Clinical trial NCT01889186
Conditions: Chronic Lymphocytic Leukemia 17p Deletion Cancer of the Blood and Bone Marrow
Keywords: Chronic Lymphocytic Leukemia 17p Deletion
Sponsor: AbbVie
Start date: 2013-06-27; Completion date: 2020-12-15
Enrollment: 158 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This was an open-label, multicenter, global study to determine the efficacy of ABT-199 (Venetoclax) monotherapy in participants with relapsed/refractory (R/R) or previously untreated chronic lymphocytic leukemia (CLL) harboring 17p deletion.

Detailed description:
This study was designed to enroll approximately 150 participants in 2 cohorts: a main cohort of approximately 100 participants, and a safety expansion (SE) cohort of approximately 50 participants. The primary objective of the main cohort was to evaluate the efficacy of ABT-199 monotherapy in participants with R/R CLL harboring the 17p deletion. The primary objective of the safety expansion cohort was to evaluate the safety of ABT-199 in approximately 50 participants with R/R CLL harboring 17p deletion treated per updated tumor lysis syndrome (TLS) prophylaxis and management measures.

Arms: arm 1: Participants received ABT-199 tablets once daily (QD) orally for up to 79 months. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. arm 2: Participants received ABT-199 tablets once daily (QD) orally for up to 68 months. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Interventions: intervention 1: ABT-199 (Main Cohort) intervention 2: ABT-199 (Safety Expansion Cohort)
Intervention descriptions: intervention 1: Participants received a test dose of ABT-199 of ≤ 20 mg on Week 1 Day 1 of the Lead-In Period. For those with significant electrolyte and/or lymphocyte changes within 24 hours of the first dose, the 20 mg dose was maintained for 7 days with escalation to 50 mg on Week 2 Day 1. If none of the electrolyte and/or lymphocyte changes occurred within 24 hours from ABT-199 20 mg dose administration, the participant was dose-escalated to 50 mg on Week 1 Day 2. After the first dose of 50 mg, if no laboratory abnormalities occurred, the participant remained on the 50 mg dose through Week 1. After receiving the 50 mg dose for approximately 1 week (6 to 7 days), the following dose escalation proceeded with weekly increases in dose: → 100 mg → 200 mg → 400 mg (or additional lead-in steps to designated 400 mg dose), as tolerated. intervention 2: Participants received an initial dose of ABT-199 of 20 mg on Week 1 Day 1 of the Lead-In Period. If one or more electrolyte changes (from the 0 hr measurement prior to dosing) suggestive of laboratory tumor lysis syndrome (LTLS) or clinical TLS (CTLS) occurred within 24 hours of the 20 mg dose, no additional doses were administered until resolution. Upon resolution of laboratory abnormalities, the 20 mg dose was continued through Week 1. If no significant findings suggestive of clinical or laboratory TLS occurred within 24 hours, the 20 mg dose was continued through Week 1 Day 7, and escalated to a dose of 50 mg on Week 2 Day 1. Those who had drug interruptions may have been allowed to escalate to and be maintained at 50 mg for 1 week after they had been on a 20 mg dose for at least 1 week (5 - 7 days). After a week at 50 mg, weekly dose escalations were implemented as follows: 100 mg → 200 mg → 400 mg (or additional lead-in steps to designated 400 mg dose) as tolerated.

Protocol documents:
Prot_000.pdf: 
NCT01889186


Venetoclax (ABT-199)
M13-982 Protocol Amendment 6
EudraCT 2012-004027-20
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
15 October 2012
Amendment 1
10 May 2013
Amendment 2
25 July 2014
Amendment 3
19 December 2014
Amendment 3.01 (Germany only)
15 April 2015
Amendment 3.02 (Germany only)
28 May 2015
Amendment 4
16 May 2016
Amendment 5
08 September 2016
The purpose of this amendment is to:
●
Update Section 1.2, Synopsis, Section 5.1, Overall Study Design and Plan:  
Description, and Section 5.3.1.1, Study Procedures, to add a Survival Extended 
Access period to the trial.
Rationale:  AbbVie feels it is an ethical approach to continue to offer 
venetoclax in the study setting to those subjects who are continuing to derive 
clinical benefit and have not withdrawn consent.  The original study design 
allowed subjects to remain on study drug only up to 2 years following last 
subject first dose.  The Extended Access period will allow subjects to continue 
on venetoclax until disease progression; up to 5 years following last subject 
first dose (12 May 2020); or until a subject chooses to switch to commercial 
supply.
●
Update Section 1.2, Synopsis, to clarify that study objectives, with the 
exception of Safety, will cease to be evaluated beyond 2 years after last subject 
first dose.
Rationale:  The Survival Extended Access period is intended only to collect 
safety and long-term MRD data for analyses.


Venetoclax (ABT-199)
M13-982 Protocol Amendment 6
EudraCT 2012-004027-20
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●
Update Section 5.1, Overall Study Design and Plan:  Description, Post-
Treatment Visits, and Section 5.3.1.1, Study Procedures, Post-Treatment, to 
discontinue post-treatment visits effective 12 May 2017.
Rationale:  As very few subjects entered the Post-Treatment period, there is 
little data to provide any meaningful, Statistical analyses.  Subjects will 
continue to be followed in Survival until disease progression or withdrawal of 
consent.
●
Update Table 2, Excluded and Cautionary Medications/Food Items.
Rationale:  Additional information has been added regarding excluded and 
cautionary medications/food.
●
Update Table 4, Study Activities, to include the activities to be performed 
during the Survival period.
Rationale:  The Survival period was not previously included in the table, so it 
has been updated to include the activities to be performed during the Survival 
Extended Access visits.
●
Update Section 5.3.1.1, Study Procedures, Quantitative Minimal Residual 
Disease (MRD) Assessment, to add the collection of blood specimen for MRD 
PCR every 12 weeks during the Survival Extended Access period for subjects 
who qualify.
Rationale: AbbVie would like to obtain additional, long-term MRD data for 
analysis. 
●
Update Section 5.4.1, Discontinuation of Individual Subjects, to allow subjects 
with progressive disease who remain on venetoclax the ability to receive other 
approved treatment agents for CLL in addition to venetoclax.
Rationale:  CLL patients with 17p deletion have limited options for treatment.  
The addition of other approved CLL agents may aid to slow the disease 
progression and extend the life of the subject.
●
Update Section 6.0, Adverse Events, to reflect changes made to the AbbVie 
protocol template.
Rationale: Additional information has been added regarding medical and 
product complaints.
●
Update Section 6.1.3, Relationship to Study Drug.


Venetoclax (ABT-199)
M13-982 Protocol Amendment 6
EudraCT 2012-004027-20
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Rationale:  Definitions for adverse event causality have been updated to 
provide a more robust description.
●
Update Section 6.1.6, Adverse Event Reporting.
Rationale: Updated to reflect change in AbbVie medical monitor and to 
remove the Oncology Safety Management phone contact number.
●
Update Section 7.0, Protocol Deviations.
Rationale: Updated to reflect changes in AbbVie Program Lead and medical 
monitor.
●
Update Section 8.1.1.2.7, Additional Exploratory Efficacy Analyses, and 
Section 8.1.4.1, Additional Exploratory Efficacy Analyses, to confirm that 
MRD-Flow data for exploratory analysis will not be collected during the 
survival extended access portion of the study.
Rationale:  Only safety and MRD-PCR will be assessed during the extended 
access portion of the study.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix G.


Venetoclax (ABT-199)
M13-982 Protocol Amendment 6
EudraCT 2012-004027-20
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M13-982
Name of Study Drug:  Venetoclax
Phase of Development:  2
Name of Active Ingredient:  Not available
Date of Protocol Synopsis: 28 February 2017
Protocol Title:  A Phase 2 Open-Label Study of the Efficacy of ABT-199 (GDC-0199) in Subjects with 
Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia Harboring the 
17p Deletion
Main Cohort Objectives:
Primary objective:  The primary objective of this cohort is to evaluate the efficacy of venetoclax 
monotherapy in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) harboring the 
17p deletion.  Efficacy will be measured by overall response rate (ORR).
Secondary objectives:  The secondary objectives are to evaluate the complete remission rate (CR), 
partial remission rate (PR), duration of overall response (DOR), progression-free survival (PFS), time to 
progression (TTP), overall survival (OS) and percent of subjects who move on to stem cell transplant.  
The safety and tolerability of venetoclax in subjects with relapsed or refractory CLL harboring 
17p deletion will also be evaluated.
Safety Expansion Cohort Objectives:
Primary objective:  A safety expansion cohort is being added with the primary objective of evaluating 
the safety of venetoclax in approximately 50 subjects with relapsed/refractory or previously untreated 
CLL harboring 17p deletion per the updated TLS prophylaxis and management measures.
Secondary objectives:  The secondary objectives are to evaluate ORR, CR rate, PR rate, duration of 
overall response (DOR), progression-free survival (PFS), time to progression (TTP), overall survival 
(OS), and percent of subjects who move on to stem cell transplant.
Exploratory objectives (both main and safety expansion cohorts):  Time to next anti-CLL treatment 
(TTNT), minimal residual disease (MRD) assessed in the peripheral blood and/or bone marrow (BM), 
pharmacokinetics, pharmacogenetics and biomarkers will be evaluated as exploratory objectives.  Health 
Economic and Patient-Reported Outcome Measures will include the MDASI (measure of subject 
reported symptoms), the EORTC QLQ-C30 and EORTC QLQ CLL16 (a measure of health related 
quality of life specific to CLL) and the EQ-5D-5L (measure of general health status) and EQ-5D-VAS.
Note:  All study objectives, with the exception of Safety and MRD analyses, will cease to be evaluated 
beyond 2 years after last subject first dose.
Investigators:  Multicenter
Study Sites:  Approximately 60 research sites globally.
Study Population:  
Main Cohort:  Relapsed or refractory CLL subjects harboring 17p deletion
Safety Expansion Cohort:  Relapsed/refractory or previously untreated CLL subjects harboring 
17p deletion (previously untreated chronic lymphocytic leukemia harboring 17p deletion patients will 
not be enrolled in Germany)
Number of Subjects to be Enrolled:  Approximately 150 (100 subjects in the main cohort and 
50 subjects in the safety expansion cohort)


