol signature. To add 
 as 
the Evidence Generation Medical Lead/Director. To replace 
 as 
the Study Project Manager with 
.
●
Revise Appendix E Schedule of Extended Access Phase.
Rationale: To add an additional year to the Schedule of Extended Access 
Phase.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
3
An itemized list of all changes made to this protocol amendment can be found in 
Appendix J.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
4
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-550
Name of Study Drug:  Venetoclax (ABT-199, 
GDC-0199)
Phase of Development:  3b
Name of Active Ingredient:  Venetoclax
Date of Protocol Synopsis:  12 October 2020
Protocol Title:  Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating the Efficacy of 
Venetoclax (ABT-199) in Relapsed/Refractory Subjects with Chronic Lymphocytic Leukemia (CLL) 
(VENICE I)
Objectives:  
Primary Objective:  The primary objective of this study is to evaluate the efficacy of venetoclax 
monotherapy in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL).  The primary 
efficacy endpoint will be measured by complete remission rate (Complete Remission Rate [CR] and 
Complete Remission with Incomplete Marrow Recovery [CRi]; CR + CRi) as assessed by the 
investigator, of the subjects who have not been previously treated with B-cell receptor inhibitor (BCRi) 
therapy.
Secondary Objectives:  The secondary objectives are to evaluate other efficacy parameters including the 
overall response rate (ORR), duration of overall response (DoR), time to progression (TTP), 
progression-free survival (PFS), overall survival (OS), and the CR rate in BCRi treated subjects.  In 
addition, quality of life will be assessed using the following patient reported outcome (PRO) 
questionnaires:  the EuroQoL 5 Dimensions (EQ-5D-5L) questionnaire, a measure of general health 
status, the Functional Assessment of Cancer Therapy – Leukemia Questionnaire (FACT-Leu), a 
leukemia-specific health related quality of life for acute and chronic disease, and the Functional 
Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F).
The safety and tolerability of venetoclax in subjects with relapsed/refractory CLL will also be evaluated.
Exploratory Objectives:  The exploratory objectives are to evaluate the level of Minimal Residual 
Disease (MRD) and the rate of MRD negativity in the peripheral blood.  
Investigators:  Multi-center
Study Sites:  Approximately 7 sites in the United States and approximately 67 sites globally.
Study Population:  Subjects with relapsed/refractory (R/R) CLL with or without the 17p deletion or 
TP53 mutation, including subjects with an unknown status, as well as R/R CLL subjects who have been 
previously treated with B-cell receptor inhibitor (BCRi) therapy.
Number of Subjects to be Enrolled:  Approximately 250 subjects
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
5
Methodology:  
This is a Phase 3b, single arm, open-label, multi-center study evaluating the efficacy of venetoclax in 
subjects with R/R CLL.  All screening procedures must be performed within 28 days prior to initial study 
drug administration.  A contrast computed tomography (CT) scan (or magnetic resonance imaging [MRI] 
if a CT with contrast is medically contraindicated) will be accepted if previously performed within 
35 days prior to study drug administration, otherwise a CT scan (or MRI) must be performed within the 
screening period of 28 days.  The starting dose of venetoclax is 20 mg once daily.  The dose must be 
gradually increased over a 5-week period up to the daily dose of 400 mg.  For all subjects, study visits 
will be conducted within 72 hours of dosing and on the first and second day of Week 1 and Week 2 
during the dose titration phase.  Beginning on Week 3, through Week 5, study visits will be conducted 
within 72 hours of dosing and on Day 1 of each week.  Additional study visits on Day 2 of each week 
should be performed for subjects who continue to be at risk for TLS, based on investigator assessment.  
Study visits will be reduced to a monthly frequency at Week 8, and at Week 48, they will be reduced to 
every 3 months until the end of study treatment (Week 108).  In countries where venetoclax is not 
commercially available, subjects who continue to derive benefit after 2 years of treatment may be able to 
extend their treatment for up to 2 additional years.  If a subject in the extended access phase of this study 
continues to derive benefit from Venetoclax after the 2-year extension, then per PI's assessment, subjects 
who are transferring to the venetoclax extension study, Study M19-388, may remain in Extended Access 
for up to additional 1 year or until the extension study is approved and initiated at the site, whichever is 
sooner.  A Disease Assessment for clinical response by physical exam and hematologic assessments will 
be performed at Screening, Week 24, Week 36 and Week 48.  To confirm the response, a CT scan will be 
performed at Week 48 on all subjects.  Biospecimens will be collected at designated time points 
throughout the study to conduct research to better characterize the disease.  MRD assessments will be 
performed by using peripheral blood specimens at Week 1 Day 1 (baseline), Week 24 and Week 48.  
When confirming a CR or CRi status per 2008 Modified International Workshop for Chronic 
Lymphocytic Leukemia National Cancer Institute Working Group (IWCLL NCI WG) criteria with a 
bone marrow (BM) biopsy and aspirate, MRD assessment of the BM aspirate should also be performed.  
After treatment discontinuation, a final visit will be performed.  Subjects will be followed for disease 
progression (if progression has not already occurred) and survival.  Post-treatment follow-up calls will be 
performed every 6 months until discontinuation from the study.  Survival information (i.e., the date and 
cause of death, post-treatment cancer therapies, date of progression etc.) will be collected.  This period 
will continue for 2 years following discontinuation of venetoclax.
The Data Monitoring Committee (DMC) will review safety data intermittently according to the DMC 
charter.  Subsequent reviews may be conducted based on recommendations from the DMC or requests 
from the Sponsor.  Details of the DMC review will be presented in the DMC charter.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
A subject will be eligible for study participation if he/she meets all of the following criteria:
1.
Age ≥ 18 years.
2.
Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
3.
Subject has relapsed/refractory disease (received at least one prior therapy). 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
6
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
4.
Diagnosis of CLL that meets published 2008 Modified IWCLL NCI-WG Guidelines and:

has an indication for treatment according to the 2008 Modified IWCLL NCI-WG criteria

has clinically measurable disease (lymphocytosis > 5 × 109/L and/or palpable and measurable 
nodes by physical exam and/or organomegaly assessed by physical exam)

subjects with or without the 17p deletion or TP53 mutation are eligible.  

subjects who have received prior B-cell receptor inhibitor therapy are also eligible (up to 
60 subjects total in the study will be enrolled).
5.
Adequate bone marrow function as follows:

hemoglobin ≥ 8.0 g/dL

platelets ≥ 25,000/mm3 without any of the following:
o
transfusion support within 14 days of Screening
o
evidence of mucosal bleeding
o
known history of major bleeding episode within 3 months of Screening
Main Exclusion:  
A subject will not be eligible for study participation if he/she meets any of the following criteria:
1.
Subject has developed Richter's transformation or Prolymphocytic leukemia (PLL)
2.
Subject has previously received venetoclax.
3.
History of active malignancies other than CLL within the past 2 years prior to first dose of 
venetoclax, with the exception of:

adequately treated in situ carcinoma of the cervix uteri

adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin

previous malignancy confined and surgically resected (or treated with other modalities) with 
curative intent.
4.
Active and uncontrolled autoimmune cytopenias (within 2 weeks prior to Screening), including 
autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP), despite low 
dose corticosteroids.
5.
Prior allogeneic stem cell transplant.
Investigational Product:
Venetoclax:  10 mg, 50 mg and 100 mg tablet
Doses:
Venetoclax will be administered orally once daily (QD), continuously.  
The starting dose of venetoclax is 20 mg QD.  After 1 week of treatment 
at 20 mg QD, the dose will be escalated to 50 mg QD followed by 
subsequent increases, each after 1 week, to 100 mg QD, 200 mg QD and 
the target dose of 400 mg QD.
Mode of Administration:
Oral
Reference Therapy:
Not applicable.
Doses:
Not applicable.
Mode of Administration:
Not applicable.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
7
Duration of Treatment:  Subjects may continue receiving venetoclax for up to 2 years provided they 
continue to tolerate the drug, have no evidence of disease progression (based on investigator assessment), 
do not have unacceptable toxicity and do not meet any of the criteria for subject discontinuation.  After 
treatment discontinuation, subjects will be followed for disease progression (if progression has not 
already occurred) and survival.  Post-treatment calls will be performed every 6 months until 
discontinuation from the study.  Survival information (i.e., the date and cause of death, post-treatment 
cancer therapies, date of progression etc.) will be collected.  This period will continue for 2 years 
following discontinuation of venetoclax.
In countries where venetoclax is not commercially available, subjects who continue to derive benefit after 
2 years of treatment may be able to extend their treatment for up to 2 additional years.  If a subject in the 
extended access phase of this study continues to derive benefit after the 2-year extension and venetoclax 
is still not commercially available in their country, they may continue their treatment for 1 additional 
year.  Per PI's assessment, subjects who are unable to transfer to the venetoclax extension study, Study 
M19-388, may remain in Extended Access for the additional 1 year or until the extension study is 
approved and initiated at the site, whichever is sooner.  AbbVie will work with the investigator on a case 
by case basis to consider the potential continuation of venetoclax therapy.
Criteria for Evaluation:
Efficacy:
Disease response will be assessed by the investigator, based on laboratory results and physical 
examinations using the 2008 Modified IWCLL NCI-WG criteria for Tumor Response including CT 
imaging and bone marrow biopsy and aspirate for subjects with CR to confirm the response (or MRI in 
the case CT is medically contraindicated).
All measurable disease must be documented at Screening by physical examination, laboratory testing, 
and CT scan (or MRI in the case CT is medically contraindicated).  During the study, clinical disease 
assessments will take place at Week 24, Week 36, and Week 48.  To confirm the response, a CT scan will 
be performed at Week 48.
Minimal Residual Disease (MRD):
A peripheral blood specimen will be collected from all subjects at Week 1 Day 1 (baseline), Week 24 and 
Week 48 to determine the level of minimal residual disease.  When confirming a CR/CRi status per 2008 
Modified IWCLL NCI-WG criteria with a bone marrow biopsy and aspirate, MRD assessment of the BM 
aspirate should also be performed.  The level of MRD and MRD negativity will be assessed.  MRD 
negativity in the 2008 Modified IWCLLNCI-WG criteria is defined as the presence of less than one CLL 
cell per 10,000 leukocytes (or below 10–4).
Pharmacokinetics:
A single pharmacokinetic (PK) blood sample will be collected from each subject and analyzed for plasma 
venetoclax concentration.
Safety:
Adverse event monitoring, vital signs, physical examination, and laboratory assessments will be 
evaluated.
The study analyses will be descriptive.  All subjects participating in the study who received at least 
one dose of venetoclax will be included in the analyses unless otherwise noted in the separate, statistical 
analysis plan (SAP).
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
8
Statistical Methods (Continued):
Efficacy:
The following efficacy endpoints will be analyzed:  Complete Remission rate (CR + CRi), Overall 
Response Rate (ORR), Duration of Overall Response (DOR), Duration of Progression-Free Survival 
(PFS) and Overall Survival (OS):
Complete Remission Rate (CR) and Complete Remission with Incomplete Marrow Recovery (CRi)
Defined as the proportion of subjects who achieved a CR or CRi (all subjects and previously BCRi 
treated subjects).
Overall Response Rate (ORR)
Defined as the proportion of subjects with an overall response (complete remission plus partial 
remission).
Duration of Response (DOR)
Defined as the number of days from the date of first response (per the 2008 Modified IWCLL NCI-WG 
criteria) to the date of disease progression.  All disease progression will be included regardless whether 
the event occurred while the subject was taking venetoclax or had previously discontinued venetoclax.
Time to Progression (TTP)
Defined as the number of days from the date of first dose of venetoclax to date of disease progression.  
All disease progression will be included regardless whether the event occurred while the subject was 
taking venetoclax or had previously discontinued venetoclax.
Duration of Progression-Free Survival (PFS)
Defined as the number of days from the date of first dose of venetoclax to the date of disease progression 
or death, whichever occurs first.  All disease progression will be included regardless whether the event 
occurred while the subject was taking venetoclax or had previously discontinued venetoclax.
Overall Survival (OS)
Defined as number of days from the date of first dose of venetoclax to the date of death.
Additional Exploratory Analyses Include:
Minimal Residual Disease (MRD) Level and Negativity Status: 
The level of MRD and the rate of MRD negativity will be assessed in the peripheral blood of all subjects 
at Week 1 Day 1 (baseline), Week 24 and Week 48.  MRD negativity will be defined as less than 
one CLL cell per 10,000 leukocytes (or below 10–4).  Additionally, bone marrow samples collected from 
subjects achieving CR/CRi will also be assessed for both the level of MRD and the rate of MRD 
negativity.  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.  The relationship between venetoclax PK and efficacy parameters including MRD level and CR 
will be evaluated.
Pharmacokinetics:
An analysis of venetoclax plasma concentrations will be performed using a population PK modeling 
approach.  
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
9
Statistical Methods (Continued):
Health Economic and Patient Reported Outcome (PRO) Measures:
Quality of life will be assessed by using the following PROs:  the EQ-5D-5L, FACT-Leu, and the 
FACIT-F.
Quality of life endpoints will be summarized based on the scoring manuals for the instrument.  
Sample Size Estimation:
Using the CR rate of 6% reported for current therapies* 250 subjects would provide approximately 90% 
power (based on an exact test for single proportions using a two-sided alpha of 5%) to reject the null 
hypothesis of 6% in favor of an alternative hypothesis that the CR rate for venetoclax monotherapy is 
12% (doubling of the CR rate).
In order to provide approximately 80% power (based on an exact test for single proportions using a 
two-sided alpha of 5%) to reject the null hypothesis of 6% CR rate in favor of an alternative hypothesis 
that the CR rate for venetoclax monotherapy is 12% (doubling of the CR rate), the study will enroll 
190 subjects who have not been previously treated with BCRi therapy.  Since there are approximately a 
total of 250 subjects, up to 60 subjects previously treated with BCRi therapy can be enrolled. 
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.
*
Resonate Trial.  ASH.  2014.  Abstract 3331.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
10
1.3
List of Abbreviations and Definition of Terms
Abbreviations
ABT-199
Study Drug Compound, "Venetoclax"
AE
Adverse Event
AIHA
Autoimmune Hemolytic Anemia
ALC
Absolute Lymphocyte Count
ALT
Alanine transaminase
AML
Acute Myeloid Leukemia
AST
Aspartate transaminase
aPTT
Activated Partial Thromboplastin Time
Bcl
B-Cell Lymphoma
BCR
B-Cell receptor
BCRi
B-Cell receptor inhibitor
BCR PI
B-cell receptor pathway inhibitor
BM
Bone Marrow
BUN
Blood Urea Nitrogen
CLL
Chronic Lymphocytic Leukemia
cm
Centimeter
CR
Complete Remission
CRi
Complete Remission with Incomplete Marrow Recovery
CT
Computed Tomography
CTLS
Clinical Tumor Lysis Syndrome
CYP3A
Cytochrome P450 3A
DNA
Deoxyribonucleic Acid
DMC
Data Monitoring Committee
DOR
Duration of Overall Response
ECOG
Eastern Cooperative Oncology Group
EQ-5D-5L
EuroQoL 5 Dimension 5 Level Questionnaire
eCCr
Estimated creatinine clearance rate using Cockcroft-Gault Formula
eCRF
Electronic Case Report Form
FACIT-F
Functional Assessment of Chronic Illness Therapy – Fatigue Scale
FACT-Leu
Functional Assessment of Cancer Therapy – Leukemia Questionnaire
FL
Follicular Lymphoma
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
11
G-CSF
Granulocyte-colony stimulating factor
GCP
Good Clinical Practice
GDC-0199
Venetoclax (ABT-199)
HDPE
High Density Polyethylene
HIV
Human Immunodeficiency Virus
Hr
Hour
HR
Hazard Ratio
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITP
Immune Thrombocytopenia
IV
Intravenous
IVIG
Intravenous immunoglobulins
IWCLL NCI WG
2008 Modified International Workshop for Chronic Lymphocytic Leukemia 
National Cancer Institute Working Group
Kg
Kilogram
LDi
Longest Diameter
LDH
Lactate Dehydrogenase
LN
Lymph Node
LTLS
Laboratory Tumor Lysis Syndrome
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliter
MM
Multiple Myeloma
mm
Millimeter
µM
Micromolar
MRD
Minimal Residual Disease
MRI
Magnetic Resonance Imaging
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
Non-Hodgkin's Lymphoma
nM
Nanomolar
nPR
Nodular Partial Remission
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
12
ORR
Overall Response Rate
OS
Overall Survival
PB
Peripheral Blood
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression-free Survival
PR
Partial Remission
PRO
Patient-reported Outcomes
PT
Prothrombin Time
QD
Once Daily
RBC
Red Blood Cell
RNA
Ribonucleic Acid
R/R
Relapsed/Refractory
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic-oxaloacetic Transaminase
SLL
Small Lymphocytic Lymphoma
SPD
Sum of the products of the greatest diameters
STAT
Immediately
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
Therapeutic Area Medical Director
TLS
Tumor Lysis Syndrome
TTP
Time to progression
ULN
Upper Limit of Normal
US
Ultrasound
VAS
Visual Analog Scale
WBC
White Blood Cell
WOCP
Women of Childbearing Potential
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
13
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...................................................................13
3.0
Introduction ...........................................................................18
3.1
Differences Statement..............................................................................25
3.2
Benefits and Risks....................................................................................25
4.0
Study Objective......................................................................26
5.0
Investigational Plan...............................................................26
5.1
Overall Study Design and Plan:  Description ..........................................26
5.2
Selection of Study Population..................................................................29
5.2.1
Inclusion Criteria .....................................................................................30
5.2.2
Exclusion Criteria ....................................................................................32
5.2.3
Prior and Concomitant Therapy...............................................................35
5.2.4
Contraception Recommendations ............................................................37
5.3
Efficacy and Safety Assessments/Variables ............................................38
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................38
5.3.1.1
Study Procedures .....................................................................................39
5.3.1.2
Collection and Handling of Biomarker Research Samples......................52
5.3.2
Drug Concentration Measurements .........................................................53
5.3.2.1
Collection of Samples for Analysis .........................................................53
5.3.2.2
Measurement Methods.............................................................................54
5.3.3
Efficacy Variables....................................................................................54
5.3.3.1
Primary Variables ....................................................................................54
5.3.3.2
Definition of Disease Progression............................................................60
5.3.4
Safety Variables.......................................................................................61
5.3.5
Pharmacokinetic Variables ......................................................................61
5.3.6
Biomarker Variables ................................................................................62
5.3.7
Health Economic and Patient-Reported Outcome Measures...................62
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
14
5.3.7.1
Functional Assessment of Cancer Therapy – Leukemia 
(FACT-Leu) Questionnaire......................................................................62
5.3.7.2
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F) Scale ......................................................................................63
5.3.7.3
EuroQol 5 Dimensions (EQ-5D-5L)........................................................64
5.4
Removal of Subjects from Therapy or Assessment.................................64
5.4.1
Discontinuation of Individual Subjects....................................................64
5.4.2
Discontinuation of Entire Study...............................................................65
5.5
Treatments................................................................................................66
5.5.1
Treatments Administered.........................................................................66
5.5.2
Identity of Investigational Product...........................................................66
5.5.2.1
Packaging and Labeling...........................................................................67
5.5.2.2
Storage and Disposition of Study Drug ...................................................67
5.5.3
Method of Assigning Subjects to Treatment Groups...............................67
5.5.4
Selection and Timing of Dose for Each Subject......................................68
5.5.5
Blinding....................................................................................................69
5.5.6
Treatment Compliance.............................................................................69
5.5.7
Drug Accountability.................................................................................70
5.6
Discussion and Justification of Study Design..........................................70
5.6.1
Discussion of Study Design and Choice of Control Groups....................70
5.6.2
Appropriateness of Measurements...........................................................70
5.6.3
Suitability of Subject Population .............................................................71
5.6.4
Selection of Doses in the Study ...............................................................71
6.0
Complaints .............................................................................71
6.1
Medical Complaints.................................................................................72
6.1.1
Definitions................................................................................................72
6.1.1.1
Adverse Event..........................................................................................72
6.1.1.2
Serious Adverse Events ...........................................................................74
6.1.1.3
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL ....................................................75
6.1.1.4
Adverse Events of Special Interest ..........................................................76
6.1.2
Adverse Event Severity............................................................................76
6.1.2.1
Adverse Events Expected Due to Study-Related Endpoints....................77
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
15
6.1.2.1.1
Deaths ......................................................................................................77
6.1.2.1.2
Lack of Efficacy or Worsening of Disease ..............................................78
6.1.3
Relationship to Study Drug......................................................................78
6.1.4
Adverse Event Collection Period.............................................................79
6.1.5
Adverse Event Reporting.........................................................................79
6.1.6
Pregnancy.................................................................................................81
6.1.7
Data Monitoring Committee....................................................................81
6.1.8
Toxicity Management ..............................................................................82
6.1.8.1
Prophylaxis and Management of Tumor Lysis Syndrome.......................82
6.1.8.2
Dose Modifications Based on Toxicities .................................................85
6.1.8.3
Management of Neutropenia....................................................................88
6.1.8.4
Immunization ...........................................................................................88
6.1.8.5
Management of Hematologic Toxicities Other Than Neutropenia 
or Lymphopenia.......................................................................................88
6.1.8.6
Management of Non-Hematologic Toxicity............................................89
6.2
Product Complaint ...................................................................................89
6.2.1
Definition .................................................................................................89
6.2.2
Reporting..................................................................................................89
7.0
Protocol Deviations................................................................90
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................91
8.1
Statistical and Analytical Plans................................................................91
8.1.1
Baseline Characteristics...........................................................................91
8.1.1.1
Demographics ..........................................................................................92
8.1.1.2
Medical Histories.....................................................................................92
8.1.2
Efficacy Endpoints...................................................................................92
8.1.2.1
Primary Efficacy Endpoints.....................................................................92
8.1.2.2
Secondary Efficacy Endpoints.................................................................92
8.1.2.3
Exploratory Efficacy Endpoints...............................................................94
8.1.3
Timing of Efficacy Endpoints and Safety Evaluations............................94
8.1.4
Additional Efficacy Analyses ..................................................................95
8.1.5
Safety .......................................................................................................96
8.1.5.1
Adverse Events ........................................................................................96
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
16
8.1.5.2
Serious Adverse Events ...........................................................................96
8.1.5.3
Deaths ......................................................................................................96
8.1.5.4
Analyses of Laboratory Data ...................................................................97
8.1.6
Pharmacokinetics .....................................................................................97
8.2
Determination of Sample Size .................................................................97
9.0
Ethics.......................................................................................98
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................98
9.2
Ethical Conduct of the Study...................................................................99
9.3
Subject Information and Consent.............................................................99
10.0
Source Documents and Case Report Form 
Completion ...........................................................................100
10.1
Source Documents .................................................................................100
10.2
Case Report Forms.................................................................................100
11.0
Data Quality Assurance ......................................................101
12.0
Use of Information...............................................................102
13.0
Completion of the Study .....................................................102
14.0
Investigator's Agreement....................................................104
15.0
Reference List ......................................................................105
List of Tables
Table 1.
Excluded and Cautionary Medications ....................................................36
Table 2.
Sample of Permitted Medications............................................................37
Table 3.
ECOG Performance Status ......................................................................44
Table 4.
Clinical Laboratory Tests.........................................................................45
Table 5.
2008 Modified IWCLL NCI-WG Criteria for Tumor Response.............59
Table 6.
Identity of Investigational Product...........................................................67
Table 7.
Recommended Dose Modifications for Toxicities ..................................86
Table 8.
Dose Modification for Toxicity During Venetoclax Treatment ..............87
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
17
List of Figures
Figure 1.
5-Week Dose-Titration Schedule.............................................................28
Figure 2.
5-Week Dose-Titration Schematic...........................................................69
Figure 3.
Adverse Event Collection ........................................................................79
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................110
Appendix B.
List of Protocol Signatories....................................................................112
Appendix C.
Sample List of Excluded and Cautionary Medications..........................113
Appendix D.
Study Activities......................................................................................114
Appendix E.
Schedule of Extended Access Phase*....................................................120
Appendix F.
Schedule of Biomarker Collection.........................................................122
Appendix G.
Definitions of Laboratory and Clinical Tumor Lysis Syndrome...........123
Appendix H.
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS)..........125
Appendix I.
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL ..................................................129
Appendix J.
Protocol Amendment:  List of Changes.................................................131
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
18
3.0
Introduction
Bcl-2 Family Proteins
The B-cell lymphoma-2 (Bcl-2) family proteins are important regulators of the intrinsic 
apoptosis pathway.  The Bcl-2 oncogene was first identified in follicular lymphoma (FL) 
where the t(14;18) chromosomal translocation results in significant over-expression of the 
protein in B-cells.  The Bcl-2 family of genes encodes a family of closely related proteins 
that possess either pro-apoptotic or anti-apoptotic activity and share up to four Bcl-2 
Homology (BH) domains.1-4  Bcl-2 overexpression is a major contributor to the 
pathogenesis of some types of lymphoid malignancies.  Bcl-2 is also overexpressed in 
acute and chronic leukemias.  Chronic lymphocytic leukemia (CLL) is a genetic disease 
where the microRNAs miR15a and miR16-1 that negatively regulate the transcription of 
Bcl-2 are deleted or down-regulated, resulting in uncontrolled expression of Bcl-2.5,6
Venetoclax (ABT-199) 
Venetoclax, also known as ABT-199, is a novel, orally bioavailable, small molecule Bcl-2 
family protein inhibitor that binds with high affinity (Ki < 0.010 nM) to antiapoptotic 
Bcl-2 and with lower affinity to other antiapoptotic Bcl-2 family proteins like B-cell 
lymphoma-extra large (Bcl-XL) and B-cell lymphoma-Walter and Eliza Hall Institute 
(Bcl-w) (> 4,000-fold and > –2,000- to > 20,000-fold lower affinity than to Bcl-2, 
respectively).8  Selective inhibition by venetoclax disrupts Bcl-2 signaling and rapidly 
induces multiple hallmarks of apoptotic cell death in Bcl-2-dependent human tumor cell 
lines.8  Importantly, venetoclax inhibition of Bcl-2 is independent of p53 activity.
A detailed discussion of the non-clinical toxicology, metabolism, and pharmacology can 
be found in the Investigator's Brochure.8
Venetoclax Clinical Data
In the Investigator's Brochure,8 a total of 2495 subjects received at least 1 dose of 
venetoclax in company sponsored studies as of 28 November 2017.  2473 of these 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
19
subjects are included in overall pooled analyses for reporting Reference Safety 
Information.  The 2473 subjects in the overall pooled analysis include 2224 oncology 
subjects (987 in monotherapy studies and 1237 in combination therapy studies), 
153 healthy volunteers, 23 subjects with hepatic impairment and 73 subjects with SLE.  
Of the 2224 oncology subjects, 1132 subjects had CLL/small lymphocytic lymphoma 
(SLL), 569 subjects had Non-Hodgkin's Lymphoma (NHL), 172 subjects had multiple 
myeloma (MM), 340 had Acute Myeloid Leukemia (AML), and 11 subjects had 
myelodysplastic syndrome (MDS).  787 subjects with blinded data have been treated with 
either venetoclax combination therapy or a comparator treatment in company-sponsored 
venetoclax oncology studies.  Doses administered in venetoclax clinical studies have 
ranged from 20 mg to 1200 mg.
The most common adverse events reported in venetoclax monotherapy studies were 
neutropenia (39.3%), nausea (31.4%) and diarrhea (24.9%).  The most common adverse 
events that were grade 3 and above were neutropenia (34.9%), anemia (13.8%) and 
thrombocytopenia (12.8%).  The most common serious adverse events were febrile 
neutropenia (6.1%), pneumonia (5.4%), malignant neoplasm progression (3.4%), and 
pyrexia (3.3%).  
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 
dose-titration phase of 5 weeks and enhanced TLS prophylaxis and monitoring measures 
were implemented in all CLL studies.  A subsequent analysis of data from subjects with 
CLL/SLL following the implementation of prophylaxis measures, who completed 
monotherapy indicated a marked reduction in severity and frequency of TLS when 
compared to the previous analysis.  None of the subjects experienced any serious 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
20
(including fatal) or nonserious event of clinical TLS (CTLS) or laboratory TLS (LTLS) or 
had study treatment discontinued because of TLS.  Since May 2014, a more personalized 
approach for prophylaxis and monitoring measures, where subjects with lower tumor 
burden could receive venetoclax on an out-patient basis, has been evaluated with no cases 
of clinical TLS.  Overall, the clinical data strongly support that the risk of TLS with 
venetoclax in CLL/SLL subjects is highest when initiating venetoclax dosing (5-week 
dose titration phase), as well as being greater in subjects with a large tumor burden.
The safety profile in combination studies is consistent with that observed in monotherapy 
studies and with known toxicity profile of combination agents.  Preliminary efficacy data 
indicate that venetoclax, both as monotherapy and in combination with other therapeutic 
agents, continues to show promising efficacy in oncology subject populations.  The 
overall response rate (ORR) in subjects with CLL/SLL was 75.0% to 81.7% (dose 
escalation and safety expansion cohorts, respectively), with a complete remission rate (CR 
+ CRi) of 32.1% in dose escalation and 11.7% in the safety expansion cohort for 
venetoclax monotherapy (Study M12-175 as of 10 June 2016).9
Additional safety and efficacy data are described in detail in the Investigator Brochure.8
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.10  Chronic lymphocytic leukemia primarily affects elderly individuals; 
however, approximately one third of subjects are less than 60 years of age at diagnosis.11  
It is currently estimated that annually approximately 15,000 people will be diagnosed with 
CLL in the United States and that almost 4,500 individuals will die of the disease.12  In 
Europe, CLL accounts for approximately 30% of all leukemias in adults with a reported 
age standardized incidence rate of 3.79 per 100,000 individuals (for CLL/SLL) in the 
years 2000 – 2002.10,13  The approximate 5-year survival rate for subjects with CLL is 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
21
73%.14  CLL presents with a variable clinical course.  Approximately one-third of subjects 
have indolent disease with prolonged median survival that does not require treatment, and 
die of causes unrelated to disease.  Another third have an initial indolent phase that is 
followed by rapid progression of the disease requiring therapy.  The remaining third have 
aggressive disease and require treatment at the time of diagnosis.  Chronic lymphocytic 
leukemia subjects will often have compromised bone marrow reserve due to their 
underlying disease.  The principal complication of CLL is immunodeficiency related to 
myelosuppression and as a result, infection is the major cause of death in subjects with 
CLL.15
Standard chemotherapeutic options for CLL cause significant immune suppression and 
myelosuppression, are not well-tolerated by the elderly population and have not 
consistently offered survival advantage.  Treatment decisions for subjects with CLL are 
made on the basis of considerations such as age, clinical stage, expected survival, and 
anticipated toxicities.  With the notable exception of allogeneic stem cell transplantation, 
CLL is currently an incurable disease, despite good initial responses to chemo 
immunotherapy.  Nonetheless, globally access to allogeneic stem cell transplant and/or 
clinical trials is limited, and treatment options for relapsed disease tend to have increased 
toxicity and reduced antitumor activity.
Chromosome 17p Deletions and TP53 Gene Mutations in Chronic Lymphocytic 
Leukemia
Chromosome 17p deletions and TP53 gene mutations are among a group of genetic 
defects that occur in subsets of subjects with CLL in addition to defects causing Bcl-2 
dysregulation.  The short arm of chromosome 17 contains the TP53 gene that encodes 
tumor protein p53, a tumor suppressor involved in deoxyribonucleic acid (DNA) repair 
activation, cell cycling regulation, and apoptosis signaling.  Standard cytotoxic 
chemotherapies used in the treatment of CLL (i.e., fludarabine, cyclophosphamide, and 
bendamustine), act by inducing DNA damage and triggering apoptosis.  The p53 tumor 
suppressor is essential for relaying the DNA damage signal to the apoptotic machinery.  
When p53 is functionally inactivated, either through mutation or deletion, these signals 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
22
are not effectively relayed and the efficacy of these agents is diminished.  Chromosome 
17p deletions and TP53 mutations occur over the course of the disease and expand under 
treatment selection pressure as a result of the resistance to chemotherapy and 
chemoimmunotherapy they confer.16-18  Notably, over 80% of subjects with 17p deletions 
also carry a TP53 mutation.17,19
The decreased likelihood of subjects with 17p deletions and/or TP53 mutations 
responding to standard chemotherapy and chemoimmunotherapy regimens is 
accompanied by a greater risk of disease progression and a shorter overall survival 
(OS).7,16-18,20  In a long-term follow up study of the effects of 17p deletions/TP53 
mutations in CLL subjects treated according to standard practice outside of a clinical 
study, survival periods measured from date of study sampling were 7.6 months or less for 
subjects with 17p deletions and/or TP53 mutations compared to 69 months for subjects 
without TP53 loss or mutations.21
Poorer outcomes in subjects with these aberrations have also been demonstrated in large 
randomized clinical treatment trials.  In the CLL8 trial (n = 817) comparing first-line 
chemoimmunotherapy (fludarabine/cyclophosphamide/rituximab) to chemotherapy alone 
(fludarabine/cyclophosphamide), multivariate analyses of prognostic indicators for 
survival at a median follow-up of 70 months found hazard ratios [HR] of 2.916 
(confidence interval [CI]:  1.779 – 4.781) and 2.715 (CI:  1.602 – 4.602) for 
progression-free survival (PFS) and OS, respectively, for subjects with 17p deletions and 
2.123 (CI:  1.400 – 3.218) and 3.014 (CI:  1.889 – 4.808), respectively, for subjects with 
TP53 mutations indicated.19  Poorer response to first-line treatment and shorter survival in 
subjects with 17p deletions and/or TP53 mutations were also observed in the CLL4 trial 
of 777 subjects randomized to chlorambucil or fludarabine with or without 
cyclophosphamide and in subjects with 17p deletions treated in the E2997 trial (n = 278) 
of fludarabine with or without cyclophosphamide.22,23
Relatively improved treatment responses have been shown in 17p deletion/TP53 mutant 
first-line and relapsed patient populations with alemtuzumab, a monoclonal antibody 
specific for B-cell surface molecule CD52, in combination with steroids 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
23
(e.g., methylprednisolone, dexamethasone).24,25  In a Phase 2 study (n = 39) the overall 
response rate, complete response (including with incomplete bone marrow recovery) rate 