Venetoclax (ABT-199)
M13-982 Protocol Amendment 6
EudraCT 2012-004027-20
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Methodology:  This is a Phase 2, open label, multicenter, study evaluating the efficacy of venetoclax in 
relapsed/refractory or previously untreated subjects with CLL harboring 17p13 deletion.  The main 
cohort will enroll approximately 100 subjects with relapsed/refractory CLL harboring 17p13 deletion to 
assess efficacy and safety of venetoclax.  The safety expansion cohort will enroll approximately 
50 subjects with relapsed/refractory or previously untreated CLL harboring 17p13 deletion to assess the 
updated TLS prophylaxis measures.  The detection of 17p13 deletion (17p del) will be determined by the 
local laboratory and/or by the central laboratory which uses the Vysis CLL FISH probe kit.  Screening 
must be performed within 28 days of study drug administration.  CT scan must be performed within 
35 days prior to study drug administration.  A bone marrow biopsy and aspirate will also be performed at 
Screening (within 35 days prior to study drug administration), and again in coordination with CT scans, 
to confirm complete remission.  Study visits will be conducted on Days 1 and 2 of each week through 
Week 5, then on Day 1 of every 4 weeks thereafter, beginning with Week 8 (e.g., Weeks 8, 12, 16, 20, 
24, etc.) until Week 36, and then Day 1 of every 12 weeks thereafter.
Diagnosis and Main Criteria for Inclusion/Exclusion
Main Inclusion:
A subject will be eligible for participation in the safety expansion cohort of the study if he/she meets the 
following criteria.
1.
Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study 
specific procedures.
2.
Subject must be ≥ 18 years of age.
3.
Subject must have diagnosis of CLL that meets published 2008 Modified IWCLL NCI-WG 
Guidelines.
!
Subject has an indication for treatment according to the 2008 Modified IWCLL NCI-WG 
Guidelines;
!
Subject has clinically measurable disease (lymphocytosis > 5 × 109/L and/or palpable and 
measurable nodes by physical exam and/or organomegally assessed by physical exam);
!
Subject must have relapsed/refractory CLL or previously untreated CLL (previously untreated 
chronic lymphocytic leukemia harboring 17p deletion patients will not be enrolled in 
Germany);
o
Refractory or relapsed CLL subjects must meet the following requirements:
!
Refractory or relapsed after receiving at least one prior line of therapy (subjects that 
have progressed after 1 cycle of treatment or have completed at least 2 cycles of 
treatment for a given line of therapy);
o
Previously untreated CLL subjects must meet the following requirements:
!
Received no prior chemotherapy or immunotherapy.  Subjects with a history of 
emergency, loco-regional radiotherapy (e.g., for relief of compressive signs or 
symptoms) are eligible.
!
CLL diagnostic criteria above and must have > 5 × 109/L B-Lymphocytes in the 
peripheral blood.


Venetoclax (ABT-199)
M13-982 Protocol Amendment 6
EudraCT 2012-004027-20
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
Subjects must have 17p deletion, assessed by local laboratory (in bone marrow or peripheral 
blood) or assessed by central laboratory (peripheral blood).  A local result obtained prior to 
study Screening may be used for eligibility.  Additionally, a confirmatory sample (peripheral 
blood) will be sent to the central laboratory.
4.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
5.
Subject must have adequate bone marrow function at Screening as follows:
!
Absolute Neutrophil Count (ANC) ≥ 1000/μL, or
!
For subjects with an ANC < 1000/μL at Screening and bone marrow heavily infiltrated with 
underlying disease (unless cytopenia is clearly due to marrow involvement of CLL), growth 
factor support may be administered after Screening and prior to the first dose of venetoclax to 
achieve the ANC eligibility criteria (≥ 1000/μL);
!
Platelets ≥ 30,000/mm3
o
without transfusion support within 14 days of Screening
o
without evidence of mucosal bleeding
o
without known history of bleeding episode within 3 months of Screening
o
without history of bleeding disorder
!
Hemoglobin ≥ 8.0 g/dL.
6. Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range 
at Screening as follows:
!
aPTT and PT not to exceed 1.5 × the upper limit of normal (ULN);
!
Calculated creatinine clearance ≥50 mL/min using 24-hour Creatinine Clearance or modified 
Cockcroft-Gault equation (using Ideal Body Mass [IBM] instead of Mass):
eCCr =
(140 – Age) × IBM (kg) × [0.85 if Female]
72 × Serum Creatinine (mg/dL)
Or, if serum creatinine is in μmol/L:
eCCr =
(140 – Age) × IBM (kg) × [1.23 if Male, 1.04 if Female]
Serum Creatinine (μmol/L)
Ideal Body Mass should be used:
IBM (kg)
=
[(height cm – 154) × 0.9] + (50 if Male, 45.5 if Female)
Note:  For subjects that have BMI of > 30 kg/m2 or < 19 kg/m2, 24-hour measured urine creatinine 
clearance is required.
!
AST and ALT ≤ 3.0 × the upper normal limit (ULN) of institution's normal range; Bilirubin 
≤1.5 × ULN.  Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 × ULN, per 
correspondence between the investigator and AbbVie medical monitor.


Venetoclax (ABT-199)
M13-982 Protocol Amendment 6
EudraCT 2012-004027-20
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
7.
Female subjects of childbearing potential and non-sterile male subjects must practice at least one of 
the following methods of birth control with partner(s) beginning with initial study drug 
administration and continuing to 30 days after the last dose of study drug:
!
Total abstinence from sexual intercourse as the preferred life style of the subject; periodic 
abstinence is not acceptable;
!
Surgically sterile partner(s); acceptable sterility surgeries are:  vasectomy, bilateral tubal 
ligation, bilateral oophorectomy or hysterectomy;
!
Intrauterine device (IUD);
If hormonal contraceptives are used, the specific contraceptive must have been used for at least 
3 months prior to study drug administration.  If the subject is currently using a hormonal 
contraceptive, she should also use a barrier method during this study from initial study drug 
administration to 30 days after the last dose of study drug.  Any contraception method must be 
continued for 30 days after the last dose of study drug.
8.
Females of childbearing potential (i.e., not postmenopausal for at least 1 year with no alternative 
medical reason or surgically sterile) must have negative results for pregnancy test performed:
!
At Screening with a serum sample obtained within 14 days prior to the first study drug 
administration, and
!
Prior to dosing with a urine sample obtained on Week 1 Day 1 (tested locally), if it has been 
> 7 days since obtaining the serum pregnancy test results.
9.
Male subjects must agree to refrain from sperm donation, from initial study drug administration 
until 90 days after the last dose of study drug.
10. For high risk subjects (as defined in Section 6.1.8.1) a pre-approval by the AbbVie medical monitor 
is required prior to enrollment.
Main Exclusion:
A subject will not be eligible for study participation if he/she meets any of the following criteria.
1.
Subject has undergone an allogeneic stem cell transplant.
2.
Subject has developed Richter's transformation confirmed by biopsy.
3.
Subject has prolymphocytic leukemia.
4.
Subject has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), 
including autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura (ITP) 
despite low dose corticosteroids.
5.
Subject has previously received venetoclax.
6.
Subject is known to be positive for HIV (due to potential drug-drug interactions between 
anti-retroviral medications and venetoclax, as well as anticipated venetoclax mechanism based 
lymphopenia that may potentially increase the risk of opportunistic infections).
7.
Subject has received the following within 30 days prior to the first dose of study drug:
!
A biologic agent (i.e., monoclonal antibodies) for anti-neoplastic intent.


Venetoclax (ABT-199)
M13-982 Protocol Amendment 6
EudraCT 2012-004027-20
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
8.
Subject has received radiotherapy within 14 days or any of the following within 5 half-lives as 
applicable prior to the first dose of study drug, or has not recovered to less than CTC grade 2 
clinically significant adverse effect(s)/toxicity(s) of the previous therapy:
!
Any anti-cancer therapy including chemotherapy,
!
Investigational therapy, including targeted small molecule agents.
9.
Subject has received the following within 7 days prior to the first dose of study drug:
!
Steroid therapy for anti-neoplastic intent;
!
CYP3A inhibitors (such as fluconazole, ketoconazole, and clarithromycin);
!
Potent CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine or St. John's Wort);
!
Coumarins (vitamin K antagonists) or warfarin or phenprocoumon (Germany); or requires the 
use of coumarins (vitamin K antagonists) or warfarin or phenprocoumon (due to potential drug-
drug interactions that may potentially increase the exposure of coumarins [vitamin K 
antagonists] or warfarin or phenprocoumon and complications of this effect).
10. Subject has consumed the following within 3 days prior to the first dose of study drug.
!
Grapefruit or grapefruit products;
!
Seville oranges (including marmalade containing Seville oranges);
!
Star fruit.
11. Subject has known allergy to both xanthine oxidase inhibitors and rasburicase.
12. Subject has a 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.
13. Subject exhibits 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.  Note:  Subjects 
with serologic evidence of prior vaccination to HBV (i.e., HBs Ag–, anti-HBs+ and anti-HBc–) 
and positive anti-HBc from IVIG may participate.
!
Febrile neutropenia.
14. Subject has a significant history of renal, pulmonary, neurologic, psychiatric, endocrinologic, 
metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the investigator 
would adversely affect his/her participating in this study.  For subjects who have required an 
intervention for any above diseases within the past 6 months correspondence with the investigator 
and the AbbVie medical monitor must occur.
15. A female subject is pregnant or breast-feeding.


Venetoclax (ABT-199)
M13-982 Protocol Amendment 6
EudraCT 2012-004027-20
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
16. Subject has a history of active malignancies other than CLL within the past 2 years prior to study 
entry, with the exception of:
!
Adequately treated in situ carcinoma of the cervix uteri;
!
Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin;
!
Previous malignancy confined and surgically resected (or treated with other modalities) with 
curative intent.
17. Subject has malabsorption syndrome or other condition that precludes enteral route of 
administration.
Investigational Product:
Venetoclax:  10 mg, 50 mg, and 100 mg tablet
Venetoclax will be administered orally once daily (QD), continuously.  
Each dose of venetoclax should be taken with approximately 240 mL 
of water within 30 minutes after the completion of breakfast or the 
subject's first meal of the day.  To mitigate the risk for TLS, a lead-in 
period will be employed to evaluate a step wise dose escalation.
Dose – Main Cohort:
Subjects will be admitted to the hospital and begin the lead-in period 
with an initial test dose of 20 mg venetoclax on Week 1 Day 1.  If no 
significant findings occur within 24 hours, then a test dose of 50 mg 
will be administered on Week 1 Day 2 followed by 50 mg venetoclax 
QD for 5 days (Week 1 Day 3 – Day 7).  If significant findings occur 
within 24 hours on Week 1 Day 1, the 20 mg dose will be maintained 
for 1 week prior to dose escalation to 50 mg on Week 2 Day 1 – 7.
After a week at 50 mg, the following dose escalation will proceed with 
weekly dose escalations →100 mg →200 mg →400 mg (or 
additional lead-in steps to designated 400 mg dose), as tolerated.
A lower starting dose and/or modification to the lead-in regimen may 
be implemented for individual subject(s) at particularly high risk for 
TLS.
Dose – Safety Expansion 
Cohort:
Single daily doses QD starting with 20 mg; dose escalations will 
proceed weekly →50 mg →100 mg →200 mg →400 mg, as 
tolerated.
A lower starting dose and/or modification to the lead-in regimen may 
be implemented for individual subject(s) at particularly high risk for 
TLS.
Mode of Administration:
Oral
Duration of Treatment:  Subjects may continue receiving study drug for up to 2 years following the 
date of the last subject enrolled provided they continue to tolerate the drug, have no evidence of disease 
progression, and do not meet any of the criteria for subject discontinuation.  The anticipated median 
treatment duration is approximately 24 months or greater.


Venetoclax (ABT-199)
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EudraCT 2012-004027-20
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Survival Assessments:  Survival information will be collected every 3 months (±7 days) for up to 
5 years after the last subject has been enrolled for subjects who have not withdrawn consent.
Richter's Transformation and Second Primary Malignancies Assessment:  Information on Richter's 
Transformation and second primary malignancies will be collected every 3 months for up to 5 years after 
the last subject has been enrolled for subjects who have not withdrawn consent.
Survival – Extended Access:  For subjects who continue to derive benefit from venetoclax treatment 
2 years following the date of the last subject enrolled, AbbVie will provide venetoclax until the subject 
develops disease progression or until 5 years following the date of last subject enrolled (12 May 2020).
Criteria for Evaluation:
Efficacy:
Response will be assessed by the investigator, based on laboratory values, physical examinations, CT 
scans (or MRI if CT scan is medically contraindicated), and bone marrow examinations, using the 
2008 Modified IWCLL NCI-WG Guidelines for Tumor Response.
In addition to being reviewed by the investigator and/or site staff, an independent review will be 
performed to assess tumor response and disease progression.  Clinical data and radiographic scans will 
be interpreted according to 2008 Modified IWCLL NCI-WG Guidelines for Tumor Response.  The 
independent review facility will provide instructions regarding the preparation and shipment of the data.  
Interpretations from the independent review will not be sent to the site.  Subject treatment management 
will be based on review by the local investigator and/or site staff.
All measurable disease must be documented at screening by physical examination, laboratory testing and 
CT scan (or MRI if CT is medically contraindicated), and bone marrow.
During the study, subjects will be assessed at each visit by a physical examination and laboratory testing.  
Clinical disease assessments will take place at baseline, monthly for the first 9 months and then every 
3 months until disease progression, death, discontinuation from the study, or study completion.
Additional radiographic studies will be performed as described below:
A CT scan must be performed to confirm the response no earlier than 8 weeks after a response is 
determined by clinical criteria (laboratory results and physical exam).  For consistency, the same method 
of imaging should be performed for a subject throughout the study.
For determination of CR, both the CT scan and bone marrow are required to be negative.
A CT scan (or MRI if CT is medically contraindicated), will be also performed in all subjects at 
36 weeks from the beginning of the study.
If a subject exhibits clinical signs of possible disease progression (i.e., increased or de novo enlargement 
of liver, spleen or lymph nodes on physical examination) without an increase in lymphocytes meeting 
PD criteria, then additional assessments including contrast enhanced CT scan (or MRI) and/or bone 
marrow must be performed within 2 weeks to confirm or rule out PD.


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Criteria for Evaluation (Continued):
MRD:
MRD for enumeration of CLL cells will be assessed using IWG-CLL recommended methods of flow 
cytometry and/or ASO-PCR. The ERIC panel based flow cytometry will be assessed by regional 
laboratories on available samples.  Specimens (bone marrow aspirate and peripheral blood) for MRD 
analysis should be collected at the same time as the bone marrow aspirate and biopsy performed for 
tumor assessments to confirm the CR/CRi.  If MRD negativity is achieved in the bone marrow no further 
MRD analyses are required.  Otherwise, MRD should be assessed at 12-week intervals thereafter (in 
peripheral blood) until MRD negativity is achieved.  Once MRD negativity is achieved and confirmed in 
peripheral blood (e.g., two MRD negative consecutive peripheral blood samples), a bone marrow 
aspirate specimen will again be collected for analysis of MRD levels to confirm the peripheral blood 
negativity.
Subjects who meet all criteria for CR/CRi with the exception of a node(s) that is enlarged around
1.5 – 2 cm may also have a bone marrow performed and MRD assessment.  If a bone marrow and MRD 
assessment was not performed at the time of the confirmatory CT scan, then they should be performed 
after the Week 36 Day 1 CT scan.  If MRD negativity is achieved in the bone marrow no further MRD 
analyses are required.  Otherwise, MRD should be assessed at 12-week intervals thereafter (in peripheral 
blood) until MRD negativity is achieved.  Once MRD negativity is achieved and confirmed in peripheral 
blood (e.g., two MRD negative consecutive peripheral blood samples), a bone marrow aspirate specimen 
will again be collected for analysis of MRD levels to confirm the peripheral blood negativity.
Pharmacokinetic:
Pharmacokinetic samples will be collected for venetoclax at designated time points throughout the study.  
Values for the PK parameters of venetoclax, including the apparent clearance (CL/F) and the apparent 
volume of distribution (V/F), may be determined using a population PK approach.  Additional 
parameters may be calculated if useful in the interpretation of the data.
Biomarkers:
Several putative biomarkers of efficacy and response may be evaluated in this study with the goal of 
defining the relationship between various disease markers and disease status that may predict the 
subject's response to therapy.  Exploratory research analyses may not be included in the clinical study 
report.
Pharmacogenetic:
DNA samples may be analyzed for genetic factors contributing to the subject's response to venetoclax.
Safety:
Adverse event monitoring, vital signs, physical examination, ECG, and laboratory assessments will be 
evaluated.  Guidelines for the prophylaxis, monitoring and management of TLS are provided.
Statistical Methods:
Main Cohort:
Efficacy:
The following efficacy analyses will be analyzed:  ORR, CR rate, PR rate, duration of overall response, 
progression-free survival, event free survival, time to progression, time to first response, time to 50% 
reduction in ALC, overall survival and percent of subjects who move on to stem cell transplant.  
Additional efficacy analyses will include time to next anti-CLL treatment, rate of minimal residual 
disease (MRD) negativity status, and Health Economic and Patient Reported Outcome (PRO) measures.