(CR/CRi), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, 
respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, 
respectively, in the 17 previously untreated subjects.  Treatment-related death occurred in 
5% of subjects, 67% of subjects experienced Grade 3/4 hematologic and 
glucocorticoid-associated toxicity, and 51% experienced Grade 3 infection.24
The tyrosine kinase inhibitors ibrutinib and idelalisib that act downstream of the B-cell 
receptor have also been shown to produce relatively improved responses compared to 
standard therapies and have been approved for use in some jurisdictions for the treatment 
of CLL subjects with 17p deletion (ibrutinib, idelalisib) or TP53 mutations (idelalisib 
only).  Ibrutinib inhibits Bruton's tyrosine kinase, an enzyme involved in B-cell receptor 
signaling, homing, and adhesion.  A Phase 3 relapsed or refractory CLL study comparing 
ofatumumab (an anti-CD20 monoclonal antibody) to ibrutinib included 127 subjects with 
the 17p deletion.  In this cohort, the median duration of PFS was 5.8 months in the 
ofatumumab arm but was not reached in the ibrutinib arm (HR 0.25; 95% CI:  0.14, 0.45).  
The overall response rate was 47.6% with ibrutinib compared with 4.7% with 
ofatumumab.  No complete responses were observed.25  Overall, 57% of subjects in the 
ibrutinib arm had at least one ≥ Grade 3 adverse event (AE).  The most frequent 
non-hematologic AEs (> 20% of subjects) with ibrutinib were diarrhea, fatigue, pyrexia, 
and nausea.26  Grade 3/4 AEs reported in ≥ 5% of the 357 subjects with mantle cell 
lymphoma or CLL that received ibrutinib during clinical development were anemia, 
neutropenia, pneumonia and thrombocytopenia.27
Idelalisib targets the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ) involved in 
signal transduction via multiple receptors including the B-cell receptor and chemokine 
receptors CXCR4 and CXCR5.  A Phase 3 study comparing combined 
idelalisib/rituximab treatment with rituximab/placebo in previously treated subjects 
reported improved PFS in the idelalisib arm among the 96 subjects enrolled with 
17p deletion or TP53 mutation (HR 0.12; CI:  0.05, 0.32).  The majority of AEs in the 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
24
study were Grade 2 and the most common in the idelalisib arm were pyrexia, fatigue, 
nausea, chills, and diarrhea.28  The overall safety profile determined in Phase 1 to 3 
studies of idelalisib in hematologic malignancies as monotherapy or in combination with 
an anti-CD20 monoclonal antibody is characterized by a very common frequency 
(≥1/10 subjects) of ≥ Grade 3 infections, neutropenia, diarrhea/colitis and increased 
transaminase.29
CLL Subjects Who Have Received Prior B-Cell Receptor Inhibitor (BCRi) Therapy
Ibrutinib and idelalisib cause rapid response with reduction in lymph node size and 
splenic mass accompanied by increased peripheral blood (PB) lymphocytosis likely 
reflecting that microenvironment modulation could prevent these cells from receiving the 
survival signals delivered by the microenvironment.30  In early trials of Ibrutinib, 
approximately 10% of the subjects developed progressive disease (PD).  Few of these 
subjects developed resistance after achieving partial response lasting ≥ 6 months.  Distinct 
single nucleotide variations were noted in these subjects.31
In addition, toxicities such as diarrhea, fatigue and pyrexia are common and can affect the 
subjects who receive these drugs.26,28
However, the mechanism of action of venetoclax is independent of the B-cell receptor 
(BCR) pathway.32  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.
Despite some improvement in disease outcomes in relapsed/refractory CLL subjects, 
including those who have received novel agents, significant toxicities remain a concern, 
complete disease responses are uncommon, and relapse is virtually inevitable.  Subjects 
carrying TP53 aberrations and those who have received prior BCRi therapy continue to 
represent a significant unmet medical need and current treatment recommendations 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
25
include participation in investigative clinical trials proceeding to allogeneic hematopoietic 
stem cell transplantation in responding subjects eligible for transplant (e.g., younger age 
with no co-morbidities and a suitable donor).16,33
Further details of disease activity observed in clinical studies with venetoclax are 
provided in the Venetoclax Investigator's Brochure.8
3.1
Differences Statement
This is the first Phase 3b study to assess the efficacy of venetoclax monotherapy in 
relapsed or refractory CLL.  The R/R CLL patient population will be enriched to include 
subjects who have previously received BCRi therapy.  This will allow for the assessment 
of deep responses in this high risk/unmet need patient population.  In this study, subjects 
will be assessed for efficacy with standard criteria.  
3.2
Benefits and Risks
There is data that shows substantial efficacy of venetoclax monotherapy in the treatment 
of relapsed/refractory CLL characterized by 17p deletions.  Venetoclax is expected to be 
as active in subject selected for TP53 mutations as these subject populations overlap and 
the oncogenic effect of both genetic defects occurs via p53 abrogation.  In addition, there 
is limited data in the BCRi failure CLL population for subjects that subsequently receive 
venetoclax and also in subjects without the 17p deletion.  Current CLL therapies do not 
reliably produce complete responses and are not curative in subjects with p53 aberrations 
or those refractory to BCRi.  Furthermore, drugs more recently approved for these 
subjects are limited by toxicity.
Clinical safety data indicate that the adverse effects of venetoclax administered with 
appropriate measures are manageable and as expected from a treatment targeting 
hematologic cells including in subjects with 17p, TP53 mutation or subjects who have 
previously received BCRi therapy.
Additional safety and efficacy data can be found in the current Investigator Brochure.8
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
26
4.0
Study Objective
The primary objective of this study is to evaluate the efficacy of venetoclax monotherapy 
in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL).  The primary 
efficacy endpoint will be measured by complete remission rate (CR + CRi) of the subjects 
who have not been previously treated with BCRi therapy, as assessed by the investigator.
The secondary objectives are to evaluate other efficacy parameters including the overall 
response rate (ORR), duration of overall response (DoR), time to progression (TTP), 
progression-free survival (PFS), overall survival (OS), and the CR rate in previously 
BCRi treated subjects. 
Additional secondary objectives will also be evaluated, as well.  Quality of life will be 
assessed using the following patient reported outcomes (PRO) questionnaires:  the 
EuroQoL 5 Dimensions (EQ-5D-5L), a measure of general health status, the Functional 
Assessment of Cancer Therapy – Leukemia Questionnaire (FACT-Leu), a leukemia-
specific health related quality of life for acute and chronic disease, and the Functional 
Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F). 
The safety and tolerability of venetoclax in subjects with relapsed/refractory CLL will 
also be evaluated.
Additional exploratory objectives will be evaluated.  Minimal Residual Disease (MRD) 
will be assessed in the peripheral blood and bone marrow (BM) by flow cytometry and 
PCR.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is an open-label, single arm, Phase 3b, multi-center study evaluating the efficacy of 
venetoclax monotherapy in relapsed/refractory CLL.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
27
This study is designed to enroll approximately 250 subjects to meet scientific objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.  
All efforts will be made to adhere to these specific enrollment numbers; however, it would 
not be ethical to deny treatment to eligible subjects already in screening as they may have 
undergone study related procedures.
Subjects in this study will be enrolled at approximately 67 research sites globally.
Subjects will undergo screening procedures within 28 days prior to initial venetoclax 
administration.  For all subjects, a contrast computed tomography (CT) scan (or medically 
indicated alternative such as magnetic resonance imaging [MRI]) will be accepted if 
previously performed within 35 days prior to venetoclax administration.  Otherwise, a CT 
scan (or MRI) must be performed within the screening period of 28 days.  Following the 
4-week Screening period, eligible subjects will initiate venetoclax and attend study visits 
within 72 hours of dosing and on the first and second day of Week 1 and Week 2 during 
the dose titration phase.  Beginning on Week 3, through Week 5, study visits will be 
conducted within 72 hours of dosing and on Day 1 of each week.  Additional study visits 
on Day 2 of each week should be performed for subjects who continue to be at risk for 
TLS, based on investigator assessment.  Study visits will be reduced to a monthly 
frequency at Week 8, and at Week 48, they will be reduced to every 3 months until the 
end of study treatment (Week 108).  As of Week 8, the visit window for scheduled visits 
is ± 2 days.  A 30 day Safety Follow-up Visit should be performed approximately 30 days 
(± 3 days) following the last dose of venetoclax (to allow for AE collection 30 days 
following last dose of study drug).  If a subject is discontinued from the study with an 
ongoing AE or an unresolved clinically significant laboratory result, the site will attempt 
to provide follow-up until the AE has resolved to a ≤ Grade 1 or baseline or it is the 
investigator's judgment that the event is unlikely to resolve.
Venetoclax will be administered orally once daily (QD), continuously.  Venetoclax tablets 
should be taken with a meal and water in the morning at approximately the same time 
each day.  To mitigate the risk for TLS, the first 5 weeks of treatment include a dose-
titration phase where venetoclax will be dosed in increments as outlined in Figure 1.  The 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
28
starting dose of venetoclax is 20 mg once daily.  The dose will be gradually increased 
over a period of 5 weeks up to the daily dose of 400 mg.
Figure 1.
5-Week Dose-Titration Schedule
Week
VENETOCLAX 
Daily Dose
1
20 mg
2
50 mg
3
100 mg
4
200 mg
5 and beyond
400 mg
Disease response will be assessed by the investigator based on laboratory results and 
physical examinations using the 2008 Modified International Workshop on CLL National 
Cancer Institute – Working Group (IWCLL NCI-WG) Guidelines for Tumor Response 
with the addition of CT imaging (or MRI).  A Disease Assessment for clinical response by 
physical exam and hematologic assessments will be performed at Screening, Week 24, 
Week 36 and Week 48.  To confirm the response, a CT scan (or MRI if CT is medically 
contraindicated) will be performed at Week 48 on all subjects and BM samples will be 
collected for subjects with CR to confirm the response.  
MRD assessments will be performed by using peripheral blood specimens at Week 1 
Day 1 (baseline), Week 24 and Week 48.  When confirming a CR status or complete 
remission with incomplete bone marrow recovery (CRi) status per IWCLL NCI-WG 
guidelines with a bone marrow aspirate and biopsy, MRD assessment of the bone marrow 
aspirate should also be performed.
Quality of life will be assessed by using the following patient reported outcome 
questionnaires:  the EQ-5D-5L, the FACT-Leu, and the FACIT-F.  Quality of life 
endpoints will be summarized based on the scoring manual for the instruments.  
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
29
Subjects may continue to receive venetoclax for up to 2 years provided they continue to 
tolerate the drug, have no evidence of disease progression (based on investigator's 
assessment), do not have unacceptable toxicity and do not meet any of the criteria for 
discontinuation (see Section 5.4.1).  A final visit will be conducted upon treatment 
discontinuation.
After treatment discontinuation, subjects will be followed for disease progression (if 
progression has not already occurred) and survival.  Post-treatment calls will be 
performed every 6 months until discontinuation from the study.  Survival information 
(i.e., the date and cause of death, post-treatment cancer therapies, date of progression, 
etc.) will be collected.  This period will continue for two years following discontinuation 
of venetoclax. 
All study procedures will be performed as outlined in Section 5.3.1.1 and Appendix D and 
Appendix E. 
For subjects who continue to derive benefit after 2 years of treatment, AbbVie will work 
with the investigator on a case by case basis to consider the potential continuation of 
venetoclax therapy.  In countries where venetoclax is commercially available, extension 
of therapy may not be allowed.
A safety analysis will be performed for all subjects participating in the study who took at 
least one dose of study drug.  For the study as a whole, serious adverse events and adverse 
events will be evaluated and summarized.  Laboratory test results and vital signs will be 
explored for trends and summarized. 
5.2
Selection of Study Population
Subjects will undergo screening procedures within 28 days prior to initial venetoclax 
administration, with the exception of the CT scan (or MRI).  A CT scan will be accepted 
if previously performed within 35 days prior to venetoclax administration.  
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
30
Adult male and female subjects who meet the inclusion criteria and who do not meet any 
of the exclusion criteria will be eligible for enrollment into the study.
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
Age ≥ 18 years.
2.
Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2. 
3.
Subject has relapsed/refractory disease (received at least one line of prior therapy). 
4.
Diagnosis of CLL that meets published 2008 Modified IWCLL NCI-WG 
Guidelines and:
●
has an indication for treatment according to the 2008 Modified IWCLL 
NCI-WG criteria
●
has clinically measurable disease (lymphocytosis > 5 × 109/L and/or palpable 
and measurable nodes by physical exam and/or organomegaly assessed by 
physical exam)
●
subjects with or without the 17p deletion or TP53 mutation are eligible.
●
subjects who have received prior B-cell receptor inhibitor therapy are also 
eligible (up to 60 subjects total will be enrolled in the study).
5.
Adequate bone marrow function as follows:
●
hemoglobin ≥ 8.0 g/dL
●
platelets ≥ 25,000/mm3, without any of the following:
○
transfusion support within 14 days of Screening
○
evidence of mucosal bleeding
○
known history of bleeding episode within three months of Screening
6.
Adequate coagulation parameters per local laboratory reference range as follows:
●
activated partial thromboplastin time (aPTT) and prothrombin time (PT) 
and/or International Normalized Ratio (INR) not to exceed 1.5 × the upper 
limit of normal (ULN)
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
31
7.
Adequate renal function per local laboratory reference range as follows: 
●
calculated creatinine clearance ≥ 50 mL/min using 24-hour creatinine 
clearance or estimated creatinine clearance using the modified Cockcroft-Gault 
equation:
Estimated creatinine clearance (eCCr) =
(140 – age) • Weight(kg) • [0.85 if female]
72 • serum creatinine (mg/dL)
or, if serum creatinine is in µmol/L:
eCCr =
(140 – Age) • Weight(kg) • [1.23 if male, 1.04 if female]
serum creatinine (µmol/L)
8.
Adequate hepatic function per local laboratory reference range as follows:
●
aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 × ULN 
●
bilirubin ≤ 1.5 × ULN.  Subjects with Gilbert's Syndrome may have a bilirubin 
> 1.5 × ULN per correspondence between the investigator and AbbVie 
Therapeutic Area Medical Director (TA MD).
9.
If female, subject must be either postmenopausal defined as: 
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause.
●
Age ≤ 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L.
OR
●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
OR
A Women of Childbearing Potential (WOCP) practicing at least one protocol 
specified method of birth control (Refer to Section 5.2.4), starting at Study Day 1 
through at least 30 days after the last dose of study drug.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
32
10.
Females of childbearing potential must have a negative serum pregnancy test result 
at Screening, and a negative urine pregnancy test at Study Day 1.  Females of 
non-childbearing potential (either postmenopausal or permanently surgically sterile 
as define above) at Screening do not require pregnancy testing.
11.
Subject voluntarily signs and dates an informed consent form that has been 
approved by an Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB) prior to the initiation of any screening or study-specific procedures.
Rationale for Inclusion Criteria
1 – 4
To select the subject population
5 – 8
For the safety of the subjects
9 – 10
The impact of venetoclax on pregnancy is unknown
11
In accordance with Harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after the last dose of study drug.
2.
Subject has developed Richter's transformation or Prolymphocytic leukemia.
3.
Subject has previously received venetoclax.
4.
History of active malignancies other than CLL within the past 2 years prior to 
first dose of venetoclax, with the exception of:
●
adequately treated in situ carcinoma of the cervix uteri
●
adequately treated basal cell carcinoma or localized squamous cell carcinoma 
of the skin
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
33
●
previous malignancy confined and surgically resected (or treated with other 
modalities) with curative intent.
5.
Active and uncontrolled autoimmune cytopenias (within 2 weeks prior to 
Screening), including autoimmune hemolytic anemia (AIHA) or idiopathic 
thrombocytopenic purpura (ITP), despite low dose corticosteroids.
6.
Prior allogeneic stem cell transplant.
7.
Treatment with the following within 30 days prior to the first dose of venetoclax:
●
a biologic agent (i.e., monoclonal antibodies) with anti-neoplastic intent.
8.
Treatment with any of the following within five half-lives or 14 days (if half-life 
unknown) as applicable prior to the first dose of venetoclax, or clinically 
significant adverse effect(s)/toxicity(s) of the previous therapy have not resolved to 
< National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v4.03 Grade 2:
●
any anti-cancer therapy including chemotherapy or radiotherapy, with the 
exception of b-cell receptor pathway inhibitors (i.e., ibrutinib, idelalisib)
●
investigational therapy, including targeted small molecule agents
9.
Treatment with any of the following within 7 days prior to the first dose of 
venetoclax:
●
Steroid therapy for anti-neoplastic intent.
●
Moderate or strong Cytochrome P450 3A (CYP3A) inducers (See Appendix C
for examples)  
10.
Treatment, administration or consumption of any of the following within 3 days
prior to the first dose of venetoclax.
●
Strong CYP3A inhibitors.  (See Appendix C for examples)
●
Moderate CYP3A inhibitors (See Appendix C for examples)
●
B-cell receptor pathway inhibitors (i.e., ibrutinib, idelalisib)
●
grapefruit or grapefruit products
●
Seville oranges (including marmalade containing Seville oranges)
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
34
●
Star fruit.
11.
Subject is known to be positive for Human Immunodeficiency Virus (HIV) (due to 
potential drug-drug interactions between anti-retroviral medications and 
venetoclax, as well as anticipated venetoclax mechanism based lymphopenia that 
may potentially increase the risk of opportunistic infections).
12.
Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk 
for TLS.
13.
Cardiovascular disability status of New York Heart Association Class ≥ 2.  Class 2 
is defined as cardiac disease in which subjects are comfortable at rest but ordinary 
physical activity, results in fatigue, palpitations, dyspnea or anginal pain.
14.
Evidence of other clinically significant uncontrolled condition(s) including, but not 
limited to:
●
uncontrolled and/or active systemic infection (viral, bacterial or fungal)
●
chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.  
●
febrile neutropenia.
15.
Significant history of renal, pulmonary, neurologic, psychiatric, endocrinologic, 
metabolic, immunologic, cardiovascular or hepatic disease that in the opinion of 
the investigator would adversely affect the subject's participation in this study.  
16.
Malabsorption syndrome or other condition that precludes enteral route of 
administration.
Rationale for Exclusion Criteria
1
The impact of venetoclax on pregnancy is unknown 
2 – 5, 7
To select the appropriate subject population
6, 8 – 16
For the safety of the subjects
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
35
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of enrollment, 
or receives during the study, must be recorded along with the reason for use, date(s) of 
administration including start and end dates, and dosage information including dose, route 
and frequency.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapy(ies).
Subjects should receive full supportive care during study participation, including 
hematopoietic growth factors, transfusion of blood products, fluid and electrolyte 
replacement, and antibiotics when appropriate.  Subjects who use oral contraceptives, 
hormone-replacement therapy, or other maintenance therapy should continue their use.
Steroid therapy for anti-neoplastic intent will not be allowed either during or within 
7 days prior to the first dose of venetoclax.
Inhaled steroids for the treatment of asthma or COPD, topical steroids, replacement 
corticosteroid therapy for an inherited or acquired deficiency are allowed.
In addition, limited corticosteroid treatment is allowed while on study for significant 
active autoimmune cytopenias, e.g., autoimmune hemolytic anemia (AIHA) or immune 
thrombocytopenia (ITP).  IVIG (intravenous immune globulin) is also allowable. 
For additional guidance regarding medications for management of neutropenia, refer to 
Section 6.1.8.3.
The AbbVie TA MD identified in Section 6.1.3 should be contacted if there are any 
questions regarding concomitant or prior therapy(ies).
General guidelines regarding excluded, cautionary and allowed medications are 
summarized in Table 1 and Table 2 below.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
36
Subjects may not consume grapefruit or grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit within the 3-day period prior to the 
first venetoclax administration and until the last day of treatment is completed due to 
possible CYP3A mediated metabolic interaction.
Table 1.
Excluded and Cautionary Medications
Excluded
Anticancer therapies including chemotherapy, radiotherapy, or other investigational therapy, 
including targeted small molecule agents:  Excluded 5 half-lives prior to first dose and throughout 
venetoclax administration
Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic effect:
Excluded 30 days prior to first dose and throughout venetoclax administration
Excluded during initiation and the dose-titration phase and Cautionary at 400 mg Steady Daily 
Dose: 
Strong CYP3A inhibitors 
Exclude during initiation and the dose-titration phase.  If subject requires use of these medications after 
the dose titration phase at steady daily 400 mg doses, use with caution and reduce the venetoclax dose by 
at least 75% during co-administration.  Resume the venetoclax dose that was used prior to initiating the 
CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor
Cautionary
Moderate CYP3A inhibitors
Avoid concomitant use of venetoclax with moderate CYP3A inhibitors at initiation and during the 
dose-titration phase.  Consider alternative treatments.  If a moderate CYP3A inhibitor must be used, 
reduce the initiation dose, titration doses and the 400 mg steady daily dose of venetoclax by at least 50%.  
Resume the venetoclax dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days after 
discontinuation of the inhibitor.  
Strong and Moderate CYP3A inducers
Avoid concomitant use of venetoclax with strong or moderate CYP3A inducers.  Consider alternative 
treatments with less CYP3A induction.
Warfarin 
P-gp substrates
BCRP substrates
OATP1B1/1B3 substrates
P-gp inhibitors
BCRP inhibitors
Note:
See Appendix C for Examples.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
37
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 TA MD if subject requires use of these 
medications or recombinant human erythropoietin.
Best supportive care and treatment 
e.g., antiemetics, antibiotics, transfusions, 
nutritional support, pain control, etc.
Permitted
Antiherpes and anti-pneumocystis prophylaxis
Permitted; if clinically indicated.
Autoimmune thrombocytopenia and hemolytic 
anemia medications
Permitted; if clinically indicated.
A sample list of excluded medications and cautionary medications that fall into these 
categories is provided in Appendix C.  It is not possible to produce a complete list of 
medications that fall into these categories, so if in question, please refer to the appropriate 
product label.
If the investigator determines that such a medication is medically necessary, the 
investigator will notify the AbbVie TA MD and discuss the investigator's use of these 
medications and the investigator's plans to medically monitor the study subject.
5.2.4
Contraception Recommendations
While participating in this research study, female subjects should not become pregnant or 
breastfeed a baby. 
If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of both) OR a Women of Childbearing Potential, 
practicing at least one of the following highly effective methods of birth control, on Study 
Day 1 (or earlier) through at least 30 days after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to Study Day 1. In addition to combined 
hormonal contraception, a barrier method must be used during this study from 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
38
initial study drug administration to 30 days after the last dose of study drug as 
drug-drug interaction with venetoclax upon the hormonal contraception is 
unknown.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1. In addition to a progestogen-only hormonal contraception, a barrier 
method must be used during this study from initial study drug administration 
to 30 days after the last dose of study drug as drug-drug interaction with 
venetoclax upon the hormonal contraception is unknown.
●
Bilateral tubal occlusion/ligation at least 1 month prior to Study Day 1.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure at least 1 month before 
study participation.
●
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success, and is the sole sexual 
partner of the WOCP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
5.3
Efficacy and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix D and Appendix E.
Unless otherwise stated, the baseline measurement for any given variable will be defined 
as the last value obtained for the variable prior to the first dose of venetoclax.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
39
5.3.1.1
Study Procedures
All study procedures outlined in Appendix D and Appendix E are discussed in detail in 
this section, with the exception of adverse event (AE) information (discussed in 
Section 6.1.1).  All study data will be recorded on electronic case report forms (eCRFs).
Informed Consent
Subjects must voluntarily sign and date an informed consent form approved by an 
IEC/IRB, prior to the initiation of any screening, study-specific procedures, or before any 
prohibited medications are withheld from the subject in order to participate in the study.  
Details about how informed consent will be obtained and documented are provided in 
Section 9.3.
Screening
Procedures performed at Screening will serve as baseline, unless repeated on Week 1 
Day 1 prior to dosing; in which case the latter will serve as baseline.  Any abnormal 
laboratory or vital sign assessment between screening and prior to administration of study 
drug will be recorded in the subject's medical history and will also serve as the subject's 
baseline.  The schedule of study visit procedures is based on subject study drug 
administration.  Scheduled study visits and/or procedures will need to be altered if there is 
an interruption in study drug administration. If study drug administration is interrupted 
for more than 3 days (i.e., adverse event), the site will contact the AbbVie study team or 
AbbVie TA MD to adjust the subject's visit schedule, procedures and/or dosing on a case 
by case basis.
Subjects who signed informed consent, have had at least one study procedure conducted, 
and are determined to be a screen failure, will not proceed in study.
Re-Screening Procedures
Subjects that initially screen fail for the study may be permitted to re-screen following re-
consent.  All Screening procedures will need to be repeated.  The subject must meet all 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
40
inclusion and none of the exclusion criteria at the time of re-screening in order to qualify 
for the study.  There is no minimum period of time a subject must wait to re-screen for the 
study.  If the subject had a complete initial screening evaluation including the CT scan 
and the re-screen visit is more than 35 days since the initial screening assessment, a CT 
scan should be repeated.  As appropriate, sites are encouraged to contact the AbbVie TA 
MD to confirm if subjects should or should not be re-screened.
Detection of 17p Deletion or TP53 Mutation
Subjects may have 17p deletion and/or TP53 mutation as assessed by local laboratory (in 
bone marrow or peripheral blood) to be considered as having this deletion/mutation.  
However, the 17p deletion or TP53 mutation is not a protocol required test for subjects to 
be enrolled in this study.  If a subject does have the 17p deletion or TP53 mutation, a 
recent test is desirable but any previous positive test is acceptable.
Medical and Oncology History
A complete medical history, including history of tobacco, nicotine-containing products 
and alcohol use, will be taken from each subject during the Screening visit, including: 
●
documentation of any clinically significant medical condition
●
a detailed oncology history including:
○
histology
○
cytogenetics
○
date of CLL diagnosis
○
stage
○
any surgical procedures
○
treatments administered (including dates, type of modality, response to 
treatment and reason for treatment discontinuation)  
On Week 1 Day 1, any additional medical history observed after signing of the informed 
consent but prior to initial venetoclax administration and not considered related to 
study-required procedures will be recorded in the subject's medical history. 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
41
Pregnancy Testing
●
WOCP must have a negative serum pregnancy test result at Screening, and a 
negative urine pregnancy test at Study Day 1.  
●
Screening – quantitative beta-human chorionic gonadotropin (β-hCG) serum 
pregnancy test.
●
Week 1 Day 1:  Urine test, if it has been > 7 days since obtaining the 
Screening serum pregnancy test results.
●
During the study a urine pregnancy test can be performed at the discretion of 
the investigator or per local guidelines.
●
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in Inclusion Criterion 9) at Screening do not 
require pregnancy testing.
Adverse Event and Concomitant Medication Assessment
On Week 1 Day 1, any protocol-related events observed from the time of signing of the 
informed consent but prior to initial venetoclax administration will be recorded as a 
serious or nonserious adverse event, if considered by the investigator to be causally 
related to the study-required procedures (See Figure 3). 
At each visit, including the Final Visit and the Post-Treatment Follow-Up, the subject's 
medical history will be reviewed and any changes from baseline will be recorded on the 
adverse event eCRF.
If a subject reports taking any over-the-counter or prescription medications, vitamins 
and/or herbal supplements or if administration of any medication becomes necessary 
beginning with Screening through the end of the study, the name of the medication, 
dosage information including dose, route and frequency, date(s) of administration 
including start and end dates, and reason for use must be recorded on the appropriate 
eCRF.  
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
42
Vital Signs
Vital signs include body temperature (oral or tympanic), weight, blood pressure and pulse.  
On days when venetoclax is administered in the clinic, blood pressure and pulse rate will 
be measured after the subject has been sitting for at least 5 minutes.
NOTE:  Starting with visit Week 8/Day 1, vital signs may be performed within 72 hours 
before or after the scheduled visit.
Physical Examination
At Screening, the subject should have a complete physical examination, including height 
and weight (height only performed during Screening).  A complete physical examination 
should include the evaluation of head, eyes, ears, nose and throat (HEENT); 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal and 
neurological systems. 
A symptom directed physical examination may be performed at all other visits (other 
than screening) and should be limited to systems of primary relevance:  cardiovascular, 
respiratory, and those associated with symptoms.
Physical Examination (Disease Assessment)
Physical examinations performed as a part of Disease Assessments (Screening, Weeks 24, 
36, 48) are to include the evaluation of the presence and degree of enlarged lymph nodes 
in two dimension (cervical, supraclavicular, axillary, inguinal and femoral nodes), 
hepatomegaly, and splenomegaly.  These lymph node evaluations should be noted on all 
physical examinations irrespective of being present or absent.  Refer to Disease 
Assessments (2008 Modified IWCLL NCI-WG Criteria) for additional information 
pertaining to methods of measurement.
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination.  New or worsened abnormalities should be recorded as AEs if appropriate. 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
43
If signs or symptoms suggestive of Richter's Syndrome are observed during physical 
examination, further assessments (i.e., nodes, Positron Emission Tomography [PET] scan) 
should be considered to exclude or confirm the transformation. 
Please refer to Appendix D and Appendix E for timing of all physical examinations.  
NOTE:  Starting with Week 8 Day 1, all Physical examinations may be performed within 
72 hours before or after the scheduled visit.
Tumor Lysis Syndrome (TLS) Risk Assessment