Venetoclax (ABT-199)
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Statistical Methods (Continued):
Safety Expansion Cohort:
Secondary Efficacy:
The following secondary efficacy analyses will be analyzed:  ORR, CR rate, PR rate, duration of overall 
response, progression-free survival, event free survival, time to progression, time to first response, time 
to 50% reduction in ALC, overall survival, and percent of subjects who move on to stem cell transplant.  
Additional efficacy analyses will include time to next anti-CLL treatment, rate of minimal residual 
disease (MRD) negativity status, and Health Economic and Patient Reported Outcome (PRO) measures.
Pharmacokinetic/Pharmacodynamic:
An analysis will be performed using a nonlinear mixed-effect population modeling approach with 
NONMEM software to describe the disposition of venetoclax, to identify significant covariates and 
explore relationship between pharmacokinetics and pharmacodynamics by combining data from this 
study with other venetoclax clinical studies.  Additional analyses may be performed if useful in the 
interpretation of the data.
Safety:
A safety analysis will be performed for all subjects participating in the study who took at least one dose 
of study drug for each cohort (main and safety expansion).  For the study as a whole, adverse events will 
be evaluated and summarized.  Laboratory values and vital signs will be explored for trends and 
summarized.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
AE
Adverse Event
ALL
Acute Lymphoblastic Leukemia
ALT
Alanine aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
ASCO
American Society of Clinical Oncology
ASO-PCR
Allele Specific Oligonucleotide Polymerase Chain Reaction
AST
Aspartate aminotransferase
aPTT
Activated Partial Thromboplastin Time
Bcl
B-Cell Lymphoma
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CLL
Chronic Lymphocytic Leukemia
cm
Centimeter
CR
Complete Remission
CRi
Complete Remission with Incomplete Marrow Recovery
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CYP2B6
Cytochrome P450 2B6
CYP2C8
Cytochrome P450 2C8
CYP2C9
Cytochrome P450 2C9
CYP2C19
Cytochrome P450 2C19
CYP2D6
Cytochrome P450 2D6
CYP3A
Cytochrome P450 3A
DLBCL
Diffuse Large B-cell Lymphoma
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DOR
Duration of Overall Response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCCr
Estimated creatinine clearance rate using Cockcroft-Gault Formula
eCRF
Electronic Case Report Form


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EFS
Event Free Survival
EMA
European Medicines Agency
ERIC
European Research Initiative in CLL
FCR
Fludarabine, cyclophosphamide, and rituximab
FDA
Food and Drug Administration
FFPE
Formalin Fixed, Paraffin Embedded
FISH
Fluorescence in situ Hybridization
FL
Follicular Lymphoma
G-CSF
Granulocyte-colony stimulating factor
GCP
Good Clinical Practice
GM-CSF
Granulocyte-macrophage colony-stimulating factor
HBsAg
Hepatitis B Surface Antigen
HDPE
High Density Polyethylene
HIV
Human Immunodeficiency Virus
hr
Hour
IBM
Ideal Body Mass
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IRC
Independent Review Committee
IRB
Institutional Review Board
IUO
Investigational Use Only
IV
Intravenous
IWCLL
International Workshop for Chronic Lymphocytic Leukemia
IxRS
Interactive Response System
kg
Kilogram
LDH
Lactate Dehydrogenase
LN
Lymph Node
LVEF
Left Ventricular Ejection Fraction
MCHC
Mean Corpuscular Hemoglobin Concentration
MCL
Mantle Cell Lymphoma
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
μg
Microgram
μM
Micromolar
mg
Milligram


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mL
Milliliter
mm
Millimeter
MM
Multiple Myeloma
MPV
Mean Platelet Volume
MRD
Minimal Residual Disease
MRI
Magnetic Resonance Imaging
MUGA
Multi Gated Acquisition Scan
NCI
National Cancer Institute
NCI-WG
National Cancer Institute-Working Group
NHL
Non-Hodgkin's Lymphoma
nM
Nanomolar
nPR
Nodular Partial Remission
NPT
Non-protocol anti-lymphoma therapy
ORR
Overall Response Rate
OS
Overall Survival
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PD
Progressive Disease
PEO
Performance Evaluation Only
PFS
Progression-free Survival
PG
Pharmacogenetic
PK
Pharmacokinetic
PR
Partial Remission
PT
Prothrombin Time
QD
Once Daily
qPCR
Quantitative Polymerase Chain Reaction
QTcF
QT interval measurement corrected by Fridericia's formula
RBC
Red Blood Cell
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic-oxaloacetic Transaminase
SGPT
Serum Glutamic-pyruvic Transaminase
SLL
Small Lymphocytic Lymphoma
SPD
Sum of the products of the greatest diameters
TLS
Tumor Lysis Syndrome
TTNT
Time to next anti-CLL treatment


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TTP
Time to Tumor Progression
ULN
Upper Limit of Normal
US
Ultrasound
VAS
Visual Analog Scale
WBC
White Blood Cell
Definition of Terms
AUC
Area under the plasma concentration-time curve
AUC0-24
Area under the plasma concentration-time curve from time zero to hour 24
Cmax
Maximum observed plasma concentration
CL/F
Apparent oral clearance
IC
Inhibitory concentration
Ki
Inhibition constant
nM
Nanomolar
QT Interval
The interval between the beginning of the QRS complex to the end of the 
T wave in an ECG
Tmax
Time to maximum observed plasma concentration
V/F
Apparent volume of distribution


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 5
1.3
List of Abbreviations and Definition of Terms...................................... 14
2.0
Table of Contents ................................................................ 18
3.0
Introduction......................................................................... 24
3.1
Differences Statement .......................................................................... 34
3.2
Benefits and Risks................................................................................ 34
4.0
Study Objectives.................................................................. 35
5.0
Investigational Plan.............................................................36
5.1
Overall Study Design and Plan:  Description ........................................ 36
5.2
Selection of Study Population............................................................... 44
5.2.1
Inclusion Criteria.................................................................................. 45
5.2.2
Exclusion Criteria................................................................................. 49
5.2.3
Prior and Concomitant Therapy............................................................ 51
5.3
Efficacy Pharmacokinetic, Pharmacodynamic, Pharmacogenetic, 
and Safety Assessments/Variables........................................................ 54
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 54
5.3.1.1
Study Procedures.................................................................................. 64
5.3.1.2
Confinement......................................................................................... 85
5.3.1.3
Meals and Dietary Requirements.......................................................... 85
5.3.1.4
Blood Samples for Pharmacogenetic Analysis (Optional) ..................... 86
5.3.1.5
Collection and Handling of Biomarker Variables.................................. 86
5.3.1.5.1
Mandatory Collections ......................................................................... 86
5.3.1.5.2
Optional Collections............................................................................. 90
5.3.2
Drug Concentration Measurements....................................................... 91
5.3.2.1
Collection of Samples for Analysis....................................................... 91
5.3.2.2
Handling/Processing of Samples........................................................... 93
5.3.2.3
Disposition of Samples......................................................................... 93
5.3.2.4
Measurement Methods ......................................................................... 93
5.3.3
Efficacy Variables................................................................................ 93


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5.3.3.1
2008 Modified IWCLL NCI-WG Guidelines for Tumor Response ....... 94
5.3.3.2
Definition of Disease Progression........................................................102
5.3.3.3
Definition of Stable Disease ................................................................103
5.3.4
Safety Variables ..................................................................................103
5.3.5
Pharmacokinetic Variables ..................................................................103
5.3.6
Pharmacogenetic Variables..................................................................103
5.3.7
Biomarker Variables............................................................................103
5.3.8
Health Economic and Patient-Reported Outcome Measures.................105
5.4
Removal of Subjects from Therapy or Assessment ..............................107
5.4.1
Discontinuation of Individual Subjects ................................................107
5.4.2
Discontinuation of Entire Study...........................................................109
5.5
Treatments ..........................................................................................109
5.5.1
Treatments Administered.....................................................................109
5.5.2
Identity of Investigational Product.......................................................110
5.5.2.1
Packaging and Labeling.......................................................................110
5.5.2.2
Storage and Disposition of Study Drug................................................110
5.5.3
Method of Assigning Subjects to Treatment Groups............................111
5.5.4
Selection and Timing of Dose for Each Subject...................................111
5.5.5
Blinding ..............................................................................................111
5.5.6
Treatment Compliance ........................................................................111
5.5.7
Drug Accountability............................................................................112
5.6
Discussion and Justification of Study Design.......................................112
5.6.1
Discussion of Study Design and Choice of Control Groups .................114
5.6.2
Appropriateness of Measurements.......................................................114
5.6.3
Suitability of Subject Population .........................................................114
5.6.4
Selection of Doses in the Study ...........................................................115
6.0
Complaints......................................................................... 115
6.1
Medical Complaints ............................................................................116
6.1.1
Definitions ..........................................................................................116
6.1.1.1
Adverse Event.....................................................................................116
6.1.1.2
Serious Adverse Events.......................................................................117
6.1.2
Adverse Event Severity .......................................................................119
6.1.3
Relationship to Study Drug..................................................................120


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6.1.4
Adverse Events Expected Due to Study Related Endpoints..................121
6.1.4.1
Deaths.................................................................................................121
6.1.4.2
Lack of Efficacy or Worsening of Disease...........................................121
6.1.5
Adverse Event Collection Period.........................................................121
6.1.6
Adverse Event Reporting.....................................................................122
6.1.7
Pregnancy............................................................................................124
6.1.8
Toxicity Management..........................................................................125
6.1.8.1
Prophylaxis and Management of Tumor Lysis Syndrome ....................125
6.1.8.2
Management of Neutropenia................................................................139
6.1.8.3
Management of Lymphopenia .............................................................140
6.1.8.4
Management of Decrease in Spermatogenesis......................................140
6.2
Product Complaint...............................................................................141
6.2.1
Definition............................................................................................141
6.2.2
Reporting ............................................................................................141
7.0
Protocol Deviations ........................................................... 142
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 143
8.1
Statistical and Analytical Plans............................................................143
8.1.1
Statistical and Analytical Plans – Main Cohort ....................................143
8.1.1.1
Baseline Parameters ............................................................................143
8.1.1.1.1
Baseline Characteristics.......................................................................143
8.1.1.1.2
Demographics .....................................................................................143
8.1.1.1.3
Medical Histories ................................................................................144
8.1.1.2
Primary Efficacy .................................................................................144
8.1.1.2.1
Primary Efficacy Analyses in Main Cohort..........................................144
8.1.1.2.2
Secondary Efficacy Analyses in Main Cohort......................................144
8.1.1.2.3
Supplemental Efficacy in Main Cohort................................................147
8.1.1.2.4
Timing of Efficacy and Safety Analyses..............................................147
8.1.1.2.5
Pharmacokinetics ................................................................................148
8.1.1.2.6
Interim Analyses .................................................................................149
8.1.1.2.7
Additional Exploratory Efficacy Analyses...........................................149
8.1.1.3
Safety..................................................................................................150
8.1.1.3.1
Adverse Events....................................................................................151


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8.1.1.3.2
Serious Adverse Events.......................................................................151
8.1.1.3.3
Deaths.................................................................................................151
8.1.1.3.4
Longitudinal Analyses of Laboratory and Vital Signs Data..................151
8.1.1.3.5
Analyses of Laboratory Data Using NCI CTCAE................................152
8.1.2
Statistical and Analytical Plans for the Safety Expansion Cohort.........152
8.1.2.1
Baseline Parameters ............................................................................153
8.1.2.1.1
Baseline Characteristics.......................................................................153
8.1.2.1.2
Demographics .....................................................................................153
8.1.2.1.3
Medical Histories ................................................................................153
8.1.3
Safety..................................................................................................153
8.1.3.1
Adverse Events....................................................................................154
8.1.3.2
Serious Adverse Events.......................................................................154
8.1.3.3
Deaths.................................................................................................154
8.1.3.4
Longitudinal Analyses of Laboratory and Vital Signs Data..................154
8.1.3.5
Analyses of Laboratory Data Using NCI CTCAE................................155
8.1.3.6
Assessment of TLS..............................................................................155
8.1.4
Efficacy Endpoints ..............................................................................156
8.1.4.1
Additional Exploratory Efficacy Analyses...........................................159
8.1.4.2
Timing of Safety Evaluations and Secondary Efficacy Endpoints........159
8.1.4.3
Pharmacokinetics ................................................................................160
8.1.4.4
Independent Data Monitoring Committee............................................161
8.2
Determination of Sample Size .............................................................161
9.0
Ethics.................................................................................. 162
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................162
9.2
Ethical Conduct of the Study...............................................................163
9.3
Subject Information and Consent.........................................................163
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 164
10.1
Source Documents...............................................................................164
10.2
Electronic Case Report Forms .............................................................164
11.0
Data Quality Assurance .................................................... 165
12.0
Use of Information ............................................................ 166


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13.0
Completion of the Study ................................................... 167
14.0
Investigator's Agreement.................................................. 169
15.0
Reference List.................................................................... 170
List of Tables
Table 1.
Historical Data on Relapsed CLL with 17p Deletion............................. 32
Table 2.
Excluded and Cautionary Medications/Food Items ............................... 53
Table 3.
Sample of Permitted Medications ......................................................... 53
Table 4.
Study Activities.................................................................................... 55
Table 5.
Schedule of PK Blood Collection for Venetoclax (and Possible 
Metabolite[s])....................................................................................... 61
Table 6.
Schedule of Biomarkers and Pharmacogenetic Sample Collection ........ 62
Table 7.
Clinical Laboratory Tests ..................................................................... 75
Table 8.
2008 Modified IWCLL NCI-WG Guidelines for Tumor Response ......100
Table 9.
Identity of Investigational Product.......................................................110
Table 10.
Dose Reduction Guidelines for Management of Neutropenia...............140
Table 11.
Sample Size Calculation......................................................................162
Table 12.
Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and 
Grading ...............................................................................................187
Table 13.
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome...........188
Table 14.
Howard Definition of Laboratory Tumor Lysis Syndrome...................188
List of Figures
Figure 1.
Dosing Schematic – Main Cohort......................................................... 38
Figure 2.
Dosing Schematic – Safety Expansion Cohort ...................................... 41
Figure 3.
Adverse Event Collection....................................................................122
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................175
Appendix B.
List of Protocol Signatories .................................................................177


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Appendix C.
Sample List of Excluded and Cautionary Medications .........................178
Appendix D.
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS)..........180
Appendix E.
Adverse Events Commonly Associated with CLL Study 
Population and/or Progression of CLL.................................................185
Appendix F.
Cairo-Bishop and Howard Definitions of Tumor Lysis Syndrome .......187
Appendix G.
Protocol Amendment:  List of Changes ...............................................189


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3.0
Introduction
Bcl-2 Family Proteins
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway.  
The Bcl-2 oncogene was first identified in follicular lymphoma where the t(14;18) 
chromosomal translocation results in significant over-expression of the protein in B-cells.  
The Bcl-2 family of genes encodes a family of closely related proteins that possess either 
pro-apoptotic or anti-apoptotic activity and share up to four Bcl-2 Homology (BH) 
domains.1-4  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 in vitro/in vivo Activity and Preclinical Pharmacokinetic Profile
Venetoclax is a novel, orally available small molecule Bcl-2 family protein inhibitor that 
binds with > 500-fold higher affinity (Ki < 0.010 nM) to Bcl-2 and with lower affinity to 
other Bcl-2 family proteins Bcl-XL (Ki – 48 nM) and Bcl-w (Ki – 245 nM).7  
Overexpression of antiapoptotic Bcl-2 family proteins is associated with increased 
resistance to chemotherapy, and antagonism of the action of these proteins might enhance 
response to such therapy and overcome resistance.  Antiapoptotic Bcl-2 family members 
are associated with tumor initiation, disease progression, and drug resistance, and making 
them compelling targets for antitumor therapy.
In vitro, venetoclax demonstrated broad cell killing activity against a panel of lymphoma 
and leukemia cells including B-cell follicular lymphomas (FLs), mantle cell lymphomas 
(MCLs), diffuse large B-cell lymphomas (DLBCLs), and acute myeloid leukemias 
(AMLs).  Venetoclax was especially potent against cell lines expressing high levels of 
Bcl-2.  Leukemia and lymphoma cell lines bearing the t(14;18) translocation were 
significantly more sensitive to venetoclax than non-mutated cell lines.