At Screening, all study subjects will be assessed for risk of developing TLS.  The risk of 
TLS is a continuum based on multiple factors, including tumor burden and comorbidities.  
Subjects with high tumor burden (e.g., any lymph node with a diameter ≥ 5 cm or high 
absolute lymphocyte count [ALC] [ALC ≥ 25 × 109/L]) are at greater risk of TLS.  
Reduced renal function (estimated creatinine clearance [eCrCl] < 80 mL/min) further 
increases the risk.  The risk may decrease as tumor burden decreases with venetoclax 
treatment.
Tumor burden assessments, including radiographic evaluation (e.g., CT scans) as well as 
chemistry/hematology assessments (refer to Table 4, Clinical Laboratory Tests) will be 
performed in all subjects prior to initiating venetoclax treatment.
Appropriate venetoclax dosing and management of subjects throughout their study 
treatment is guided by their individual risk for developing TLS.  Risk-based TLS 
prophylaxis and management measures are described in Section 6.1.8.1.
Eastern Cooperative Oncology Group (ECOG) Performance Status
For all subjects, the ECOG performance status47 will be performed as outlined in 
Appendix D and Appendix E.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
44
It is recommended, where possible, that a subject's performance status will be assessed by 
the same person throughout the study.  ECOG performance status will be assessed as 
follows:
Table 3.
ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair.
NOTE:  Starting at Week 24 Day 1, ECOG performance status may be performed within 
72 hours before or after the scheduled visit.
Coagulation Panel
Prothrombin time (PT) and/or International Normalized Ratio (INR) and activated partial 
thromboplastin time (aPTT) will be collected and will be analyzed by the local laboratory 
during Screening only.
Hematology and Chemistry
Hematology and chemistry will be analyzed by the local laboratory.  Required tests are 
listed in Table 4. 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
45
Table 4.
Clinical Laboratory Tests
Hematology
Chemistry
Coagulationa
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Lymphocytes
Platelet count (estimate not 
acceptable)
Reticulocyte count
Blood Urea Nitrogen (BUN)*
Creatinine 
Total bilirubin
Alanine Aminotransferase 
(ALT)
Aspartate Aminotransferase 
(AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acidb
Glucose
Albumin
Lactate dehydrogenase (LDH)
Prothrombin time (PT) 
AND/OR
International Normalized Ratio 
(INR)
Activated partial thromboplastin 
time (aPTT)
*
Urea may be reported instead of BUN.
a.
Performed at Screening and as clinically indicated.
b.
For samples from subjects treated with rasburicase:  rasburicase causes enzymatic degradation of the uric acid in 
blood/plasma/serum samples left at room temperature, potentially resulting in spuriously low plasma uric acid 
assay readings.  The following special sample handling procedure must be followed to avoid ex vivo uric acid 
degradation.  Uric acid must be analyzed in plasma.  Blood must be collected into pre-chilled tubes containing 
heparin anticoagulant.  Immediately immerse plasma samples for uric acid measurement in an ice water bath.  
Plasma samples must be prepared by centrifugation in a pre-cooled centrifuge (4°C).  Finally, the plasma must be 
maintained in an ice water bath and analyzed for uric acid within 4 hours of collection.
PRE-DOSE LABS:
Prior to the Initial Dose of Venetoclax, for all Subjects:
●
During the Screening Period:  For all subjects, the chemistry/hematology panel 
(see Table 4, Clinical Laboratory Tests) is required.
○
Pre-existing abnormalities should be corrected 
●
Within 72 hours of Week 1 Day 1:  If the screening labs were done more than 
72h before the planned first dose, the chemistry/hematology panel should be 
repeated.  These results should be reviewed prior to dosing.
○
Labs should be assessed and pre-existing abnormalities should be 
corrected.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
46
●
On the day of Week 1 Day 1:  Before dosing, the chemistry/hematology panel 
should be drawn.
The results of the labs drawn on Week 1 Day 1 need to be reviewed prior to 
dosing IF an additional lab draw within 72 hours of the initial dose at Week 1 
Day 1 was not drawn AND reviewed.  
Prior to Each Subsequent Dose Increase, for all Subjects:
●
Within 72 hours of each subsequent dose increase:  The chemistry/hematology 
panel should be repeated.  The results should be reviewed prior to dose 
increasing.
●
Prior to dosing, on the day of each subsequent dose increase:  Before dosing, 
the chemistry/hematology panel should be drawn.  The results of the labs 
drawn on Day 1 of each dose increase need to be reviewed prior to dosing IF
an additional lab draw within 72 hours of the dose increase was not drawn 
AND reviewed.  
POST-DOSE LABS:
For all subjects, the chemistry/hematology panel (refer to Table 4, Clinical Laboratory 
Tests) should be monitored at 6 to 8 hours and at 24 hours after the first dose of 
venetoclax (20 mg) and after the first dose increase (50 mg).  Electrolyte abnormalities 
should be corrected promptly.  The next venetoclax doses (the Day 2 20 mg venetoclax 
dose and the Day 2 50 mg venetoclax dose) should not be administered until the 24 hour 
lab results have been evaluated.  Electrolyte abnormalities should be corrected promptly.  
For subjects who continue to be at risk of TLS, the same lab monitoring schedule (i.e., 6 
to 8 hour and 24-hr post dose) should be followed at the subsequent dose increases. 
This monitoring is also recommended during the re-initiation of the therapy after a dose 
interruption.
Additional monitoring may be required based on the risk assessment by the investigator 
and as directed by the AbbVie TA MD. 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
47
Local laboratories will be utilized to process and provide results for clinical laboratory 
tests allowing for immediate subject medical management.  The principal investigator or 
sub-investigator will review, initial, and date all laboratory results used for subject 
treatment management after receipt from the local laboratory.  Local laboratory values 
will be entered by the site directly onto the appropriate eCRF and laboratory normal 
ranges for the laboratory that is used will be provided to the AbbVie Clinical Team.
A laboratory test value that requires a subject to be discontinued from the study, requires a 
subject to receive treatment, meets protocol specific criteria (see Section 6.1.8 regarding 
toxicity management), or if the Investigator considers clinically significant will be 
recorded as an adverse event.
NOTE:  Starting with Week 8/Day 1, clinical laboratory tests may be collected within 
72 hours prior to the scheduled visit.  
Disease Assessments (2008 Modified IWCLL NCI-WG Criteria)
All measurable disease must be documented at Screening (baseline), prior to the first dose 
of venetoclax, for all subjects based on the analysis of clinical laboratory tests 
(hematology), disease assessment physical examination, contrast-enhanced CT scan of 
involved neck, chest, abdomen and pelvis (or MRI, if CT scan with contrast is medically 
contraindicated).  Bone marrow examinations at screening are not required but results will 
be recorded if available. 
For all subjects, clinical response will be assessed by the investigator at Week 24, 
Week 36 and Week 48.  Disease response will be based on the analysis of clinical 
laboratory tests and a disease assessment physical examination.  To confirm the response, 
a contrast-enhanced CT scan (or MRI, if CT scan with contrast is medically 
contraindicated) will be performed at Week 48 for all subjects.  Subjects will be evaluated 
using the 2008 Modified IWCLL NCI-WG criteria for Tumor Response with the addition 
of CT imaging (or MRI).  
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
48
For determination of complete remission (CR), the CT scan and bone marrow are required 
to be negative, per the IWCLL NCI-WG criteria.  It is recommended that the CT scan is 
performed first; if it does confirm a clinical response, then a bone marrow biopsy will be 
obtained.  If a CT scan is performed and does not confirm a clinical response, a bone 
marrow biopsy should not be obtained.
If a subject exhibits clinical signs of possible disease progression (i.e., increased or 
de novo enlargement of liver, spleen or lymph nodes on physical examination) without an 
increase in lymphocytes meeting the progression of disease criteria, then additional 
assessments including contrast-enhanced CT scan and/or bone marrow can be performed 
to confirm or rule out disease progression. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 
For any subject who has not experienced progressive disease (PD) at the time of 
permanent discontinuation of venetoclax, follow-up phone calls will continue until death, 
discontinuation from the study or upon study completion.
Response criteria definitions are outlined in 2008 Modified IWCLL-WG Criteria for 
Tumor Response.  See Table 5.
For patients with only Partial Remission at Week 48 an additional CT and a bone marrow 
examination can be done between Week 48 and Week 108 to confirm CR if there is a 
possibility that a patient is in Complete Remission based on laboratory tests and a disease 
assessment physical examination.
NOTE:  Disease assessments may be performed approximately 7 days prior to the 
scheduled visit.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
49
Computed Tomography Scans (or Magnetic Resonance Imaging)
A CT scan with contrast will be accepted if previously performed within 35 days prior to 
the first dose of venetoclax.  Otherwise, a CT scan must be performed within the 
Screening window (28 days) for all subjects.  A CT scan will be performed for all subjects 
at Week 48 to confirm disease response.  Contrast-enhanced CT scans including neck, 
chest, abdomen, and pelvis will be performed to assess response to treatment.  A contrast-
enhanced MRI of the neck, chest, abdomen and pelvis with a non-contrast CT scan of the 
chest may be used for subjects in whom a contrast CT is medically contraindicated 
(i.e., subjects with a severe allergy to CT contrast agents or subjects with impaired renal 
clearance).  Whichever method is used at Screening should be consistently used 
throughout the duration of the study. 
Any CT scan (or MRI) performed as standard of care throughout the study should be 
captured on the eCRF.
NOTE:  CT scans (or MRI) may be performed 7 days prior to the scheduled visit.
Bone Marrow Aspirate and Biopsy
At baseline, a bone marrow aspirate and biopsy are not required; however results should 
be recorded if available.  If the subject achieves a CR by clinical criteria and confirmatory 
CT scan, a bone marrow aspirate and biopsy will be performed to confirm the CR.  
Whenever possible the bone marrow aspirate for biomarker MRD assessment should be 
split from this sample.  If a CT scan is performed and does not confirm a CR, a bone 
marrow biopsy should not be obtained. 
Bone marrow aspirates and biopsies performed as standard of care throughout the study 
should also be captured on an eCRF.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
50
Subject Calendars/Diaries
For all subjects, subject calendars/diaries will be provided at the Week 20 visit.  Subjects 
will be instructed to bring their calendars/diaries back to the site to be reviewed at the 
Week 24 visit. 
Subjects will be instructed to record the date and time of each dose taken (indicating if 
any doses of study drug are missed) from Week 20 to Week 24, and whether or not the 
dose was taken with a meal.  This information will be transcribed into the eCRF.
At the Week 24 visit, 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
Quality of life will be assessed using the following questionnaires:  the EQ-5D-5L the 
FACT-Leu and the FACIT-F.
Quality of life will be assessed at baseline (Week 1, Day 1 prior to the first dose), Week 4, 
Week 12, Week 24, and then every 3 months until the end of study treatment (Week 108).  
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 5.3.7, Health Economic and Patient-Reported Outcome Measures, 
for further information.
Final Visit
Upon treatment discontinuation (See Section 5.4.1), the reason(s) for discontinuation will 
be recorded in the eCRFs and a Final Visit will be performed.  The Final Visit procedures 
as listed in Appendix D and Appendix E should be performed as soon as possible after 
study drug discontinuation.
At the Final Visit, all used/unused study drug and the subject's calendars/diaries, if 
applicable are to be returned to the site and drug accountability performed.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
51
30-Day Safety Visit
A 30-Day Safety Follow-up Visit should be performed approximately 30 days (± 3 days) 
following the last dose of venetoclax (to allow for AE collection 30 days following last 
dose of study drug).  Refer to Appendix D and Appendix E for procedures to be 
performed.  
If a subject has an ongoing AE or an unresolved clinically significant laboratory result 
30 days following last dose of study drug, the site will attempt to provide follow-up until 
the AE has resolved to a ≤ Grade 1 or baseline or it is the investigator's judgment that the 
event is unlikely to resolve.  
Additionally, CT or MRI scans are not required, however if collected by the site as 
standard of care, the data should be recorded in EDC.
Post-Treatment and Survival Assessments 
After treatment discontinuation, subjects will be followed for disease progression (if 
progression has not already occurred) and survival.  Post-treatment calls will be 
performed every 6 months until discontinuation from the study.  Survival information 
(i.e., the date and cause of death, post-treatment cancer therapies, date of progression etc.) 
will be collected.  This period will continue for 2 years following discontinuation of 
venetoclax.
Extended Access Phase
In countries where venetoclax is not commercially available, subjects who continue to 
derive benefit after 2 years of treatment may be able to extend their treatment for up to 
2 additional years.  If a subject in the extended access phase of this study continues to 
derive benefit from Venetoclax after the 2-year extension, then per PI's assessment, 
subjects who are transferring to the venetoclax extension study, Study M19-388, may 
remain in Extended Access for up to additional 1 year or until the extension study is 
approved and initiated at the site, whichever is sooner.  AbbVie will work with the 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
52
investigator on a case by case basis to consider the potential continuation of venetoclax 
therapy.  The Extended Access Visits will include:
●
Collection of Survival information
●
AE/SAE/Con Med assessment
●
Study drug reconciliation and dispensing
All other procedures should be performed as standard of care.  The specific study 
assessments to be performed during these visits are detailed in Appendix E Study 
Activities.
Assignment of Subject Numbers
Subjects will be assigned unique consecutive subject numbers at screening, as described 
in Section 5.5.3.  The results of all screening evaluations must be within clinically 
acceptable limits, upon review by the investigator before a subject can be administered 
study drug.  Subjects will not be enrolled in the study if laboratory or other screening 
results are unacceptable.
5.3.1.2
Collection and Handling of Biomarker Research Samples
Biospecimens may be utilized to evaluate known and/or novel disease-related or drug-
related biomarkers.  The biomarker rationale will be discussed in the Biomarker Research 
Variables Section (Section 5.3.6).
Biomarker Samples
Minimal Residual Disease (MRD) Assessment
Peripheral blood for MRD will be collected from all subjects as outlined in Appendix D
and Appendix E.  
When confirming a CR or CRi status per the 2008 Modified IWCLL NCI-WG criteria 
with a bone marrow biopsy, whenever possible, a bone marrow aspirate should be 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
53
collected for MRD assessment.  The bone marrow aspirate should be split and a sample 
sent to the Central Laboratory.
All biomarker samples should be labeled and shipped as outlined in the study-specific 
laboratory manual.
AbbVie (or people or companies working with AbbVie) will store the samples in a secure 
storage space with adequate measures to protect confidentiality.  The samples may be 
retained while research on venetoclax, or drugs of this class, or this disease and related 
conditions continues, but for no longer than 20 years after study completion, or per local 
requirement.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for venetoclax and possible metabolite(s) will be collected by venipuncture 
per Appendix D and Appendix E.  The date and time (to the nearest minute) of the last 
dose and second to last dose of venetoclax will be recorded on the eCRF.  The date and 
time (to the nearest minute) of each blood sample collection will be recorded on the 
sample requisition form.
Blood samples (3 mL) for venetoclax assay will be collected at the following time:
●
Week 24 Day 1:  0 hour (pre-dose)
A total of 1 blood sample is planned to be collected per subject for venetoclax PK 
analysis.  Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing, and shipment.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
54
5.3.2.2
Measurement Methods
Plasma concentrations of venetoclax will be determined by the Drug Analysis Department 
at AbbVie using validated methods.  Plasma concentrations of other possible metabolites 
from venetoclax may be determined with validated or non-validated methods.
5.3.3
Efficacy Variables
The primary objective of this study is to evaluate the efficacy of venetoclax monotherapy 
in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL).  The primary 
efficacy endpoint will be measured by complete remission rate (CR + CRi) of the subjects 
who have not been previously treated with B-cell receptor inhibitor (BCRi) therapy, as 
assessed by the investigator.
The secondary objectives are to evaluate other efficacy parameters including the overall 
response rate (ORR), duration of overall response (DoR), time to progression, (TTP), 
progression-free survival (PFS), overall survival (OS), and the CR rate in BCRi treated 
subjects.
Additional secondary objectives will be evaluated.  Health Economic and 
Patient-Reported Outcome Measures will include the EQ-5D-5L, the FACT-Leu and the 
FACIT-F.  Minimal residual disease (MRD) and the rate of MRD negativity in the 
peripheral blood are assessed as exploratory objectives in the peripheral blood and bone 
marrow (BM) by flow cytometry, PCR and/or sequencing.
Analyses of these endpoints are described in Section 8.0.
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), disease assessment physical 
examination, CT scan including neck, chest, abdomen, and pelvis (or MRI if CT with 
contrast is medically contraindicated); bone marrow aspirate are not required but results 
will be recorded if available.  Subjects will be evaluated against the 2008 Modified 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
55
IWCLL NCI-WG Criteria for Tumor Response46 with CT imaging (or MRI). A BM 
sample assessment is required to confirm CR.
At screening (baseline), all measurable disease must be documented by laboratory testing 
(hematologic status), physical examination, and CT scan.  All baseline evaluations should 
be performed as closely as possible to the beginning of treatment and not more than 
4 weeks before the beginning of the treatment with the exception of the CT scan (or MRI) 
which will be accepted if previously performed within 35 days prior to study drug 
initiation.  During the study, subjects will have a disease assessment at Week 24, Week 36 
and Week 48.  To confirm the response, a CT scan will be performed at Week 48 on all 
subjects.  For subjects with CR as response at Week 48, a BM sample is required to 
confirm the response.  
Methods of Measurement
Disease response and progression will be assessed by analysis of peripheral blood, clinical 
examination, radiographic scans and bone marrow aspirate and biopsy.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.
Details on the analysis of peripheral blood required to assess response are provided in 
Section 5.3.1.2. 
A full disease assessment physical examination should be performed to assess the extent 
of disease involvement.  Physical examinations should include the evaluation of the 
presence and degree of enlarged lymph nodes in two dimension (cervical, supraclavicular, 
axillary, inguinal and femoral nodes), hepatomegaly, and splenomegaly.  These should be 
noted on all examinations irrespective of being present or absent.  All measurements 
should be taken and recorded in metric notation using a ruler or calipers.  Clinical lesions 
will only be considered measurable when they are superficial (e.g., palpable lymph 
nodes).  The diameter, in two planes, of the largest palpable nodes in each of the 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
56
following sites should be measured:  cervical, supraclavicular, axillary, inguinal, and 
femoral.  The presence of hepatomegaly and splenomegaly should be performed.
The 12 largest bi-dimensional lesions should be recorded in the eCRF.  
●
Target Lesions:  A maximum of 12 target lesions may be selected (up to 
6 nodal and 6 extra nodal).  Target nodal lesions must be abnormal (> 1.5 cm 
in LDi [Longest Diameter] at baseline), clearly measurable and suitable for 
consistent, reproducible measurement in at least two perpendicular 
dimensions.  Target extra nodal lesions must be > 1 cm in two perpendicular 
diameters at baseline.
●
Non-Target Lesions:  Sites will be classified as non-target lesions where 
disease is present but not selected for target lesions.  A maximum of 
10 non-target lesions can be selected.  Non-target nodal lesions must be 
abnormal (> 1.5 cm in LDi at baseline).  Non-target extra nodal lesions must 
be > 1 cm in two perpendicular diameters.  Nodal and extra nodal lesions that 
were not selected as target lesions at baseline can be followed as non-target 
lesions.
Computed tomography (CT) is the preferred method to measure lesions selected for 
response assessment.  CT scans (with contrast) should include neck, chest, abdomen, and 
pelvis scans.  CT scans for response assessment may be limited to areas of prior 
involvement only, if required by local regulatory authorities.  A contrast-enhanced MRI of 
the neck, chest, abdomen and pelvis with a non-contrast CT scan of the chest may be used 
if CT with contrast is medically contraindicated (e.g., severe contrast allergy).  If MRIs 
are used instead of CT scans, MRIs should be used consistently throughout the study.  
Conventional CT and MRI should be performed with cuts of 5 mm or less in slice 
thickness contiguously.  Spiral CT should be performed by use of 5 mm contiguous 
reconstruction algorithm; this specification applies to the regions of the neck, chest, 
abdomen and pelvis at baseline and follow-ups.  The 12 largest bi-dimensional lesions 
should be recorded in the eCRF (6 nodal and 6 extra nodal).
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
57
For accurate overall response evaluation, ultrasound (US) should not be used to measure 
tumor lesions.
Details on bone marrow biopsy and aspirate are provided in Section 5.3.1.1.  Study 
Procedures.
Tumor Response Criteria
Complete Remission (CR)
CR requires all of the following criteria:
●
Peripheral blood lymphocytes (evaluated by blood and differential count) 
below 4 × 109/L (4000/µL)
●
Absence of lymphadenopathy (nodes > 15 mm in longest diameter or any extra 
nodal disease) by physical examination and CT scan
●
No hepatomegaly or splenomegaly by physical examination (as determined by 
measurement below the relevant costal margin)
●
Absence of disease or constitutional symptoms (B symptoms:  unexplained 
fevers > 38°C or 100.4°F, drenching night sweats, > 10% body mass weight 
loss in the preceding 6 months)
●
Blood counts above the following laboratory values:
○
Neutrophils > 1.5 × 109/L [1500/µL] (without the need for exogenous 
growth factors)
○
Platelets > 100 × 109/L [100,000/µL] (without the need for platelet 
transfusion or exogenous growth factors)
○
Hemoglobin > 110 g/L [11 g/dL] (without the need for blood transfusions 
or exogenous erythropoietin)
●
Bone marrow at least normocellular for age, < 30% of nucleated cells being 
lymphocytes.  Lymphoid nodules should be absent.  Bone marrow aspirate and 
biopsy should be performed after CR/CRi has been achieved.  If the bone 
marrow is hypocellular, a repeat determination should be made in 4 weeks or 
when peripheral blood counts have recovered.  A marrow biopsy should be 
compared to a pre-treatment marrow if available.  Subjects who are otherwise 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
58
in a complete remission, but bone marrow nodules can be identified 
histologically should be considered to be nodular PR (nPR).  
Immunohistochemistry (IHC) should be performed to define whether these 
nodules are composed of primarily T cells or lymphocytes other than CLL 
cells, or CLL cells.
Complete Remission with Incomplete Marrow Recovery (CRi)
Subjects who fulfill the criteria for CR (including bone marrow) but who have persistent 
cytopenia (anemia or thrombocytopenia or neutropenia) apparently unrelated to CLL but 
related to drug toxicity will be considered CRi.  The marrow evaluation described above 
should be performed with scrutiny and not show any clonal infiltrate.
Partial Remission (PR)
To be considered a PR at least 2 of the following must be met:
●
≥ 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.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
59
Table 5.
2008 Modified IWCLL NCI-WG Criteria for Tumor Response
Parameter
Complete Remission 
(CR) All Criteria 
Must be Meta
Partial Remission 
(PR) at Least 
2 Criteria from 
Group A AND at 
Least 1 Criterion 
from Group B 
Must be Met
Progressive Disease 
(PD) at Least 
1 Criterion from 
Group A OR 
1 Criterion from 
Group B Must be Metb
Stable Disease 
(SD) All Criteria 
Must be Met
Group A
Lymphadenopathy
None > 1.5 cm
Decrease ≥ 50%c
Increase ≥ 50%d or any 
new LN > 1.5 cm
Change of –49% 
to +49%e
Blood 
Lymphocytes
< 4000/µL
Decrease ≥ 50% 
from baseline
Increase ≥ 50% over 
baseline (≥ 5000/µL)
Change of –49% 
to +49%
Hepatomegalyf
None
Decrease ≥ 50%
Increase ≥ 50%g
Change of –49% 
to +49%
Splenomegalyf 
None
Decrease ≥ 50%
Increase ≥ 50%g
Change of –49% 
to +49%
Marrow
Normocellular, 
< 30% lymphocytes, 
no B lymphoid 
nodules; hypocellular 
marrow defines CRi
N/A
N/A
N/A
Group B
Platelet Count
> 100,000/µLh
> 100,000/µL or 
increase ≥ 50% 
over baselineh
Decrease of ≥ 50% from 
baseline secondary to 
CLL
Change of –49% 
to +49%
Hemoglobin
> 11.0 g/dLh
> 11.0 g/dL or 
increase ≥ 50% 
over baselineh
Decrease of > 2 g/dL 
from baseline secondary 
to CLL
Increase to 
≤11.0 g/dL over 
baseline, or 
decrease < 2 g/dL
Neutrophils
> 1500/µLh
> 1500/µL or 
increase ≥ 50% 
over baselineh
Decrease ≥ 50% from 
baseline secondary to 
CLL
N/A
New Lesions
None
None
Appearance of new 
palpable lymph nodes 
(> 1.5 cm in longest 
diameter) or any new 
extra nodal lesion 
(regardless of size) or 
transformation to a more 
aggressive histology, 
e.g., Richter Syndromed
None
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
60
Table 5.
2008 Modified IWCLL NCI-WG Criteria for Tumor Response 
(Continued)
Parameter
Complete Remission 
(CR) All Criteria 
Must be Meta
Partial Remission 
(PR) at Least 
2 Criteria from 
Group A AND at 
Least 1 Criterion 
from Group B 
Must be Met
Progressive Disease 
(PD) at Least 
1 Criterion from 
Group A OR 
1 Criterion from 
Group B Must be Metb
Stable Disease 
(SD) All Criteria 
Must be Met
Other Considerations
Non-Target 
Lesions
Nodes must be 
normal size as 
visually estimated; 
extra nodal and other 
assessable disease 
should be absent
No 
change/decreased
Unequivocal progression
No change or 
decrease or non-
substantial 
increase
Target Extra 
Nodal Disease
Absence of any extra 
nodal disease by 
physical examination 
(palpable, visualized 
extra nodal) and CT 
scan
≥ 50% decrease in 
SPD
≥ 50% increase in the 
longest diameter of any 
extra nodal lesion
Not CR, CRi, PR, 
or PD
CLL = chronic lymphocytic leukemia; LN = lymph nodes; N/A = Not applicable; SPD = sum of the products of 
diameters; CRi = complete remission with incomplete marrow recovery
a.
CR also requires the lack of disease-related constitutional symptoms.
b.
Transformation to a more aggressive histology (e.g., Richter Syndrome) would also qualify as a PD.
c.
Sum of the products of multiple LNs (as evaluated by CT scans).  Note in eCRF if by physical examination only.
d.
Increase in SPD of multiple nodes, or in greatest diameter of any previous site, or appearance of any new 
lymphadenopathy or organomegaly.  Degree of change in LN or lymphocyte counts should be measured from nadir 
(lowest post-treatment) values.
e.
Sum products of up to 6 LNs or LN masses (target lesions), with no increase in an LN or new enlarged LN.  
Increase of < 25% in small LNs (< 2 cm) not significant.  Decreases should be measured compared to baseline 
(pre-treatment) values.
f.
If enlarged before therapy.
g.
An increase in the previously noted enlargement of the liver or spleen by 50% or more or the de novo appearance 
of hepatomegaly or splenomegaly.
h.
Without the need for exogenous growth factors or transfusions.
5.3.3.2
Definition of Disease Progression
Disease progression according to 2008 Modified IWCLL NCI-WG Criteria for Tumor 
Response is characterized by at least one of the following:
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
61
●
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:  serious adverse 
event and adverse event monitoring including AEs of special interest (Section 6.1.1.4), 
vital signs, physical examination, and laboratory assessments.  Certain types of events 
require immediate reporting to the Sponsor, as outlined in Section 6.1.5.  Safety will be 
monitored on an ongoing basis and summarize periodically in aggregate safety reports and 
end of study.
5.3.5
Pharmacokinetic Variables
Values for the PK parameters of venetoclax, including the apparent clearance (CL/F), will 
be determined using a population PK modeling approach.  Additional parameters may be 
calculated if useful in the interpretation of the data.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
62
5.3.6
Biomarker Variables
Biomarker Research Variables
Peripheral blood and/or bone marrow biospecimens will be collected to conduct 
exploratory analyses to investigate biomarkers.  The types of biomarkers to be analyzed 
may include, but are not limited to, nucleic acids, proteins, lipids or metabolites.  Cells 
isolated from the peripheral blood/bone marrow may be analyzed to assess specific 
genetic mutations within the tumor cells, or to track the tumor cells to determine the 
presence of minimal residual disease.  Additionally, the expression levels (RNA or 
protein) of molecules involved in controlling the apoptosis machinery, including but not 
limited to BCL-2 family members, may also be correlated with efficacy.  
Evaluations may include analyzing biomarkers related to the pathway(s) targeted by the 
study drug or those believed to be related to the disease or to drug response.  The 
information learned from analyzing these samples may be used to investigate factors 
influencing response to treatment, scientific questions related to CLL, and/or in the 
development of new therapies and diagnostic tests.  The results of biomarker testing may 
not be included with the study summary.
5.3.7
Health Economic and Patient-Reported Outcome Measures
5.3.7.1
Functional Assessment of Cancer Therapy – Leukemia 
(FACT-Leu) Questionnaire
The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess subject 
health-related quality of life (HRQoL) and leukemia-specific symptoms using a 'core' set 
of questions (Functional Assessment of Cancer Therapy-General; FACT-G), as well as a 
cancer site-specific leukemia subscale.34  The FACT-G is a 27-item compilation of 
general questions scored on a 5-point scale ranging from 0 = "not at all" to 4 = "very 
much."35  The items are divided into 4 primary HRQOL domains:  Physical Well-being 
(7 items; score range, 0 – 28), Social/Family Well-being (7 items; score range, 0 – 28), 
Emotional Well-being (6 items; score range, 0 – 24), Functional Well-being (7 items; 
score range, 0 – 28).36
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
63
The leukemia-specific subscale consists of 17 items (score range, 0 – 68) that assess 
subject concerns relating to leukemia.  Three summary scales:  FACT-Trial Outcome 
Index (score range, 0 – 124) a summary scale composed of the Physical Well-being, 
Functional Well-being, and leukemia-specific subscales; FACT-G (score range, 0 – 108) 
and the FACT-Leukemia Total (score range, 0 – 176) can also be calculated.  Higher 
scores are reflective of better HRQOL.  Minimally important differences (MIDs) have 
been identified for the different FACT-Leu scales:  Physical Well-being, 2 – 3 points; 
Social/Family Well-being, not available; Emotional Well-being, 2 points; Functional 
Well-being, 2 – 3 points; FACT-G, 3 – 7 points; Leukemia-specific subscale, 4 – 7 points; 
FACT-Trial Outcome Index, 5 – 6 points; and FACT-Leukemia Total, 6 – 12 points. 
Scores will be summarized descriptively at each assessment.  The impact of treatment on 
quality of life over time will be assessed by calculating the change in scores from baseline 
at each assessment time point.  Scores will be calculated according to the FACT-Leu 
scoring manual. 
5.3.7.2
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F) Scale
The FACIT-F measures fatigue and its effect on functioning and daily activities.37  The 
FACIT-F has 13 items answered on a 5-point rating scale based on a 7-day recall period.  
Scores range from 0 to 52, with lower scores reflecting greater fatigue.  The instrument 
has shown good reliability and validity based on analyses of the general population in the 
United States, subjects with cancer, and subjects with rheumatoid arthritis.37-39  The MID 
of the FACIT-F scale has been determined to be 3 points.40
Scores will be summarized descriptively at each assessment. The impact of treatment on 
fatigue over time will be assessed by calculating the change in score from baseline at each 
assessment time point.  Scores will be calculated according to the FACIT-F scoring 
manual.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
64
5.3.7.3
EuroQol 5 Dimensions (EQ-5D-5L)
The EuroQol 5 Dimensions (EQ-5D-5L) is a generic preference instrument that has been 
validated in numerous populations.41,42  The EQ-5D-5L has five dimensions:  mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression.  These dimensions are 