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Venetoclax inhibited subcutaneous murine xenograft growth of human tumor cell lines 
derived from acute lymphoblastic leukemia (ALL) and Non-Hodgkin's Lymphoma 
(NHL).  The drug was also active in a model of disseminated ALL.
The pharmacokinetic profile of venetoclax was evaluated in multiple animal species.  In 
mouse, rat, monkey and dog, the venetoclax pharmacokinetic profile was characterized by 
low plasma clearance and low volumes of distribution.  Half-lives ranged from 2.2 hours 
in monkey to 12 hours in dog.  Food had a marked effect on the oral bioavailability in 
dog.
Venetoclax has high protein binding to human, rat, dog, and monkey plasma proteins 
(> 99.9%).  In rats, venetoclax was widely distributed into liver, kidneys, spleen, heart, 
lungs, small intestine, and white fat, but was poorly distributed in testes, brain, muscle, 
and bone.  Metabolism was the major route of elimination with biliary excretion of the 
parent drug playing the secondary role in rats.  Venetoclax showed moderate metabolic 
stability in in vitro hepatic systems across species tested, except for low to moderate 
stability in dog hepatocytes.
In vivo, venetoclax was metabolized by CYP3A4; it was not a potent inhibitor of 
CYP3A4, CYP1A2, CYP2B6, CYP2C19, or CYP2D6 (IC50 > 30 μM); it did not induce 
CYP3A4 or CYP1A2 at concentrations up to 10 μM.  Venetoclax is a substrate for P-gp 
and BCRP.  Studies in Oatp1a/b cluster KO mice indicated that venetoclax may be an 
OATP substrate.  Active uptake of venetoclax or M27 metabolite was not observed in 
cells overexpressing OATP1B1, OATP1B3 or OCT1.  Venetoclax is a P-gp, BCRP and 
OATP1B1 inhibitor in vitro.
Venetoclax exhibited potent activity against patient-derived CLL cells treated ex vivo, 
killing these cells with an average concentration required for 50% effect (EC50) of 
0.006 μM (n = 35; note that not all subject samples are from venetoclax trials).  
Venetoclax was equally potent against the subset of CLL samples bearing the high-risk 
17p deletion, with an average EC50 of 0.008 μM (n = 5), indicating that venetoclax may 
have a significant utility in treating subjects with this high-risk disease.


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Venetoclax Nonclinical Toxicology
Venetoclax has been assessed in repeated-dose general toxicology studies, and in genetic, 
developmental/reproductive, phototoxicity, and safety pharmacology studies.
The primary toxicities associated with repeat-dose administration of venetoclax were 
effects on the hematologic system (decreased lymphocytes and red blood cell [RBC] 
mass) in mice, rats and dogs, the male reproductive system (testicular germ cell depletion 
in dogs) and embryofetal toxicity in mice.  Other noteworthy findings were epithelial 
single cell necrosis in multiple tissues and hair coat color change, both in dogs.
In mice, rats, and dogs, venetoclax produced robust decreases in lymphocytes in the 
peripheral blood (up to 75% in mice, 64% in rats, and 81% in dogs) and in lymphoid 
tissues.  These findings are consistent with the expected pharmacologic effects of 
venetoclax (a selective Bcl-2 inhibitor).8  In mice, total lymphocyte counts at 
600 mg/kg/day after 4 weeks of dosing were minimally decreased 21% to 6% relative to 
concurrent controls at the end of the 4-week recovery period.  In dogs, the recovery of 
peripheral blood decreases in total lymphocytes and lymphocyte subsets (CD4+ T-cells 
and CD8+ T-cells and [CD21+] mature B cells) was prolonged, requiring up to 18 weeks 
after a single dose or after completion of 2 weeks of dosing.  B-cells were the most 
sensitive lymphocyte subtype based on the magnitude of decrease (> 90%) and/or the 
length of time required for recovery.  Lymphocyte decreases in lymphoid tissues were 
reversible in mice and dogs.  Venetoclax produced dose-related decreases in RBC mass 
due to decreased cellular hemoglobin in mice and dogs; these effects were adverse at the 
highest dosages in the 4-week mouse and dog studies and were reversible.  In studies to 
select carcinogenicity dose levels, RBC mass decreases were also observed in rats and 
were generally more severe than in mice or dogs.  Venetoclax produced adverse, non-dose 
related microscopic findings of testicular germ cell depletion in dogs at all doses tested; 
reversibility was not observed following a 4-week recovery period.  There were no 
testicular effects in mice.  Venetoclax resulted in increased post-implantation loss and 
decreased fetal body weights in the mouse embryo fetal development study at the highest 
dosage administered (150 mg/kg/day); the no-observed-adverse-effect-level (NOAEL) 


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was defined at the mid dose of 50 mg/kg/day.  In mice and rabbits, venetoclax was not 
teratogenic, and there were no other effects on development or fertility.
Additional noteworthy effects of venetoclax included white hair coat discoloration in dogs 
(occurring after approximately 3 months of dosing in the 9-month study) and minimal to 
mild single cell necrosis in multiple epithelial tissues (e.g., gallbladder and exocrine 
pancreas) in dogs.  None of these effects was considered to be adverse.
There was no evidence of in vitro or in vivo genetic toxicity of venetoclax, and there was 
no evidence of cutaneous phototoxicity of venetoclax in an in vivo study in Crl:SKH1-hr 
female hairless mice.
Other minor effects of venetoclax were observed in dogs.  (1) At the high dosage of 
150 mg/kg/day in the 4-week study had clinical signs of swelling of the skin on the ears, 
head (cranial area), and forepaws and/or hindpaws.  Most but not all animals (8 of 
10 dogs) were affected, and in 3 dogs the swelling reaction was observed after the 
first dose.  The clinical signs were limited to the 150 mg/kg/dosage, were transient and 
sporadic in occurrence, and were absent during the recovery period.  A mechanistic basis 
for the swelling reactions was not established, but the clinical signs were mild to moderate 
in severity and reversible, and there were no signs of anaphylaxis.  (2) Dose-related, 
transient post dose emesis, increased salivation, and fecal alterations (unformed or watery 
feces) were observed at dosages of ≥ 5 mg/kg/day.  These clinical signs were present 
throughout the dosing phase, but were not dose-limiting and were not observed in the 
recovery phase.  In the 9-month dog study, non-adverse decreases in mean body weight 
and body weight gain, associated with decreases in food consumption, were observed at 
≥2 mg/kg/day.
M27 is a major human metabolite of venetoclax.  Although observed in mice and dogs, 
M27 is present at much lower levels (0.05- to 0.09-fold), as compared with steady-state 
levels in humans, and therefore is a disproportionate metabolite.  By in silico analysis, 
M27 does not generate new alerts for mutagenicity, as compared with the venetoclax 
parent compound.  M27 shows low in vitro potency (at least 58-fold less than parent) and 


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produced no evidence of in vitro genotoxicity in Ames and chromosome aberration 
assays.  In a secondary pharmacology receptor panel screening study, M27 produced 
significant displacement of control-specific binding at the delta-opioid receptor (DOP 
Ki = 0.65 μM); however, when evaluated in a functional assay, agonist or antagonist 
activity was not observed at the DOP receptor up to a maximum concentration of 10 μM.  
No CNS or respiratory adverse events that could be attributed to off-target receptor-
mediated pharmacologic effects of M27 have been observed in clinical trial subjects.
Venetoclax was tested in a battery of safety pharmacology assays, and produced no 
effects in the CNS/neurobehavioral or respiratory studies in mice at oral doses up to and 
including the highest dose of 600 mg/kg.  No effects on QTc were observed up to a 
maximum plasma concentration of 46 μg/mL in dogs.  In conscious dogs, venetoclax did 
not produce any cardiovascular effects up to and including the highest oral dose of 
150 mg/kg (Cmax = 16 μg/mL).  In the anesthetized dog at higher plasma concentrations, 
venetoclax produced mild reductions in myocardial contractility (6% – 13%) and cardiac 
output (–11% to –19%) at plasma concentrations of ≥ 16 μg/mL and ≥ 32 μg/mL, 
respectively.  These concentrations are greater than the plasma concentration of 
venetoclax in oncology subjects (2.8 μg/mL at the 600 mg dose).
On the basis of nonclinical safety pharmacology and toxicology evaluations of 
venetoclax, and on the basis of nonclinical and human studies of related antiapoptotic Bcl-
2 family protein inhibitors, potential mechanism-based toxicities may include 
lymphopenia and neutropenia,9 signs of tumor lysis, reduction in red cell mass, decreased 
spermatogenesis, skin swelling, and hair hypopigmentation.  Although no effects of 
venetoclax on female reproductive tissues have been observed in general repeat-dose 
toxicology studies, embryo-fetal toxicity studies in animals have identified a fetal toxicity 
risk.  Thrombocytopenia has not been observed in toxicology studies in mice and dogs.  
These findings are consistent with venetoclax as a Bcl-2 specific (Bcl-XL sparing) 
inhibitor.  Consequently, thrombocytopenia is not expected to be a dose limiting toxicity 
(DLT) clinically.


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A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the Investigator's Brochure.10
Venetoclax Clinical Exposure
As of 28 November 2016, on the basis of data available in the AbbVie and 
Genentech/Roche clinical databases, a total of 2573 subjects have been exposed to at least 
1 dose of venetoclax in the oncology development programs.  Of these 2573, 
1429 subjects had CLL/small lymphocytic leukemia (SLL), 637 subjects had NHL, 
180 subjects had MM, and 327 had AML.  An additional 114 subjects were healthy 
volunteers.  A total of 749 oncology subjects received the drug as monotherapy, and 
1922 received the drug in combination with other therapies.
Doses administered in venetoclax clinical studies have ranged from 20 mg to 1200 mg.  
Multiple ongoing Phase 1/2 AbbVie and Phase 1/2/3 Genentech/Roche clinical studies are 
evaluating safety, tolerability, pharmacokinetics, and efficacy of venetoclax as 
monotherapy or in combination with other therapies (rituximab [R], obinutuzumab 
(GA101) [G], rituximab or obinutuzumab plus CHOP [cyclophosphamide, doxorubicin, 
vincristine, and prednisone; R-CHOP or G-CHOP, respectively], BR, bendamustine plus 
obinutuzumab [BG], bortezomib plus dexamethasone, azacitidine or decitabine, and 
cytarabine) in subjects with hematologic malignancies.  Data are available from DDI 
studies of venetoclax interaction with ketoconazole, with rifampin, and with warfarin.  
Additionally, two Phase 3 studies are ongoing:  one study in relapsed/refractory (R/R) 
CLL exploring the combination of venetoclax and rituximab against BR and one Phase 3 
study in first-line CLL exploring the combination of venetoclax and obinutuzumab 
against obinutuzumab plus chlorambucil.
Based on nonclinical and clinical data available with venetoclax administration, important 
identified risks are tumor lysis syndrome (TLS) and neutropenia, particularly in the CLL 
indication.  Infection is a potential risk.  Other adverse events commonly observed with 
venetoclax include nausea, diarrhea, and other hematological effects (including, anemia, 
thrombocytopenia, and lymphopenia).  Decreased spermatogenesis has been observed in 


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nonclinical studies with dogs and could present a risk to male infertility.  In addition, as 
venetoclax is being evaluated in subjects with relapsed/refractory (R/R) disease who had 
previously been treated with various cytotoxic agents, second primary malignancies are 
closely monitored.
Five dose limiting toxicities (DLTs) of tumor lysis syndrome (TLS) and 2 DLTs of 
fatalities in the setting of TLS were reported in the venetoclax clinical program for 
subjects with CLL/SLL (Study M12-175 and Study M13-365).  The 5 DLTs of TLS 
occurred in Study M12-175 at either the starting dose of 100 or 200 mg venetoclax 
(3 subjects in Cohort 1) or the lower initial dose of 50 mg venetoclax implemented to 
minimize the risk of TLS (1 subject each in Cohorts 2 and 4).  The sixth DLT of TLS 
occurred at the maximum designated cohort dose administered in the study (Cohort 8, 
1200 mg), and the subject experienced sudden death.  In Study M13-365, there was a 
single DLT of death due to grade 5 hyperkalemia in a setting of TLS at the 50 mg initial 
dose.  (Additionally, single non-DLT adverse events of TLS were reported in a subject 
with MCL in Study M12-175 and a subject with CLL in Study M13-365).  Events of 
laboratory TLS were also observed in 2 subjects during dosing in Study GP28331 at the 
step-up dose of 50 mg venetoclax.  Additional DLTs included 2 cases of febrile 
neutropenia and 1 case of neutropenia in subjects with CLL and NHL, and 1 case each of 
histiocytosis hematophagic and thrombocytopenia in subjects with NHL (both considered 
related to rituximab rather than venetoclax).
Updated safety and efficacy data are described in detail in the Investigator Brochure.10
Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia is a lymphoproliferative disorder characterized by a 
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.11  Chronic lymphocytic leukemia primarily affects elderly individuals; 
however, approximately one third of patients are less than 60 years of age at diagnosis.12  


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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.13  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 – 2002.11,14  The approximate 5-year survival rate for patients with CLL is 
73%.15  CLL presents with a variable clinical course.  Approximately one-third of patients 
have indolent disease with prolonged median survival that does not require treatment and 
die of causes unrelated to disease.  Another third have an initial indolent phase that is 
followed by rapid progression of the disease requiring therapy.  The remaining third have 
aggressive disease and require treatment at the time of diagnosis. Chronic lymphocytic 
leukemia patients will often have compromised bone marrow reserve due to their 
underlying disease.  The principal complication of CLL is immunodeficiency related to 
myelosuppression and as a result, infection is the major cause of death in patients with 
CLL.16
Standard chemotherapeutic options for CLL cause significant immune suppression and 
myelosuppression, are not well-tolerated by the elderly population and have not 
consistently offered survival advantage.  Treatment decisions for patients with CLL are 
made on the basis of considerations such as age, clinical stage, expected survival, and 
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.
17p Deletion in Relapsed or Refractory CLL
17p deletion is a chromosomal aberration of prognostic relevance in CLL and accounts for 
up to 30% of all relapsed/refractory subjects with CLL due to clonal cell evolution or the 
selection pressure of chemotherapy and chemoimmunotherapy.17-20


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At the time study was initiated, there were no treatments approved specifically to meet the 
need of the 17p deletion population and the median OS in relapsed CLL patients with 17p 
deletion is less than 24 months.  Active treatments for the broader CLL population, such 
as fludarabine based regimens and alkylators, have been associated with poor response in 
the 17p patient population.17  In a recent study conducted in subjects with relapsed CLL 
treated with FCR, PFS and OS were 5 months and 10.5 months, respectively, in subjects 
with 17p deletion, compared to 20.9 months and 46.5 months in subjects who did not have 
chromosome 17 abnormalities.21  Overall response rates were also significantly lower in 
the patients with 17p deletion, with 35% of subjects achieving partial remission, no CR 
and 5% nodular PR (nPR), compared to 74% response rate, with 30% CR and 14% nPR in 
the CLL subjects without 17p deletion (Table 1).21
Table 1.
Historical Data on Relapsed CLL with 17p Deletion
Drug/Regimen
CLL Population
Number of 
17p Deleted 
Patients 
Enrolled
Response
PFS
ORR
CR
Ofatumumab22
double refractory
31
29%
NA
PFS 5.7 m
Alemtuzumab#23
relapsed/refractory
31
39%
NA
PFS 5.8 m
Alemtuzumab#+steroids24
relapsed*
22
77%
14%
PFS 6.5 m
Bendamustine+Rituximab25
relapsed/refractory
14
7.10%
7.10%
PFS 6.8 m
FCR21
relapsed
20
35%
5%
PFS 5 m
*
In 17p deleted patients only.
#
The marketing authorization for Alemtuzumab has been withdrawn at the request of the marketing-authorization 
holder.
In the CLL population harboring 17p deletion, immunochemotherapy based regimens 
such as BR provide short durations of response with the median PFS of approximately 
6.8 months and ORR of 7% (Table 1).25  Although novel therapies, such as alemtuzumab 
based regimens and ofatumumab, show an improvement in ORR, the duration of response 
is still poor and the median PFS is approximately 6 months (Table 1).22-24  Also 
alemtuzumab has limited use due to its toxicity profile.24  Due to the limited effectiveness 
of available therapies, treatment guidelines recommend enrollment in clinical trials and in 
eligible patients who achieve a response allogeneic transplant, as preferred treatment 


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options for patients with 17p deletion.26,27  Nonetheless, globally the access to allogeneic 
transplant and/or clinical trials is limited, and physicians often continue to use 
immunochemotherapy.
17p Deletion in Previously Untreated CLL
Deletions of the short arm of chromosome 17 (17p deletion) are found in 3% to 10% of 
CLL cases at diagnosis.28
Untreated CLL patients who harbor the 17p deletion have generally a short first remission 
if they respond to standard treatment.  17p deletion is prognostic marker for nonresponse 
to conventional chemotherapy and there is no standard treatment for patients with 
previously untreated CLL.28
Thus, alternative therapeutic approaches, which act independently of the p53 signaling 
pathway are needed.
Study Rationale
CLL patients with the 17p deletion have a poor prognosis characterized by suboptimal 
responses to first-line and subsequent therapies.  There are currently no treatments 
approved and labeled specifically to meet the need of the 17p deletion population.  
Because treatment with the conventional therapy is poor, the treatment guidelines26,27
recommend that CLL patients with 17p deletion (as well as TP53 mutations) should be 
treated within new clinical trials from the start.  Those who achieve a response to initial 
therapy should be considered for an allogeneic transplant.  For patients not eligible for an 
allogeneic transplant or clinical trial, until very recently suggested regimens included 
alemtuzumab, high-dose methylprednisolone (HDMP) or ofatumumab.  None of these 
regimens have been shown to be superior to any other therapy in relapsed 17p deletion 
patients and median PFS with treatment with these agents was less than 7 months.