measured on a five level scale:  no problems, slight problems, moderate problems, severe 
problems, and extreme problems.  The scores for the 5 dimensions are used to compute a 
single utility index score ranging from zero (0.0) to 1 (1.0) representing the general health 
status of the individual.  The EQ-5D-5L also contains a visual analog scale (VAS) to 
assess the subject's overall health.  The MID for the EQ-5D utility index score in cancer 
subjects is 0.08, and the MID for EQ-5D VAS is 7.43,44
Each of the five dimensions of the EQ-5D-5L, the VAS and overall utility score will be 
calculated using the EuroQol scoring manual, and summarized (mean, std. dev., median) 
at each assessment.  The impact of treatment over time will be assessed by calculating the 
change in score from baseline at each assessment time point. 
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study and/or study drug treatment at any 
time.  In addition, the investigator may discontinue a subject from study drug treatment at 
any time if the investigator considers it necessary for any reason including:
●
The investigator believes it is in the best interest of the subject
●
Subject's response to therapy is unsatisfactory, as evidenced by progression of 
disease while on study drug
●
The subject requires other cancer treatment (e.g., radiotherapy, cancer-related 
surgery as a result of tumor progression, alternate anti-neoplastic agents) 
during the study period
●
unacceptable toxicity
●
The subject becomes pregnant while on the study
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
65
●
drug/protocol non-compliance
The investigator will inform AbbVie prior to discontinuing a subject from the study by 
contacting the Clinical Team Leader as identified in Section 7.0.  All subjects will be 
included for analysis of safety data.  Subjects who withdraw from the study will not be 
replaced unless they are not evaluable.
Subjects will continue to be followed for unresolved AEs and survival information for any 
subject who has not experienced PD at the time of venetoclax discontinuation.  
Final Visit
Upon study drug discontinuation and/or upon discontinuation from the study, the 
reason(s) for discontinuation will be recorded in electronic case report forms (eCRFs) and 
a final visit will be performed.  The final visit procedures as listed in Appendix D should 
be performed as soon as possible after discontinuation from study drug.
30-Day Safety Follow-Up Visit
A 30-Day Safety Follow-up Visit should be performed approximately 30 days (± 3 days) 
following the last dose of venetoclax.  The 30 day safety follow up procedures listed in 
Appendix D should be performed.
Post Treatment and Survival Follow-Up Calls
For subjects who discontinue venetoclax therapy, but do not discontinue the study, post 
treatment follow-up calls will be performed every 6 months (± 7 days) for survival 
information (i.e., disease progression, the date and cause of death, post-treatment cancer 
therapies, etc.) and will be collected via telephone calls for a period of 2 years and 
recorded in the eCRFs.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
66
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Venetoclax tablets should be taken orally once daily with a meal and water in the morning 
at approximately the same time each day.  Venetoclax tablets should be swallowed whole 
and not chewed, crushed, or broken prior to swallowing.
If the subject misses a dose of venetoclax within 8 hours of the time it is taken, the subject 
should take the missed dose as soon as possible on the same day and resume the normal 
daily dosing schedule the following day.  If a subject misses a dose by more than 8 hours, 
the subject should not take the missed dose and resume the normal daily dosing schedule 
the following day.
In cases of vomiting after taking venetoclax, no additional dose (tablets) should be taken 
that day.  The next dose should be taken at the usual time the following day.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 6.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
67
Table 6.
Identity of Investigational Product
Study Drug
Trademark
Formulation
Route of 
Administration
Manufacturer
Venetoclax
N/A
10 mg Tablet 
Film coated
Oral
AbbVie
Venetoclax
N/A
50 mg Tablet 
Film coated
Oral
AbbVie
Venetoclax
N/A
100 mg Tablet 
Film coated
Oral
AbbVie
Each site will be responsible for tracking the lot numbers and expiration dates for all 
non-investigational medicinal products (e.g., generic name and generic name) that are 
dispensed.
5.5.2.1
Packaging and Labeling
The venetoclax tablets will be packaged in blister packs during the dose-titration phase 
and in high density polyethylene (HDPE) plastic bottles thereafter to accommodate the 
study design.  Each container will be labeled as required per country requirements.  
Labels must remain affixed to the container.
5.5.2.2
Storage and Disposition of Study Drug
The venetoclax supplied in this study is for investigational use only, and must only be 
used within this study.  All study drug must be maintained under adequate security and 
stored under conditions specified on the label until dispensed for subject use or returned to 
AbbVie or representative.
The tablets must be stored at a controlled room temperature of 15° to 25°C (59° to 77°F).
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects are assigned to the same treatment group in this single arm study.  Subjects 
will be allocated a unique consecutive subject number at Screening.  Subject numbers will 
consist of 5 digits (XXX01), with the first three digits denoting site number and the last 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
68
2 digits as the subject number, beginning with 01.  All subjects will be enrolled using an 
(Interactive Response Technology) IRT.  Before the study is initiated, each site will be 
provided with the IRT user instructions, which provides direction on how to use the IRT 
via the Web or the telephone.  Since this is an open-label study, subjects will maintain the 
same subject number, regardless of the number of re-screens and through the duration of 
the study.  The site, in conjunction with the Sponsor, will be responsible for assignment of 
all unique subject numbers at Screening and dose assignments if the subject is not a 
screening failure.
5.5.4
Selection and Timing of Dose for Each Subject
Venetoclax will be administered orally once daily (QD) beginning with a dose-titration 
phase.  As shown in Figure 2, the initial venetoclax dose is 20 mg QD.  After 1 week of 
treatment at 20 mg QD, the dose will be escalated to 50 mg QD followed by subsequent 
increases, each after 1 week, to 100 mg QD, 200 mg QD and the maximum dose of 
400 mg QD.  The maximum dose of venetoclax for this protocol will not exceed 400 mg 
per day.  The 5-week dose-titration phase is designed to gradually reduce tumor burden 
(debulk) and decrease the risk of tumor lysis syndrome.  All study subjects will be 
categorized at Screening according to their risk for developing TLS.  Their dose 
management, including during the dose-titration phase, will be conducted in accordance 
with their risk for developing TLS (see Section 6.1.8.1) and may include dose delay 
and/or dose reduction as required for prophylaxis and management of TLS.  
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
69
Figure 2.
5-Week Dose-Titration Schematic
5.5.5
Blinding
This is an open-label, single arm study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
To document compliance with the treatment regimen, subjects will be instructed to return 
all unused tablets and/or containers, even if empty and any other study related items as 
necessary, to the study coordinator at scheduled study visits.  Compliance will be 
monitored and documented by the study coordinator on the appropriate form.  The study 
coordinator will question the subject regarding adherence to the dosing regimen, record 
the number of tablets and/or containers returned, the date returned and determine 
treatment compliance before dispensing new venetoclax to the subject.  Compliance 
below 80% will require counseling of the subject by study site personnel.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
70
5.5.7
Drug Accountability
Investigator or representative will verify that study drug supplies are received intact and in 
the correct amounts.  Documentation of the receipt of supplies will be supported by a 
signed and dated Proof of Receipt or similar shipping document in IRT.  A current 
(running) and accurate inventory of venetoclax will be kept by the site and will include lot 
number, Proof of Receipt number(s), container numbers, blister pack numbers, subject 
initials, initials of person who dispensed the drug and the date study drug was 
administered for each subject.  An overall accountability of study drug will be performed 
and verified by AbbVie monitor(s) throughout the study and at the study site closeout 
visit.  All study drug unit doses must be inventoried, accounted for, and returned to 
AbbVie or destroyed per instructions from AbbVie and according to local regulations.  
All original containers (containing partially used or unused study drug) will be returned to 
AbbVie according to instructions from AbbVie or the designated monitor(s).  If 
pre-arranged between AbbVie and the site, destruction of used and unused study drug 
containers will be performed at the site.  Empty containers will be destroyed at the site.  
Labels must remain attached to the containers.
The investigator and/or named sub-investigators agree not to supply study medication to 
any persons not enrolled in the study.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
Study M15-550 is being conducted primarily to assess the efficacy of venetoclax 
monotherapy.  This study is a single-arm trial; therefore, there is no control group or 
treatment blinding.  The study will be conducted at multiple study centers globally to 
ensure a broad representation of the patient population and clinical care settings. 
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
71
5.6.3
Suitability of Subject Population
Venetoclax monotherapy has shown favorable activity in relapsed/refractory CLL subjects 
including subjects with 17p deletions.  Venetoclax is expected to be as active in subjects 
selected for TP53 mutations as these patient populations overlap and the oncogenic effect 
of both genetic defects occurs via p53 abrogation.  In addition, venetoclax has shown 
activity in subjects with relapsed or refractory CLL who have been previously treated with 
a B-cell receptor inhibitor.  These subjects can participate in this study and may have 
relapsed or be refractory to ibrutinib, or idelalisib containing regimen.
All subjects enrolled in the study will have adequate performance status and hematologic, 
renal and hepatic function to undergo venetoclax treatment.  
5.6.4
Selection of Doses in the Study
Venetoclax dosing will be introduced at an initial dose of 20 mg QD and escalated to a 
final dose of 400 mg QD.  The maximum dose of venetoclax for this protocol will not 
exceed 400 mg per day.  The daily dose will be titrated in the following weekly 
increments, as tolerated:  20 mg, 50 mg, 100 mg, 200 mg, and 400 mg.  The 400 mg final 
dose was selected for the ongoing, Phase 2 study of venetoclax monotherapy in 
relapsed/refractory CLL subjects with 17p deletion (Study M13-982) based on 
time-to-response and logistic regression modelling of data from CLL/SLL subjects 
enrolled in the Phase 1 Study M12-175.
The initial 20 mg venetoclax dose and weekly incremental increases in the dose-titration 
phase were implemented for Study M13-982 to reduce the risk of TLS.  Preliminary 
safety data from that study indicate the initial dose, the dose-titration phase and the final 
maximum dose are tolerable.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
72
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1.1
through 6.1.6.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
73
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 6.1.8 Toxicity 
Management) or if the investigator considers them to be adverse events.
For this protocol, disease progression is an efficacy endpoint.  These data will be captured 
as efficacy assessment data only.  Thus, events that are clearly consistent with the 
expected pattern of progression of the underlying disease (such as transformation to more 
aggressive histology) will result in discontinuation from the study and should not be 
recorded as adverse events but reported on the Study Completion eCRF.  However, if a 
subject experiences an adverse event (e.g., pneumonia, pyrexia, fatigue, etc.) and is also 
found to have disease progression, report the adverse event.  If there is any uncertainty as 
to whether an event is due to disease progression, it should be reported as an adverse 
event.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done, will be considered an adverse event.
A treatment-emergent AE is defined as any AE reported by a subject with onset or 
worsening from the time that the first dose of venetoclax is administered until 30 days 
have elapsed following discontinuation of venetoclax administration.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
74
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).
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
75
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, 
life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective 
or spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.  Deaths related to disease progression will 
not be recorded as serious adverse events (see Section 6.1.2.1.1).  
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 an SAE, unless there is an 
additional reason for hospitalization or an additional criterion for seriousness other than 
hospitalization (e.g., abnormal post-dose TLS laboratories that necessitate therapeutic 
medical intervention, etc.).
Hospitalization of a subject following the 30-Day Safety Follow-Up visit due to a 
subsequent line of therapy will not be captured as a SAE.
6.1.1.3
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL
Certain AEs are anticipated to occur in the study population at some frequency 
independent of drug exposure.  Such events include known consequences of CLL 
(e.g., symptoms, disease progression) and events unlikely to be related to the underlying 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
76
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 I.
These AEs may occur alone or in various combinations and are considered expected for 
reporting purposes for this protocol.
Cytopenias (anemia, neutropenia, or thrombocytopenia) are part of the natural history of 
CLL.  Persistent cytopenias at the same CTCAE grade as reported at baseline are not to be 
captured as adverse events, unless they fulfill a seriousness criteria, result in permanent 
discontinuation of a study drug, or the investigator had an identifiable cause other than the 
underlying disease.  However, all laboratory data should be entered regardless of whether 
an adverse event is reported.
Although exempted from expedited reporting to certain Health Authorities and ECs/IRBs 
as individual cases, if an event commonly associated with CLL or progression of CLL 
meets seriousness criteria, it must be reported to AbbVie within 24 hours of the site being 
made aware of the SAE (as defined in Section 6.1.5).  However, if the event was 
unequivocally due to disease progression, it should not be reported as an adverse event 
even if serious or fatal.  For deaths related to disease progression, the date and cause of 
death will be recorded on the appropriate case report form, but the death will not be 
expedited as an individual case safety report (ICSR) to regulatory authorities.
6.1.1.4
Adverse Events of Special Interest
TLS and neutropenia are identified risks.  Serious Infection is a potential risk. 
6.1.2
Adverse Event Severity
The investigator will rate the severity of each AE according to the NCI CTCAE v4.03.  If 
a reported AE increases in severity, the initial AE should be given an outcome date and a 
new AE must be reported on a different onset date than the end date of the previous 
adverse event to reflect the change in severity.  The dates on the AEs cannot overlap.  For 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
77
all reported SAEs that increase in severity, the supplemental eCRFs also need to be 
updated to reflect any changes due to the increase in severity. 
For AEs not captured by the NCI CTCAE, the following should be used:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities (moderate).
Grade 3
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating (moderate to severe).
Grade 4
The adverse event is life-threatening requiring urgent intervention 
(severe).
Grade 5
The adverse event resulted in death of the subject (severe).
6.1.2.1
Adverse Events Expected Due to Study-Related Endpoints
6.1.2.1.1
Deaths 
For this protocol, overall survival is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 6.1.4) that are attributed by 
the investigator solely to progression of CLL should be recorded ONLY on the Study 
Completion eCRF.  All other on-study deaths, regardless of relationship to study drug, 
must be recorded on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 6.1.5).  Death should be considered an outcome and not a distinct event.  The 
event or condition that caused or contributed to the fatal outcome should be recorded as 
the single medical concept on the Adverse Event eCRF.  Generally, only one such event 
should be reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a subject with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the subject was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
78
death later becomes available (e.g., after autopsy), "unexplained death" should be replaced 
by the established cause of death.  During survival follow-up, deaths attributed to 
progression of CLL should be recorded only on the Survival eCRF.
6.1.2.1.2
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease are also considered an expected outcome for this study and will not be 
subject to expedited reporting.
6.1.3
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
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other Cause" of event must be provided by the investigator for the SAE.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
79
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of venetoclax administration until 30 days, 
following discontinuation of venetoclax administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, protocol related 
serious adverse events and nonserious adverse events will be collected from the time the 
subject signed the study-specific informed consent.
All AEs should be followed until resolution, return to baseline or determined to be stable 
per the investigator.
Adverse event information will be collected as shown in Figure 3.
Figure 3.
Adverse Event Collection
*
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
81
Phone:  +1 (973) 784-6402
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure. 
6.1.6
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 the last dose of venetoclax.  Male subjects should be 
informed that contraceptive measures should be taken by their female partners. 
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  In the event of a pregnancy occurring in the partner of an 
enrolled subject, written informed consent for release of medical information from the 
partner must be obtained prior to the collection of any pregnancy-specific information and 
the pregnancy will be followed to outcome.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome of 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, stillbirth or congenital anomaly is considered a serious adverse event and must 
be reported to AbbVie within 24 hours of the site becoming aware of the event.
6.1.7
Data Monitoring Committee
A Data Monitoring Committee (DMC) will review safety data intermittently according to 
the DMC charter.  Details of the DMC review are presented in the DMC charter.  The 
separate charter has been created to provide detailed descriptions of the schedule of 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
82
analyses and the DMC meetings.  DMC membership, responsibilities and the description 
of the data coordinating center are documented in the charter.   
6.1.8
Toxicity Management
6.1.8.1
Prophylaxis and Management of Tumor Lysis Syndrome
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 
5-week dose-titration phase.  Changes in electrolytes consistent with TLS that require 
prompt management can occur as early as 6 – 8 hours following the first dose of 
venetoclax and at each dose increase. 
Risk Assessment for tumor lysis syndrome:  The risk of TLS is a continuum based on 
multiple factors, including tumor burden and comorbidities.  Subjects with high tumor 
burden (e.g., any lymph node with a diameter ≥5 cm or high absolute lymphocyte count 
[ALC > 25 × 109/L]) are a greater risk of TLS.  Reduced renal function (creatinine 
clearance [CrCl] < 80 mL/min) further increases the risk.  The risk may decrease as tumor 
burden decreases with venetoclax treatment. 
Additional comorbidities may further increase the risk for TLS.
Prior to initiating venetoclax, tumor burden assessment, including radiographic evaluation 
(refer to Section 5.3.1.1 Study Procedures – CT scans) must be performed for all subjects 
during Screening.  The full blood chemistry/hematology panel (refer to Table 4 Clinical 
Laboratory Tests) should be performed in all subjects during the Screening period in order 
to assess eligibility and to correct pre-existing abnormalities. 
If the chemistry/hematology panel was assessed more than 72 hours prior to the 1st dose of 
venetoclax, an additional full lab panel should be performed and reviewed within 72 hours 
prior to dosing in order to make a treatment decision.
Prophylaxis for tumor lysis syndrome:  The prophylaxis measures listed below should be 
followed.  More intensive measures (including hospitalization) should be employed as 
overall risk increases: 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
83
Hydration:  
Subjects should be adequately hydrated prior to starting treatment with venetoclax and 
during the dose-titration phase.  The recommended volume is 1.5 to 2.0 L 
(approximately 6 to 8 glasses) of water each day.  Subjects should be instructed to 
drink water starting 2 days before and on the day of the first dose, and every time the 
dose is increased.  Intravenous (IV) fluids should be administered as indicated based 
on overall risk of TLS or for those who cannot maintain an adequate level of oral 
hydration.  For subjects for whom volume overload is considered a significant risk, 
hospitalization should be considered.
Anti-hyperuricemic agents:  Anti-hyperuricemic agents should be administered 2 to 
3 days prior to starting treatment with venetoclax and may be continued through the 
titration phase. 
Laboratory Assessments:
PRE-DOSE LABS
Prior to the initial dose of venetoclax, for all subjects:
●
During the Screening Period:  For all subjects, the chemistry/hematology panel 
(see Table 4 Clinical Laboratory Tests) is required.
○
Pre-existing abnormalities should be corrected
●
Within 72 hours of Week 1 Day 1:  If the screening labs were more than 72h 
before the planned first dose, the chemistry/hematology panel should be repeated.  
These results should be reviewed before dosing.
○
Labs should be assessed and pre-existing abnormalities should be corrected
●
On the day of Week 1 Day 1:  Before dosing, the chemistry/hematology panel 
should be drawn.  The results of the labs drawn on Week 1 Day 1 need to be 
reviewed prior to dosing IF an additional lab within 72 hours of the initial dose at 
Week 1 Day 1 was not drawn AND reviewed.  
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
84
Prior to each subsequent dose increase, for all subjects:
●
Within 72 hours of each subsequent dose increase:  The chemistry/hematology 
panel should be repeated.  The results should be reviewed prior to dose increasing.
●
Prior to dosing, on the day of each subsequent dose increase:  Before dosing, the 
chemistry/hematology panel should be drawn.  The results of the labs drawn on 
Day 1 of each dose increase need to be reviewed prior to dosing IF an additional 
lab draw within 72 hours of the dose increase were not drawn AND reviewed.  
POST-DOSE LABS:
For all subjects, the chemistry/hematology panel (refer to Table 4 Clinical Laboratory 
Tests) should be monitored at 6 to 8 hours and at 24 hours after the first dose of 
venetoclax (20 mg) and after the first dose increase (50 mg).  Electrolyte 
abnormalities should be corrected promptly.  The next venetoclax doses (Day 2 20 mg 
venetoclax dose and Day 2 50 mg venetoclax dose) should not be administered until 
the 24 hour lab results have been evaluated.  Electrolyte abnormalities should be 
corrected promptly.  For subjects who continue to be at risk of TLS, the same lab 
monitoring schedule (i.e., 6 to 8 hour and 24-hr post dose) should be followed at the 
subsequent dose increases.
This monitoring is also recommended during the re-initiation of the therapy after a 
dose interruption.
Hospitalization:  Based on investigator assessment, some subjects, especially those at 
greater risk of TLS may require hospitalization on the day of the first dose of 
venetoclax for more intensive prophylaxis and monitoring through the first 24 hours.  
Hospitalization should be considered for subsequent dose increases based on 
reassessment of risk. 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
85
6.1.8.2
Dose Modifications Based on Toxicities
Dosing interruption and/or dose reduction may be required.  See Table 7 for dose 
modifications for hematologic and other toxicities related to venetoclax.  For subjects who 
have had a dosing interruption greater than 1 week during the first 5 weeks of dose 
titration or greater than 2 weeks when at the daily dose of 400 mg, TLS risk should be 
reassessed to determine if restarting at a reduced dose is necessary (e.g., all or some levels 
of the dose titration).
Tumor Lysis Syndrome
If a subject experiences blood chemistry changes suggestive of TLS, the following day's 
venetoclax dose should be withheld.  If resolved within 24 to 48 hours of last dose, 
treatment with venetoclax can be resumed at the same dose.  For events of clinical TLS or 
blood chemistry changes requiring more than 48 hours to resolve, treatment should be 
resumed at a reduced dose (see Table 7 and Table 8).  When resuming treatment with 
venetoclax after interruption due to TLS, the instructions for Prophylaxis for tumor lysis 
syndrome should be followed.
Other Toxicities
Treatment with venetoclax should be withheld for any grade 3 or 4 non-haematological, 
grade 3 or 4 neutropenia with infection or fever, or grade 4 haematological toxicities, 
except lymphopenia.  To reduce the risk of infection associated with neutropenia, 
granulocyte-colony stimulating factor (G-CSF) may be administered with venetoclax if 
clinically indicated.  Once the toxicity has resolved to grade 1 or baseline level (recovery), 
therapy with venetoclax may be restarted at the same dose.  If the toxicity recurs, and for 
any subsequent occurrences, the dose reduction guidelines in Table 7 and Table 8 should 
be followed when resuming treatment with venetoclax following resolution.  A larger 
dose reduction may occur at the discretion of the investigator.  For subjects who require 
dose reductions to less than 100 mg for more than 2 weeks due to adverse events, 
discontinuation of venetoclax should be considered.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
86
Table 7.
Recommended Dose Modifications for Toxicities
Event
Occurrence
Action
Tumor Lysis Syndrome
Blood chemistry 
changes or 
symptoms 
suggestive of TLS
Any
Withhold the next day's dose.  If resolved within 24 –
48 hours of last dose, resume at the same dose.
For any blood chemistry changes requiring more than 
48 hours to resolve, resume at a reduced dose (see 
Table 8). 
For any events of clinical TLS,a resume at a reduced dose 
following resolution (see Table 8).
Non-Hematologic Toxicities
Grade 3 or 4 non-
hematologic 
toxicities 
1st occurrence
Interrupt venetoclax 
Once the toxicity has resolved to Grade 1 or baseline 
level, venetoclax therapy may be resumed at the same 
dose.  No dose modification is required. 
2nd and subsequent 
occurrences
Interrupt venetoclax. 
Follow dose reduction guidelines in Table 8 when 
resuming treatment with venetoclax after resolution.  A 
larger dose reduction may occur at the discretion of the 
investigator. 
Hematologic Toxicities
Grade 3 or 4 
neutropenia with 
infection or fever; or 
Grade 4 hematologic 
toxicities (except 
lymphopenia) 
1st occurrence
Interrupt venetoclax. 
To reduce the infection risks associated with neutropenia, 
granulocyte-colony stimulating factor (G-CSF) may be 
administered with venetoclax if clinically indicated.  
Once the toxicity has resolved to Grade 1 or baseline 
level, venetoclax therapy may be resumed at the same 
dose. 
2nd and subsequent 
occurrence
Interrupt venetoclax. 
Consider using G-CSF as clinically indicated.  Follow 
dose reduction guidelines in Table 8 when resuming 
treatment with venetoclax after resolution.  Additional 
dose reductions may occur at the discretion of the 
physician.
Consider discontinuing venetoclax for subjects who require dose reductions to less than 100 mg for more 
than 2 weeks.
a.
Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac 
arrhythmias and/or seizures or sudden death.
Note:
Adverse reactions were graded using NCI CTCAE version 4.03.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
87
Table 8.
Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg
Restart Dose, mga
400
300
300
200
200
100
100
50
50
20
20
10
a.
During the dose titration phase, continue the reduced dose for 1 week before increasing the dose.
Dose Modifications for Use with CYP3A Inhibitors
Concomitant use of venetoclax with strong or moderate CYP3A inhibitors increases 
venetoclax exposure and may increase the risk for TLS at initiation and during the 
dose-titration phase.  Concomitant use of venetoclax with strong CYP3A inhibitors at 
initiation and during the dose-titration phase is contraindicated. 
Concomitant use of venetoclax with moderate CYP3A inhibitors at initiation and during 
the dose-titration phase should be avoided.  Alternative treatments should be considered.  
If a moderate CYP3A inhibitor must be used, the initiation and titration doses of 
venetoclax should be reduced by at least 50%.  Subjects should be monitored more closely 
for signs of toxicities. 
For subjects who have completed the dose-titration phase and are on a steady daily dose 
of venetoclax, the venetoclax dose should be reduced by at least 50% when used 
concomitantly with moderate CYP3A inhibitors and by at least 75% when used 
concomitantly with strong CYP3A inhibitors.  Subjects should be monitored more closely 
for signs of toxicities.  The venetoclax dose that was used prior to initiating the CYP3A 
inhibitor should be resumed 2 to 3 days after discontinuation of the CYP3A inhibitor.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
88
Missed Dose
If a subject misses a dose of venetoclax within 8 hours of the time it is usually taken, the 
subject should take the missed dose as soon as possible and resume the normal daily 
dosing schedule.  If a subject misses a dose by more than 8 hours, the subject should not 
take the missed dose and should resume the usual dosing schedule the following day.
If a subject vomits following dosing, no additional dose should be taken that day.  The 
next prescribed dose should be taken at the usual time the following day.
6.1.8.3
Management of Neutropenia
Nonclinical and clinical experience indicates that venetoclax may cause neutropenia.  
Subjects with a history of neutropenia who have received multiple prior therapies and/or 
have significant bone marrow involvement may be at a particularly high risk.
Grade 3 or 4 neutropenia has been reported in subjects treated with venetoclax.  Complete 
blood counts should be monitored throughout the treatment period.  Dose interruptions or 
dose reductions are recommended for subjects with severe neutropenia.  Supportive 
measures including antimicrobials for any signs of infection and prophylactic use of 
growth factors (e.g., G-CSF) should be considered. 
6.1.8.4
Immunization 
Live attenuated vaccines should not be administered prior to, during, or after treatment 
with venetoclax until B-cell recovery occurs.  The safety and efficacy of immunization 
with live attenuated vaccines during or following venetoclax therapy have not been 
studied.  Patients should be advised that vaccinations may be less effective.
6.1.8.5
Management of Hematologic Toxicities Other Than 
Neutropenia or Lymphopenia 
Venetoclax treatment should be withheld for any Grade 4 hematologic toxicity.  Once the 
toxicity has resolved to Grade 1 or baseline level (recovery), venetoclax may be re-started 
at the same dose.  If the toxicity recurs, the dose reduction guidelines in Table 8 should be 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
89
followed when resuming study treatment following resolution.  Additional dose 
reductions may occur at the discretion of the physician.
6.1.8.6
Management of Non-Hematologic Toxicity
Venetoclax treatment should be withheld for any clinically relevant ≥ Grade 3 
non-hematologic toxicity.  Once the toxicity has resolved to Grade 1 or baseline level 
(recovery), venetoclax may be re-started at the same dose.  If the toxicity recurs, the dose 
reduction guidelines in Table 8 should be followed when resuming study treatment 
following resolution.  Additional dose reductions may occur at the discretion of the 
physician.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event by entering the product 
complaint in RAVE, the EDC system.  If the EDC system is not operable, the Product 
Complaint Form should be used and emailed to:  RD_PQC_QA@abbvie.com within 
24 hours of the study site's knowledge of the event.  Product Complaints occurring during 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
90
the study will be followed-up to a satisfactory conclusion.  All follow-up information is to 
be reported to the Sponsor (or an authorized representative) and documented in source as 
required by the Sponsor.  Product Complaints associated with adverse events will be 
reported in the study summary.  All other complaints will be monitored on an ongoing 
basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and their assigned AbbVie Clinical Monitor(s).  In addition, 
the following AbbVie representatives should be contacted: 
 




Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
92
8.1.1.1
Demographics
Descriptive statistics will be provided for baseline demographic variables.  Age, height 
and weight will be summarized with means, medians, standard deviations and ranges.  
Frequencies and percentages will be provided for gender and race.
8.1.1.2
Medical Histories
Frequencies and percentages will be summarized for each medical history parameter.
8.1.2
Efficacy Endpoints
8.1.2.1
Primary Efficacy Endpoints
The primary efficacy endpoint will be complete remission rate (CR + CRi) of the subjects 
who have not been previously treated with BCRi therapy defined as the proportion of 
subjects achieving a CR or CRi as their best response (per the investigator assessment) 
based on IWCLL NCI-WG criteria.
In addition, the ninety-five percent (95%) confidence interval based on binomial 
distribution will be constructed for the calculated CR rate.
The assessment of response will be performed when all subjects enrolled have completed 
their Week 48 disease assessment, or after all enrolled subjects have discontinued 
venetoclax, whichever is earlier.  Subjects who have not achieved complete remission 
(CR + CRi) prior to this time will be considered to be non-responders in the calculation of 
CR rate.
8.1.2.2
Secondary Efficacy Endpoints
Key secondary efficacy endpoints will include overall response rate, duration of response, 
time to progression, progression-free survival, overall survival, and the CR rate in 
previously BCRi treated subjects.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
93
ORR will be assessed as the proportion of subjects with an overall response (CR + CRi + 
nPR + PR) based on the IWCLL NCI-WG criteria.  The ninety-five percent (95%) 
confidence interval based on binomial distribution will be constructed for the calculated 
CR rate.
Duration of response will be defined as the number of days from the date of first response 
(CR, CRi, nPR, or PR) to the earliest recurrence or PD.  If a subject is still responding, 
then the subject's data will be censored at the date of the subject's last available disease 
assessment.  For subjects who never experience response, the subject's data will be 
censored on the date of enrollment.  Duration of 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 
taking the study drug or had previously discontinued the study drug.  If the subject does 
not experience disease progression, then the data will be censored at the date of last 
available disease assessment.  Data for subjects who receive non-protocol, CLL therapy 
prior to disease progression will be censored at the last disease assessment prior to 
receiving non-protocol therapy.  Data for subjects without any disease assessments 
performed after the baseline visit will be censored at the time of enrollment plus 1 day.  
TTP will be analyzed by Kaplan-Meier methodology using data for all subjects enrolled.  
Median time TTP will be calculated and 95% confidence interval for median time TTP 
will be presented.
Progression-free survival (PFS) will be defined as the number of days from the date of 
first dose to the date of earliest disease progression or death.  All disease progression will 
be included regardless whether the event occurred while the subject was taking the study 
drug or had previously discontinued the study drug.  If the subject does not experience 
disease progression or death, then the data will be censored at the date of last disease 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
94
assessment.  Data for subjects who receive non-protocol CLL therapy prior to disease 
progression will be censored at the last disease assessment prior to receiving non-protocol 
therapy.  Data for subjects without any disease assessments performed after the baseline 
visit will be censored at the time of enrollment plus 1 day.  PFS will be analyzed by 
Kaplan-Meier methodology using data for all subjects enrolled.  Median time PFS will be 
calculated and 95% confidence interval for median time PFS will be presented.
Overall survival (OS) will be defined as number of days from the date of first dose to the 
date of death for all dosed subjects.  For subjects who did not die, their data will be 
censored at the date of last study visit or the last known date to be alive, whichever is 
later.  OS will be analyzed by Kaplan-Meier methodology using data from all enrolled 
subjects.  Median time survival will be estimated and 95% confidence interval for the 
median time survival will be presented.
The CR rate (CR + CRi) in previously treated BCRi subjects will be assessed based on the 
2008 Modified IWCLL NCI-WG criteria.  The ninety-five percent (95%) confidence 
interval based on binomial distribution will be constructed for the calculated CR rate.
8.1.2.3
Exploratory Efficacy Endpoints
The rate of MRD negativity in subjects will be summarized.  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.  In addition, the 
relationship between venetoclax PK and efficacy parameters including MRD level and CR 
will be evaluated.
8.1.3
Timing of Efficacy Endpoints and Safety Evaluations
The date the last enrolled subjects has completed their Week 48 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 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
95
data cut-off date.  During this data collection period, active subjects will continue to 
receive venetoclax, as applicable.  When data collection is complete and all data 
management quality assurance (QA) and quality control (QC) procedures are performed, 
the clinical database data will be extracted for documentation and statistical analyses.  
Any active subjects will continue to receive venetoclax until they discontinue or for up to 
2 years.  Once the last enrolled subject discontinues/completes the study, the study will be 
considered complete and all remaining data will be collected and entered into the clinical 
database.
8.1.4
Additional Efficacy Analyses
Health Economic and Patient Reported Outcome measures will include the FACT-Leu, 
the FACIT-F, and the EQ-5D-5L.
For the FACT-Leu, scores will be summarized descriptively at each assessment.  The 
impact of treatment on quality of life over time will be assessed by calculating the change 
in scores from baseline at each assessment time point.  Scores will be calculated according 
to the FACT-Leu scoring manual.  
For the FACIT-F, scores will be summarized descriptively at each assessment.  The 
impact of treatment on fatigue over time will be assessed by calculating the change in 
score from baseline at each assessment time point.  Scores will be calculated according to 
the FACIT-F scoring manual.
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.  The impact of treatment over time will be assessed 
by calculating the change in score from baseline to each assessment time point.
Alternative statistical analyses may be performed if deemed necessary and helpful in 
understanding the drug effect.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
96
8.1.5
Safety
The safety of venetoclax will be assessed by evaluating study drug exposure, adverse 
events, serious adverse events, all deaths, and laboratory parameters.
Safety analyses will be performed for all subjects who take at least one dose of 
venetoclax.
8.1.5.1
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.  In addition, the 
percentage of subjects experiencing an adverse event at a NCI CTCAE toxicity grade, and 
relationship to study drug will be provided.
8.1.5.2
Serious Adverse Events
Serious adverse events will be summarized using the same methods as Adverse Events 
described above.
8.1.5.3
Deaths
The number of subject deaths will be summarized (1) for deaths occurring within 30 days 
of the last dose of study drug, and (2) for deaths occurring more than 30 days of the last 
dose of study drug.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
97
8.1.5.4
Analyses of Laboratory Data 
Where applicable, blood chemistry and hematology determinations will be categorized 
according to NCI CTCAE version 4.03 grades, and shifts from baseline NCI CTCAE 
grades to maximum and final post-baseline grades will be assessed.
The baseline and final grades will be defined respectively as the grade of the last 
measurement collected prior to the first dose of study drug, and as the last post-baseline 
measurement collected no more than 30 days after the last dose of study drug.  The 
percentage of subjects experiencing a shift from baseline grades of 0 to 2 to maximum 
post-baseline grades of 3 to 4, and from baseline grades of 0 to 2 to final post-baseline 
grades of 3 to 4 will be summarized.  Detailed listings of data for subjects experiencing 
NCI CTCAE Grade 3 to 4 blood chemistry and hematology values will be provided.  All 
measurements collected, regardless of the number of days after the last dose of study 
drug, will be included in these listings.
8.1.6
Pharmacokinetics
Plasma concentrations of venetoclax will be tabulated for each subject.
An analysis of venetoclax plasma concentrations will be performed using a nonlinear 
mixed-effect population PK modeling approach.  The relationship between venetoclax PK 
and efficacy, including MRD level and CR, will also be evaluated.  The results from the 
population PK analysis and evaluation of efficacy may not be reported within the clinical 
study report.  Additional analyses may be performed if useful in the interpretation of the 
data.
8.2
Determination of Sample Size
Using the CR rate of 6% reported for current therapies45 250 subjects would provide 
approximately 90% power (based on an exact test for single proportions using a two-sided 
alpha of 5%) to reject the null hypothesis of 6% in favor of an alternative hypothesis that 
the CR rate for venetoclax monotherapy is 12% (doubling of the CR rate).
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
98
In order to provide approximately 80% power (based on an exact test for single 
proportions using a two-sided alpha of 5%) to reject the null hypothesis of 6% CR rate in 
favor of an alternative hypothesis that the CR rate for venetoclax monotherapy is 12% 
(doubling of the CR rate), the study will enroll 190 subjects who have not been previously 
treated with BCRi therapy.  Since there are approximately a total of 250 subjects, up to 
60 subjects previously treated with BCRi therapy can be enrolled.  
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 and approval by 
Regulatory Authority(ies), if required by local regulations, prior to implementation of any 
changes made to the study design.  The investigator will be required to submit, maintain 
and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP and all other applicable regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
99
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix 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.
In the event a subject withdraws consent to participate from the study, stored biomarker 
samples will continue to be used for research and analysis.  In the event that a subject 
would like to withdraw consent for research using these samples, the subject may request 
that their samples be withdrawn.  Once AbbVie receives the request, remaining biomarker 
samples will be destroyed.  If the subject changes his/her consent, and the samples have 
already been tested, those results will still remain as part of the overall research data.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
100
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 Awareness Date (SAE CRF) may serve 
as the source for this data point.  This adverse event data point required for eCRF 
completion can be entered directly in the eCRF.
The following patient reported outcomes (PRO) assessments will be completed by the 
subject and will be considered source documentation:
●
EQ-5D-5L
●
FACT-Leu
●
FACIT-F
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 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
101
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the Investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
Principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
PRO data is collected directly onto paper source by the subjects.  The completion of these 
forms is verified by the site staff.  The forms are entered into the clinical database and 
then can be viewed within the EDC system by the site staff.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigative sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
11.0
Data Quality Assurance
To ensure data integrity and subject safety, a study monitor will continuously, throughout 
the study, verify that all subjects sign the informed consent prior to any study specific 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
102
procedures being conducted, that the protocol procedures are being followed 
appropriately, and that the information provided in the eCRF is complete, accurate, and 
supported by information in source documents.  Computer logic and manual checks will 
be created to identify items such as inconsistent study dates.  Any necessary corrections 
will be made to the eCRF.
12.0
Use of Information
Any research that may be done using research samples from this study will be 
experimental in nature and the results will not be suitable for clinical decision making or 
patient management.  Hence, the subject will not be informed of individual results, should 
analyses be performed, nor will anyone not directly involved in this research.  
Correspondingly, researchers will have no access to subject identifiers.  Individual results 
will not be reported to anyone not directly involved in this research other than for 
regulatory purposes.  Data from research may be provided to investigators and used in 
scientific publications or presented at medical conventions.  Research information will be 
published or presented only in a way that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must submit, maintain and archive any records related to the study 
according to ICH GCP and all other applicable regulatory requirements.  If the 
investigator is not able to retain the records, he/she must notify AbbVie to arrange 
alternative archiving options.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
103
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit or date of the last 
follow-up contact, whichever is later.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
104
14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for venetoclax.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating 
the Efficacy of Venetoclax (ABT-199) in Relapsed/Refractory 
Subjects with Chronic Lymphocytic Leukemia (CLL) (VENICE I)
Protocol Date:
12 October 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
105
15.0
Reference List
1.
Willis S, Day CL, Hinds MG, et al.  The Bcl-2-regulated apoptotic pathway.  J Cell 
Sci.  2003;116 (Pt 20):4053-6.
2.
Cory S, Adams JM.  The Bcl-2 family:  regulators of the cellular life-or-death 
switch.  Nature Reviews.  Cancer.  2002;2(9):647-56.
3.
Borner C.  The Bcl-2 protein family:  sensors and checkpoints for life-or-death 
decisions.  Molecular Immunology.  2003;39(11):615-47.
4.
Cory S, Huang DCS, Adam 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.  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):202-208.
8.
AbbVie.  Venetoclax Investigator's Brochure Edition 9.  08 March 2018.
9.
Roberts A, Davids M, Pagel J, et al.  Targeting BCL2 with venetoclax in relapsed 
chronic lymphocytic leukemia.  N Engl J Med.  2016;374(4):311-22.
10.
Jaglowski S, Jones JA.  Choosing first-line therapy for chronic lymphocytic 
leukemia.  Expert Rev Anticancer Ther.  2011;11(9):1379-90.
11.
Zwiebel JA, Cheson BD.  Chronic lymphocytic leukemia:  staging and prognostic 
factors.  Semin Oncol.  1998;25(1):42-59.
12.
American Cancer Society:  Cancer Facts and Figures 2013.  Atlanta, GA:  
American Cancer Society, 2013.
13.
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.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
106
14.
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.
15.
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.
16.
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. 
17.
Stilgenbauer S, Zenz T.  Understanding and managing ultra high-risk chronic 
lymphocytic leukemia.  Hematology Am Soc Hematol Educ Program.  
2010;2010:481-8. 
18.
Zent CS, Burack WR.  Mutations in chronic lymphocytic leukemia and how they 
affect therapy choice:  focus on NOTCH1, SF3B1, and TP53.  Hematology Am 
Soc Hematol Educ Program.  2014;2014(1):119-24. 
19.
Stilgenbauer S, Schnaiter A, Paschka P et al.  Gene mutations and treatment 
outcome in chronic lymphocytic leukemia:  results from the CLL8 trial.  Blood.  
2014;123(21):3247-54. 
20.
Tam CS, Stilgenbauer S.  How best to manage patients with chronic lymphocytic 
leukemia with 17p deletion and/or TP53 mutation?  Leuk Lymphoma.  2015:1-7. 
21.
Zenz T, Kröber A, Scherer K et al.  Monoallelic TP53 inactivation is associated 
with poor prognosis in chronic lymphocytic leukemia:  results from a detailed 
genetic characterization with long-term follow-up.  Blood.  2008;112(8):3322-9. 
22.
Gonzalez D, Martinez P, Wade R et al.  Mutational status of the TP53 gene as a 
predictor of response and survival in patients with chronic lymphocytic leukemia:  
results from the LRF CLL4 trial.  J Clin Oncol.  2011;29(16):2223-9. 
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
107
23.
Lucas DM, Ruppert AS, Lozanski G, et al.  Cytogenetic prioritization with 
inclusion of molecular markers predicts outcome in previously untreated patients 
with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus 
cyclophosphamide:  a long-term follow-up study of the US intergroup phase III 
trial E2997.  Leuk Lymphoma.  2015:1-7. 
24.
Pettitt AR, Jackson R, Carruthers S, et al.  Alemtuzumab in combination with 
methylprednisolone is a highly effective induction regimen for patients with 
chronic lymphocytic leukemia and deletion of TP53:  final results of the National 
Cancer Research Institute CLL206 trial.  J Clin Oncol.  2012;30(14):1647-55. 
25.
Stilgenbauer S, Cymbalista F, Leblond V et al.  Alemtuzumab combined with 
dexamethasone, followed by alemtuzumab maintenance or Allo-SCT in "ultra 
high-risk" CLL:  final results from the CLL2O phase II study.  ASH 2014, San 
Francisco, abstract no. 1991.  2014a.
26.
Byrd JC, Brown JR, O'Brien S et al.  Ibrutinib versus of atumumab in previously 
treated chronic lymphoid leukemia.  N Engl J Med.  2014;371(3):213-23. 
27.
Ibrutinib [Summary of Product Characteristics].  2014.  Available from:  
http://www.ema.europa.eu/ema.
28.
Furman RR, Sharman JP, Coutre SE, et al.  Idelalisib and rituximab in relapsed 
chronic lymphocytic leukemia.  N Engl J Med.  2014;370(11):997-1007. 
29.
Idelalisib [Summary of Product Characteristics].  2014.  Available from:  
http://www.ema.europa.eu/ema.   
30.
Oppezzo P, Dighiero G.  "Role of the B-cell receptor and the microenvironment in 
chronic lymphocytic leukemia."  Blood Cancer J.  2013;3:e149.
31.
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.
32.
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.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
108
33.
Eichorst B, Dreyling M, Robak T, et al.  Chronic lymphocytic leukemia:  ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up.  Ann Oncol.  
2011;22 (Suppl 6):vi504.
34.
Cella D, Jensen SE, Webster K, et al.  Measuring health-related quality of life in 
leukemia:  the Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) 
Questionnaire.  Value Health.  2012;15:1051-8.
35.
Cella DF, Tulsky DS, Gray G, et al.  The Functional Assessment of Cancer 
Therapy (FACT) scale:  development and validation of the general measure.  J Clin 
Oncol.  1993;11(3):570-9.
36.
Cella D.  The manual of the Functional Assessment of Chronic Illness Therapy 
(FACIT) measurement system.  Center on outcomes, research and education.  
Evanston Northwestern Healthcare and Northwestern University.  1997.
37.
Yellen SB, Cella DF, Webster K, et al.  Measuring fatigue and other anemia-related 
symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system.  J Pain Symptom Manage.  1997;13:63-74.
38.
Cella D, Yount S, Sorensen M, et al.  Validation of the Functional Assessment of 
Chronic Illness Therapy Fatigue scale relative to other instrumentation in patients 
with rheumatoid arthritis.  J Rheumatol.  2005;32:811-9.
39.
Cella D, Lai JS, Chang CH, et al.  Fatigue in cancer patients compared with fatigue 
in the general United States population.  Cancer.  2002;94:528-38.
40.
Cella DF, Eton DT, Lai JS, et al.  Combining anchor and distribution-based 
methods to derive minimal clinically important differences on the functional 
assessment of cancer therapy (FACT) anaemia and fatigue scales.  J Pain Symptom 
Manage.  2002;24:547-61.
41.
Herdman M, Gudex C, Lloyd A, et al.  Development and preliminary testing of the 
new five-level version of EQ-5D (EQ-5D-5L).  Qual Life Res.  
2011;20(10):1727-36.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
109
42.
Oppe M, Devlin NJ, van Hout B, et al.  A program of methodological research to 
arrive at the new international EQ-5D-5L valuation protocol.  Value Health.  
2014;17:445-53.
43.
Pickard AS, Neary MP, Cella D.  Estimation of minimally important differences in 
EQ-5D utility and VAS scores in cancer.  Health Qual Life Outcomes.  
2007;5:70-8.
44.
Cella D, Pickard AS, Duh MS, et al.  Health-related quality of life in patients with 
advanced renal cell carcinoma receiving pazopanib or placebo in a randomized 
phase III trial.  Eur J Cancer.  2012;48:311-23.
45.
Resonate Trial.  ASH.  2014.  Abstract 3331.
46.
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and 
treatment of chronic lymphocytic leukemia:  a report from the International 
Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute-Working Group 1996 guidelines.  Blood.  2008;111:5446-56.  [Erratum, 
Blood.  2008;112:5259.]
47.
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the 
Eastern Cooperative Oncology Group.  Am J Clin Oncol.  1982;5(6):649-55.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
110
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.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
111
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.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
112
Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Head of Statistics, Oncology
Statistics
Assistant Medical Director
Medical Affairs 
Sr. Medical Director
Safety
Evidence Generation Medical Lead/Director
Medical Affairs
Study Project Manager I
Clinical
Associate Director
Clinical Pharmacology
 




Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
114
Appendix D.
Study Activities
Screening Through Week 5 Day 2
Activity
Scra
Within 
72 Hours 
of W1 
D1 
W1 
D1
W1 
D2
Within 
72 Hours 
of W2 
D1 
W2 
D1
W2 
D2
Within 
72 Hours 
of W3 
D1 
W3 
D1
W3 
D2
Within 
72 Hours 
of W4 
D1 
W4 
D1
W4 
D2
Within 
72 Hours 
of W5 
D1 
W5 
D1
W5 
D2
Informed Consent
X
17p Deletion or TP53 Mutation
Xb
Medical History/Oncology History 
Assessment
X
X
Pregnancy Testc
X
X
Adverse Event/Concomitant 
Medication Assessment
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examinatione
X
X
X
X
X
X
TLS Risk Assessmentf
X
ECOG Performance Status
X
X
Coagulation Panel
X
Hematology/Chemistryg
X
Xh
Xi
Xj
Xk
Xl
Xj
Xk
Xl
Xm
Xk
Xl
Xm
Xk
Xl
Xm
Disease Assessmentsn
X
Contrasted CT or MRI Scano
X
Bone Marrow Aspirate and Biopsyp
MRD Assessment in Peripheral 
Bloodq
X
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
115
Activity
Scra
Within 
72 Hours 
of W1 
D1 
W1 
D1
W1 
D2
Within 
72 Hours 
of W2 
D1 
W2 
D1
W2 
D2
Within 
72 Hours 
of W3 
D1 
W3 
D1
W3 
D2
Within 
72 Hours 
of W4 
D1 
W4 
D1
W4 
D2
Within 
72 Hours 
of W5 
D1 
W5 
D1
W5 
D2
Venetoclax dispensation and 
accountabilityr
X
X
X
X
X
X
X
X
X
X
Quality of Life Questionnaires 
(FACT-Leu, FACIT-Fatigue, 
EQ-5D-5L)s
X
X
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
116
Week 8 Through Post-Treatment Follow-Up
Activity
W8 
D1
W12 
D1
W16 
D1
W20 
D1
W24 
D1
W28 
D1
W32 
D1
W36 
D1
W40 
D1
W44 
D1
W48 
D1
Every 
12 Weeks 
Starting 
At W48
Week 
108/ 
Final 
Visit
30 Day 
Safety 
Visitt
Post-
Treatment 
Follow-Upu
Adverse Event/Concomitant 
Medication Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examinatione*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Statusv
X
X
X
X
Hematology/Chemistry**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease Assessmentn*
X
X
X
Contrasted CT or MRI Scano
X
Bone Marrow Aspirate and Biopsyp
Xo
MRD Assessment in Peripheral Bloodq
X
X
PK samplew
X
Venetoclax dispensation and 
accountability*** 
X
X
X
X
X
X
X
X
X
X
X
X
Xy
Dispense/Collect Subject 
Calendars/Diaries
X
X
Quality of Life Questionnaires (FACT-
Leu, FACIT-Fatigue, EQ 5D-5L)s
X
X
X
X
X
X
Collection of Survival Informationx
X
X
Scr = Screening; W = Wk = Week; D = Day; Post-Treat = Post-Treatment; FV = Final Visit
Study Windows:
*
Within 72 hours before or after scheduled visit starting with Week 8 Day 1.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
117
**
Within 72 hours prior to scheduled visit starting with Week 8 Day 1.
*** As of Week 8 the visit window for scheduled visits is ± 2 days.
a.
Subjects will undergo screening procedures within 28 days prior to the first study drug administration, except where otherwise indicated.
b.
Subjects who have 17p deletion or TP53 mutation as assessed by local laboratory (in bone marrow or peripheral blood) may be considered for enrollment.  A recent test is 
desirable but any previous positive test is acceptable.  Subjects that do not have the 17p deletion or TP53 mutation or have an unknown status are also eligible.
c.
For females of childbearing potential, as defined in the protocol, a urine pregnancy test must be obtained and processed locally at Week 1 Day 1, if it has been > 7 days since 
obtaining the serum pregnancy results at Screening.  During the study, a urine pregnancy test can be performed at the discretion of the investigator or per local guidelines.
d.
All protocol-related serious adverse events and nonserious adverse events must be collected from the signing of the study-specific informed consent until study drug 
administration.
e.
A complete physical examination will be performed at Screening.  A symptom directed physical examination may be performed as needed.  Refer to Section 5.3.1.1 Physical 
Examination, for more details.
f.
For subjects who have a dose interruption lasting more than 1 week during the first 5 weeks of dose-titration or more than 2 weeks when at the daily dose of 400 mg, the TLS 
risk should be reassessed to determine if restarting at a reduced dose is necessary.
g.
All clinical laboratory tests will be analyzed by the local laboratory.  Required tests are listed in Table 4 Clinical Laboratory Tests, refer to Section 5.3.1.1 Study Procedures, 
sub header Hematology and Chemistry as well as Section 6.1.8 Toxicity Management, for more details. 
h.
For all subjects, if the screening labs were done more than 72 hours before the planned first dose, the chemistry/hematology panel should be repeated and results reviewed 
prior to the initial dose in order to make a treatment decision.  Labs should be assessed and pre-existing abnormalities should be corrected. 
i.
For all subjects, on the day of Week 1 Day 1, before dosing, the chemistry/hematology panel should be collected.  The results of the labs drawn on Week 1 Day 1 need to be 
reviewed prior to dosing IF an additional lab within 72 hours of the initial dose at Week 1 Day 1 was not drawn AND reviewed.  
j.
For all subjects, the chemistry/hematology panel should be monitored at 6 to 8 hours and at 24 hours after the first dose of venetoclax (20 mg) and after the first dose increase 
(50 mg).  The next venetoclax doses should not be administered until the 24 hour lab results have been evaluated.  Electrolyte abnormalities should be corrected promptly.  
Note:  There is a ± 2 hour window around the 24 hour lab draw. 
k.
For all subjects, within 72 hours of each subsequent dose increase, the chemistry/hematology panel should be repeated.  The results should be reviewed prior to dose 
increasing.
l.
Prior to dosing, on the day of each subsequent dose increase, the chemistry/hematology panel is required.  The results of the labs drawn on Day 1 of each dose increase need 
to be reviewed prior to dosing IF additional labs within 72 hours of the dose increase were not drawn AND reviewed. 
m.
For subjects who continue to be at risk of TLS, the same lab monitoring schedule of 6 to 8 hour and 24-hr post dose should be followed at the subsequent dose increases.  
Note:  There is a ± 2 hour window around the 24 hour lab draw.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
118
n.
All measurable disease must be documented at Screening by laboratory testing, physical examination and CT scans (or MRI if CT is medically contraindicated); bone marrow 
examinations are not required at screening but results will be recorded if available.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment.  For all subsequent disease assessments, disease response will be assessed by the investigator based on the analysis of clinical laboratory tests (hematology) and a 
complete physical examination at Week 24, Week 36 and Week 48.
o.
CT scans with contrast (or MRI if CT is medically contraindicated) should include neck, chest, abdomen and pelvic sequences can be accepted if previously performed within 
35 days prior to the initial venetoclax dose.  Otherwise, CT scans (or MRI) must be performed within the 28 day screening period.  To confirm response, a CT scan (or MRI) 
must be performed at Week 48 for all subjects.  CT scans (or MRI) may be performed 7 days prior to the scheduled Week 48 visit.  If a subject exhibits clinical signs of 
possible disease progression (i.e., increased or de novo enlargement of liver, spleen or lymph nodes on physical examination) without an increase in lymphocytes meeting the 
progression of disease criteria, then additional assessments including contrast-enhanced CT scan and/or bone marrow can be performed to confirm or rule out disease 
progression.  Refer to Section 5.3.1.1 Computed Tomography Scans and Disease Assessments, for more details.  For patients with only Partial Remission at Week 48, an
additional CT and a bone marrow examination can be done between Week 48 and Week 108 to confirm CR if there is a possibility that a patient is in Complete Remission 
based on laboratory tests and a disease assessment physical exam.
p.
For determination of complete remission (CR), the CT scan and bone marrow are required to be negative, per the IWCLL NCI-WG guidelines.  If the subject achieves a CR 
by clinical criteria and confirmatory CT scan, a bone marrow aspirate and biopsy will be performed to confirm the CR.  Whenever possible the bone marrow aspirate for 
biomarker MRD assessment should be split from this sample.  Refer to Section 5.3.1.1 Disease Assessments and Bone Marrow Aspirate and Biopsy, for more details.
q.
MRD will be assessed by using peripheral blood at Week 1 Day 1 (baseline), Week 24 and Week 48.  Refer to Section 5.3.1.1 and Section 5.3.1.2 for more details.  When 
confirming a complete remission (CR + CRi) status per 2008 Modified IWCLL NCI-WG criteria with a bone marrow biopsy and aspirate.  The aspirate should be split and a 
sample sent to the central laboratory for MRD analysis. 
r.
Venetoclax tablets should be taken orally once daily with a meal and water in the morning at approximately the same time each day.  Dosing may occur at study visits on 
Week 1 Days 1 & 2 through Week 5 Days 1 & 2.
s.
The Quality of Life Questionnaires should be administered and completed prior to any other study procedures being performed at these visits.  Refer to Section 5.3.7, Health 
Economic and Patient-Reported Outcome Measures, for further information.  
t.
30-Day Safety Follow-up visit should occur approximately 30 days (± 3 days) after the last dose of venetoclax.
u.
Upon discontinuation of study drug treatment, survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 6 months 
(± 7 days) for a period of 2 years.
v.
ECOG performance status may be performed within 72 hours before or after the scheduled visit starting with Week 24.
w.
Collect (immediately) prior to venetoclax dosing (0 hour) on Week 24 Day 1.  The date and time (to the nearest minute) the venetoclax doses were taken, and whether or not 
the venetoclax doses were taken with a meal, will be recorded on the eCRF for the Week 24 Day 1 venetoclax PK day and for the 2 days prior to the Week 24 Day 1.  
x.
Survival information includes i.e., the date/cause of death, post treatment cancer therapies, etc.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
119
y.
In countries where venetoclax is not commercially available, subjects who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 
2 additional years AbbVie will work with the investigator on a case by case basis to consider the potential continuation of venetoclax therapy.  Subjects who participate in the 
2 year Extended Access phase will have study drug assigned at Week 108.  For patients that are not participating in the 2 year Extended Access phase, the Week 108 visit is 
the Final visit.  The specific study assessments to be performed at the Extended Access visits are detailed in Appendix E, Study Activities.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
120
Appendix E.
Schedule of Extended Access Phase*
Procedure
Week 
108
Week 
120
Week 
132
Week 
144
Week 
156
Week 
168
Week 
180
Week 
192
Week 
204
Week 
216
Week 
228
Week 
240
Week 
252
Week 
264
Final 
Visit
30 Day 
Safety 
Visitd
Post 
Treatment 
Follow upe
Vital signs**
X
X
X
Physical 
Examinationa**
X
X
X
ECOG 
Performance 
Status**
X
X
X
Hematology/ 
Chemistry***
X
X
X
Adverse Event/ 
Concomitant 
Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Venetoclax 
dispensation and 
accountability****
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collection of 
Survival 
Informationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life 
Questionnaires 
(FACT-Leu, 
FACIT-Fatigue, 
EQ-5D-5L)c
X
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
121
*
In countries where venetoclax is not commercially available, subjects who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 
2 additional years.  AbbVie will work with the investigator on a case by case basis to consider the potential continuation of venetoclax therapy.
**
Within 72 hours before or after scheduled visit.
*** Within 72 hours prior to scheduled visit.
****The visit window for scheduled visits is ± 2 days.
a.
Refer to Section 5.3.1.1 Physical Examination, for more details.
b.
Survival information includes i.e., the date/cause of death, post treatment cancer therapies, etc.
c.
The Quality of Life Questionnaires should be administered and completed prior to any other study procedures being performed at these visits.  Refer to Section 5.3.7, Health 
Economic and Patient-Reported Outcome Measures, for further information.  
d.
30-Day Safety Follow-up visit should occur approximately 30 days (± 3 days) after the last dose of venetoclax.
e.
Upon discontinuation of study drug treatment, survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 6 months 
(± 7 days) for a period of 2 years.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
122
Appendix F.
Schedule of Biomarker Collection
Sample Collections 
(Sample Type)
Week 1 
Day 1
Week 24 
Day 1
Week 48 
Day 1
Confirmation 
of CR/CRi
Comments
MRD Assessment
Peripheral Blood
X
X
X
X
12 mL, EDTA Tube, 
Ship DOC
Bone Marrow 
Aspiratea
X
2 – 3 mL, EDTA Tube, 
Ship DOC
a.
Whenever possible the bone marrow aspirate should be split and a sample sent to the central laboratory for 
biomarker MRD analysis.  
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
123
Appendix G.
Definitions of Laboratory and Clinical Tumor Lysis Syndrome
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  
2011;364(19):1844-54.
Metabolic 
Abnormality
Criteria for Classification of 
Laboratory Tumor Lysis Syndrome
Criteria for Classification of 
Clinical Tumor Lysis Syndrome
Hyperruricemia
Uric acid > 8.0 mg/dL 
(475.8 µmol/liter) in adults or above 
the upper limit of the normal range for 
age in children
Hyperphosphatemia
Phosphorus > 4.5 mg/dL 
(1.5 mmol/liter) in adults or 
> 6.5 mg/dL (2.1 mmol/liter) in 
children
Hyperkalemia
Potassium > 6.0 mmol/liter
Cardiac dysrhythmia or sudden death 
probably or definitely caused by 
hyperkalemia
Hypocalcemia
Corrected calcium < 7.0 mg/dL 
(1.75 mmol/liter) or ionized calcium 
< 1.12 (0.3 mmol/liter)†
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesias, muscle 
twitching, carpopedal spasm, 
Trousseau's sign, Chvostek's sign, 
laryngospasm, or bronchospasm), 
hypotension, or heart failure 
probably or definitely caused by 
hypocalcemia
Acute kidney injury‡
Not applicable
Increase in the serum creatinine level 
of 0.3 mg/dL (26.5 µmol/liter) (or a 
single value > 1.5 times the upper 
limit of the age-appropriate normal 
range if no baseline creatinine 
measurement is available) or the 
presence of oliguria, defined as an 
average urine output < 0.5 mL/kg/hr 
for 6 hrs
†
The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × 
(4-albumin in grams per deciliter).
‡
Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 µmol per 
liter) or a period of oliguria lasting 6 hours or more.  By definition, if acute kidney injury is present, the subject has 
clinical tumor lysis syndrome.  Data about acute kidney injury from Levin et al.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
124
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.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
125
Appendix H.
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS)
Section 1:  First Dose of Venetoclax or Dose Escalation
●
Within the first 24 hours after either the first dose or dose escalation, if any 
laboratory criteria below are met, the subject should be hospitalized for 
monitoring and the investigator notified. No additional venetoclax doses 
should be administered until resolution.  Rapidly rising serum potassium is a 
medical emergency.
●
Nephrology (or other acute dialysis service) should be contacted/consulted (per 
institutional standards to ensure emergency dialysis is available) on admission 
for any subject hospitalized prophylactically or in response to laboratory 
changes.
●
IV fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at 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.
●
Monitor for symptoms or signs of TLS (e.g., fever, chills, tachycardia, nausea, 
vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, 
paresthesias, mental status changes, confusion and seizures). If any clinical 
features are observed, recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour STAT.
●
Vital signs should be taken at time of all blood draws or any intervention.
●
The management recommendations below focus on the minimum initial 
responses required. If a diagnosis of TLS is established, ongoing intensive 
monitoring and multi-disciplinary management will be per institutional 
protocols.
In addition to the recommendations in the table below, for subjects receiving the first dose 
of venetoclax.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
126
●
For potassium increase ≥ 0.5 mmol/L from baseline, or any value 
> 5.0 mmol/L, recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour STAT and follow first guideline.
●
For phosphorus increase of > 0.5 mg/dL AND > 4.5 mg/dL, administer 
phosphate binder and recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour STAT.
Abnormality
Management Recommendations
Hyperkalemia (Including Rapidly Rising Potassium)
Potassium ≥ 0.5 mmol/L increase from 
prior value (even if potassium within 
normal limits [WNL])