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Venetoclax Mechanism of Action Compared with Other Therapeutic Agents
Many chemotherapeutics used in treating CLL, including fludarabine, cyclophosphamide, 
and bendamustine, act by inducing deoxyribonucleic acid (DNA) damage and triggering 
apoptosis.  The p53 tumor suppressor is essential for relaying the DNA damage signal to 
the apoptotic machinery via upregulation of BH3-only proteins like Noxa and Puma.29,30  
When p53 is functionally inactivated, either through mutation or deletion, these signals 
are not effectively relayed and the efficacy of these agents is blunted.23,31  However, 
because venetoclax bypasses these signaling events and inhibits Bcl-2 directly, it is 
expected to be equally effective in p53 wildtype and 17p del tumors.
Preliminary Clinical Data
Early results from the ongoing venetoclax first-in-human Study M12-175 (as of 
03 February 2014) have demonstrated activity in 21 evaluable relapsed/refractory CLL 
subjects with 17p deletion who were treated with venetoclax.  Fifteen (15) of the 
21 subjects have > 50% reduction in absolute lymphocyte count and/or 50% reduction in 
lymph node measurements by CT scan, results consistent with at least a partial remission 
(71% ORR).  Three subjects meet criteria for CR/CRi (complete remission with 
incomplete bone marrow recovery).  These encouraging preliminary data indicate that 
venetoclax may be beneficial in this unique patient population.
3.1
Differences Statement
This is the first Phase 2 study for venetoclax monotherapy.  Safety data and preliminary 
efficacy responses in the 17p deletion CLL population from Phase 1 support moving into 
Phase 2.
3.2
Benefits and Risks
The preliminary data of venetoclax monotherapy in subjects with CLL show a favorable 
benefit.  The risk profile of the drug supports the continuous dosing of venetoclax in this 
indication.  Dose titration and a prophylactic regimen of hydration and uric acid reducers, 
along with laboratory monitoring, provide adequate protection from the potential risk of 


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serious adverse events of TLS.  In addition, safety will be reviewed on an ongoing basis 
by the Sponsor to evaluate accumulated safety data to assess any trends that would require 
modifications to the trial.
The encouraging preliminary data from the ongoing venetoclax first-in-human 
Study M12-175 indicate that venetoclax may be beneficial in subjects with relapsed CLL 
harboring 17p deletion.
Additionally, for previously untreated subjects with CLL harboring 17p deletion, 
venetoclax could provide an alternative treatment with the absence or reduction of the 
toxicities commonly associated with to the standard aggressive chemotherapy.
4.0
Study Objectives
Main Cohort
The primary objective of this cohort is to evaluate the efficacy of venetoclax monotherapy 
in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) harboring the 
17p deletion.  Efficacy will be measured by overall response rate (ORR).
The secondary objectives are to evaluate the complete remission rate (CR rate), partial 
remission rate (PR rate), duration of overall response (DOR), progression-free survival 
(PFS), event-free survival,  time to progression (TTP), time to first response, time to 50% 
reduction in ALC, overall survival (OS) and percent of subjects who move on to stem cell 
transplant.  The safety and tolerability of venetoclax in subjects with relapsed or 
refractory CLL harboring 17p deletion will also be evaluated.
Safety Expansion Cohort
The primary objective of the safety expansion cohort is to evaluate the safety of 
venetoclax in approximately 50 subjects with relapsed/refractory or previously untreated 
CLL harboring 17p deletion treated per the updated TLS prophylaxis and management 
measures.


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The secondary objectives are to evaluate ORR, CR rate, PR rate, duration of overall 
response, progression-free survival, event-free survival, time to progression, time to 
first response, time to 50% reduction in ALC, overall survival, and percent of subjects 
who move on to stem cell transplant.
Exploratory objectives will be evaluated in both cohorts.  Time to next anti-CLL 
treatment (TTNT) and minimal residual disease (MRD), assessed in the peripheral blood 
and/or bone marrow (BM), will be measured.  Pharmacokinetics, pharmacogenetics and 
biomarkers will also be evaluated as exploratory objectives.  Health Economic and 
Patient-Reported Outcome Measures will include the MDASI (measure of subject 
reported symptoms), the EORTC QLQ-C30 and EORTC QLQ CLL16 (a measure of 
health related quality of life specific to CLL) and the EQ-5D-5L (measure of general 
health status) and EQ-5D-VAS.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is an open-label, single arm, multicenter, global study to determine the efficacy of 
venetoclax monotherapy in subjects with relapsed/refractory or previously untreated 
chronic lymphocytic leukemia harboring 17p deletion sponsored by AbbVie in 
collaboration with Genentech/Roche.  Previously untreated chronic lymphocytic leukemia 
harboring 17p deletion patients will not be enrolled in Germany.
This study is designed to enroll in the main cohort approximately 100 subjects with 
relapsed or refractory chronic lymphocytic leukemia harboring 17p deletion, as confirmed 
by the central laboratory, and in the safety expansion cohort approximately 50 subjects 
with relapsed/refractory or previously untreated chronic lymphocytic leukemia harboring 
17p deletion as confirmed by local or central laboratory, to meet scientific and regulatory 
objectives without enrolling an undue number of subjects in alignment with ethical 
considerations.  Therefore, if the target number of subjects has been enrolled, there is a 
possibility that additional subjects in screening will not be enrolled.


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Subjects in this study will be enrolled at approximately 60 research sites.
After approximately 20 subjects have completed at least 12 weeks of study treatment in 
the main cohort, a safety analysis will be conducted by an Independent Data Monitoring 
Committee (IDMC).  In the safety expansion cohort, interim analysis results will be 
reviewed by the IDMC after approximately 20 subjects have completed approximately 
2 – 3 weeks of the lead-in period.
Main Cohort Dosing Schedule
NOTE:  Enrollment in the main cohort is complete, and all subjects have completed the 
lead-in period under Protocol Amendment 1.
Venetoclax will be administered orally once daily (QD), continuously.  Each dose of 
venetoclax should be taken with approximately 240 mL of water within 30 minutes after 
the completion of breakfast or the subject's first meal of the day.  To mitigate the risk for 
TLS, a lead-in period (up to 5 weeks) will be employed to evaluate a step wise dose 
escalation.  All subjects will be admitted to the hospital and begin the lead-in period with 
an initial test dose of 20 mg venetoclax on Week 1 Day 1.  If no significant findings occur 
within 24 hours, then a test dose of 50 mg will be administered on Week 1 Day 2 followed 
by 50 mg venetoclax QD for 5 days (Week 1 Day 3 – Day 7).  If significant findings occur 
within 24 hours of the initial test dose of 20 mg venetoclax on Week 1 Day 1, the 20 mg 
dose will be maintained for 1 week prior to dose escalation to 50 mg on Week 2 
Day 1 – 7.
After a week at 50 mg, the following dose escalation will proceed with weekly dose 
escalations → 100 mg →200 mg → 400 mg (or additional lead-in steps to designated 
400 mg dose), as tolerated.
A lower starting dose and/or modification to the lead-in regimen may be implemented for 
individual subject(s) at particularly high risk for TLS (Figure 1).


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Figure 1.
Dosing Schematic – Main Cohort
Lead-in Period
Every subject will receive a test dose of 20 mg on Week 1, Day 1 of the lead-in period.
1.
If one or more electrolyte changes (from the predose value) meeting Cairo-Bishop 
criteria occurs within 24 hours of the 20 mg dose and is confirmed on the next 
laboratory test (1 – 2 hours later), no additional venetoclax doses will be 
administered until resolution.  (For Cairo Bishop criteria, see Appendix F, 
Cairo-Bishop and Howard Definitions of Tumor Lysis Syndrome.  See Appendix D, 
Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome [TLS], for procedures to follow.)  Upon 
laboratory abnormalities resolution, the subject will remain on the 20 mg dose 
through Week 1 (e.g., Week 1 Day 2 – Week 1 Day 7).
and/or
2.
For subjects with a predose lymphocyte count ≥ 5000/mm3, if a decrease (from the 
predose value) in lymphocyte count ≥ 30% occurs within 24 hours of the 20 mg 
dose on Day 1, the subject will remain on the 20 mg dose through Week 1 
(e.g., Week 1 Day 2 – Week 1 Day 7).


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For subjects who meet the electrolyte and/or lymphocyte changes described in 1 and/or 2 
above, escalation to 50 mg will occur on Week 2 Day 1 of the lead-in period.  Subjects 
who had drug interruptions may escalate to 50 mg after they have been on a 20 mg dose 
for approximately a week (e.g., 5, 6 days).
If none of the electrolyte and/or lymphocyte changes described in 1 and/or 2 above occur 
within 24 hours from venetoclax 20 mg dose administration, the subject, while 