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT.  If further ≥ 0.2 mmol/L increase in potassium, but 
still < upper limit of normal (ULN), manage as per potassium 
≥ULN.  Otherwise recheck in 1 hour.

Resume per protocol testing if change in potassium is < 0.2 mmol/L, 
and potassium < ULN, and no other evidence of tumor lysis.

At the discretion of the investigator, may recheck prior to 
hospitalization.  If stable or decreased, and still WNL, 
hospitalization is at the discretion of the investigator.  Potassium, 
phosphorus, uric acid, calcium and creatinine must be rechecked 
within 24 hours.
Potassium > upper limit of normal

Perform STAT ECG and commence telemetry.

Nephrology (or other acute dialysis service) notification with 
consideration of initiating dialysis.

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV × 1.

Administer calcium gluconate 100 to 200 mg/kg IV slowly if there 
is ECG/telemetry evidence of life-threatening arrhythmias.

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT.
o
If potassium < ULN 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium and creatinine 1, 2 and 4 hrs., if no other 
evidence of tumor lysis.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
127
Abnormality
Management Recommendations
Potassium ≥ 6.0 mmol/L (6.0 mEq/L) 
and/or symptomatic (e.g., muscle 
cramps, weakness, paresthesias, 
nausea, vomiting, diarrhea)

Perform STAT ECG and commence telemetry.

Nephrology (or other acute dialysis service) assessment with 
consideration of initiating dialysis.

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV × 1.

Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV.

Administer sodium bicarbonate 1 to 2 mEq/kg IV push.
o
If sodium bicarbonate is used, rasburicase should not be used 
as this may exacerbate calcium phosphate precipitation.

Administer calcium gluconate 100 to 200 mg/kg IV slowly if there 
is ECG/telemetry evidence of life-threatening arrhythmias.  Do not 
administer in same IV line as sodium bicarbonate.

Recheck potassium, phosphorus, uric acid, calcium and creatinine 
every hour STAT.
Hyperuricemia
Uric acid ≥ 8.0 mg/dL (476 µmol/L)

Consider rasburicase* (dose based on local guidelines and/or 
institutional standards).
o
If rasburicase is used, sodium bicarbonate should not be used 
as this may exacerbate calcium phosphate precipitation.

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hr STAT.
Uric acid ≥ 10 mg/dL (595 µmol/L) 
OR 
Uric acid ≥ 8.0 mg/dL (476 µmol/L) 
with 25% increase and creatinine 
increase ≥ 0.3 mg/dL 
(≥0.027 mmol/L) from pre-dose level

Administer rasburicase* (dose based on local guidelines and/or 
institutional standards).
o
When rasburicase is used, sodium bicarbonate should not be 
used as this may exacerbate calcium phosphate precipitation.

Notify nephrology (or other acute dialysis service).

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT.
o
If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 4 hrs., 
later, if no other evidence of tumor lysis.
Calcium ≤ 7.0 mg/dL (1.75 mmol/L) 
AND
Subject symptomatic (e.g., muscle 
cramps, hypotension, tetany, cardiac 
arrhythmias)

Administer calcium gluconate 50 to 100 mg/kg IV slowly with ECG 
monitoring.

Telemetry.

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hr STAT.
o
If calcium normalized 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 4 hrs., 
later, if no other evidence of tumor lysis.

Calculate corrected calcium and check ionized calcium if albumin 
low.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
128
Abnormality
Management Recommendations
Hyperphosphatemia
Phosphorus ≥ 5.0 mg/dL 
(1.615 mmol/L) with ≥ 0.5 mg/dL 
(0.16 mmol/L) increase

Administer a phosphate binder (e.g., aluminum hydroxide, calcium 
carbonate, sevelamer hydroxide, or lanthanum carbonate).

Nephrology (or other acute dialysis service) notification (dialysis 
required for phosphorus ≥ 10 mg/dL).

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hr STAT.
o
If phosphorus < 5.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 4 hrs., 
later, if no other evidence of tumor lysis.
Creatinine
Increase ≥ 25% from baseline

Start or increase rate of IV fluids.

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 to 2 hours STAT.
*
Check rasburicase label for contraindications.
Section 2:  Ongoing Dosing of Venetoclax
Management of electrolyte changes from last value at intervals > 24 hours after either the 
first dose or dose escalation (e.g., 48 or 72 hours) are as below.
Note:  If the subject is hospitalized, no additional venetoclax doses should be 
administered until resolution.
●
For potassium, admit subject for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or 
any level > upper limit of normal.
○
Refer to the management guidelines for electrolyte changes observed 
within the first 24 hours after either the first dose or dose escalation (see 
prior table).
●
If a smaller potassium increase is observed that does not meet the criteria for 
admission above, recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 24 hours and confirm no evidence of tumor lysis prior to further 
venetoclax dosing.
●
For uric acid, calcium, phosphorus and creatinine, refer to the management 
guidelines for electrolyte changes observed within the first 24 hours after 
either the first dose or dose escalation (see prior table).
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
129
Appendix I.
Adverse Events Commonly Associated with CLL Study Population 
and/or Progression of CLL
Disease-Related Events – CLL
Lymphadenopathy 
Splenomegaly 
Hepatomegaly
Leukemia cutis (macules, papules, plaques, nodules, ulcers, or blisters) Lymphocytosis
Cytopenias (neutropenia, anemia and thrombocytopenia) 
Febrile neutropenia
Autoimmune hemolytic anemia 
Autoimmune thrombocytopenia 
Hypogammaglobulinemia
Infections (bacterial, viral, and fungal) 
Second primary cancers, all types Fatigue
Unexplained weight loss
Pyrexia
Bruising
Minor hemorrhages
Pain, all types
Malignant neoplasm progression, including death
Population-Related Comorbidities
Hypertension
Rheumatoid arthritis/osteoarthritis
Hyperlipidemia
Peptic ulcer
Inflammatory bowel disease
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
130
Coronary artery disease
Peripheral vascular disease
Cardiomyopathy 
Valvular disease 
Atrial fibrillation 
Diabetes mellitus
Chronic obstructive pulmonary disease
Cerebrovascular accident
Transient ischemia attack
 




Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
132
Section 1.2  Synopsis
Subsection Methodology:
First paragraph
Add:  new eleventh sentence
If a subject in the extended access phase of this study continues to derive benefit from 
Venetoclax after the 2-year extension, then per PI's assessment, subjects who are 
transferring to the venetoclax extension study, Study M19-388, may remain in Extended 
Access for up to additional 1 year or until the extension study is approved and initiated at 
the site, whichever is sooner.
Section 1.2  Synopsis
Subsection Duration of Treatment:
Last paragraph
Add:  new second and third sentence
If a subject in the extended access phase of this study continues to derive benefit after the 
2-year extension and venetoclax is still not commercially available in their country, they 
may continue their treatment for 1 additional year.  Per PI's assessment, subjects who are 
unable to transfer to the venetoclax extension study, Study M19-388, may remain in 
Extended Access for the additional 1 year or until the extension study is approved and 
initiated at the site, whichever is sooner.
Section 5.3.1.1  Study Procedures
Subsection Extended Access Phase
First paragraph
Add:  new second sentence
If a subject in the extended access phase of this study continues to derive benefit from 
Venetoclax after the 2-year extension, then per PI's assessment, subjects who are 
transferring to the venetoclax extension study, Study M19-388, may remain in Extended 
Access for up to additional 1 year or until the extension study is approved and initiated at 
the site, whichever is sooner.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
133
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Assistant Director
Statistics
Medical Director
Medical Affairs 
Sr. Medical Director
Safety
Group Project Director
Clinical
Study Project Manager I
Clinical
Associate Director
Clinical Pharmacology
Has been changed to read:
Name
Title
Functional Area
Head of Statistics, Oncology
Statistics
Assistant Medical Director
Medical Affairs
Sr. Medical Director
Safety
Evidence Generation Medical Lead/Director
Medical Affairs
Study Project Manager I
Clinical
Associate Director
Clinical Pharmacology
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
134
Appendix E.  Schedule of Extended Access Phase*
Previously read:
Procedure
Week 
108
Week 
120
Week 
132
Week 
144
Week 
156
Week 
168
Week 
180
Week 
192
Week 
204
Week 216/ 
Final Visit
30 Day 
Safety 
Visitd
Post 
Treatment 
Follow upe
Vital signs**
X
X
X
Physical Examinationa**
X
X
X
ECOG Performance Status**
X
X
X
Hematology/Chemistry***
X
X
X
Adverse Event/Concomitant 
Medication Assessment
X
X
X
X
X
X
X
X
X
X
X
X
Venetoclax dispensation and 
accountability****
X
X
X
X
X
X
X
X
X
Collection of Survival 
Informationb
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life 
Questionnaires (FACT-Leu, 
FACIT-Fatigue, EQ-5D-5L)c
X
*
In countries where venetoclax is not commercially available, subjects who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 
2 additional years.  AbbVie will work with the investigator on a case by case basis to consider the potential continuation of venetoclax therapy.
**
Within 72 hours before or after scheduled visit.
*** Within 72 hours prior to scheduled visit.
****The visit window for scheduled visits is ± 2 days.
a.
Refer to Section 5.3.1.1 Physical Examination, for more details.
b.
Survival information includes i.e., the date/cause of death, post treatment cancer therapies, etc.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
135
c.
The Quality of Life Questionnaires should be administered and completed prior to any other study procedures being performed at these visits.  Refer to Section 5.3.7, Health 
Economic and Patient-Reported Outcome Measures, for further information.  
d.
30-Day Safety Follow-up visit should occur approximately 30 days (± 3 days) after the last dose of venetoclax.
e.
Upon discontinuation of study drug treatment, survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 6 months 
(± 7 days) for a period of 2 years.
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
136
Has been changed to read:
Procedure
Week 
108
Week 
120
Week 
132
Week 
144
Week 
156
Week 
168
Week 
180
Week 
192
Week 
204
Week 
216
Week 
228
Week 
240
Week 
252
Week 
264
Final 
Visit
30 Day 
Safety 
Visitd
Post 
Treatment 
Follow upe
Vital signs**
X
X
X
Physical 
Examinationa**
X
X
X
ECOG 
Performance 
Status**
X
X
X
Hematology/ 
Chemistry***
X
X
X
Adverse Event/ 
Concomitant 
Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Venetoclax 
dispensation and 
accountability****
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collection of 
Survival 
Informationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life 
Questionnaires 
(FACT-Leu, 
FACIT-Fatigue, 
EQ-5D-5L)c
X
 


Venetoclax (ABT-199, GDC-0199)
M15-550 Protocol Amendment 0.02.01.01.01 (ROW)
EudraCT 2015-003667-11
137
*
In countries where venetoclax is not commercially available, subjects who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 
2 additional years.  AbbVie will work with the investigator on a case by case basis to consider the potential continuation of venetoclax therapy.
**
Within 72 hours before or after scheduled visit.
*** Within 72 hours prior to scheduled visit.
****The visit window for scheduled visits is ± 2 days.
a.
Refer to Section 5.3.1.1 Physical Examination, for more details.
b.
Survival information includes i.e., the date/cause of death, post treatment cancer therapies, etc.
c.
The Quality of Life Questionnaires should be administered and completed prior to any other study procedures being performed at these visits.  Refer to Section 5.3.7, Health 
Economic and Patient-Reported Outcome Measures, for further information.  
d.
30-Day Safety Follow-up visit should occur approximately 30 days (± 3 days) after the last dose of venetoclax.
e.
Upon discontinuation of study drug treatment, survival information (i.e., the date/cause of death, post treatment cancer therapies, etc.) will be collected every 6 months 
(± 7 days) for a period of 2 years.
 

SAP_000.pdf: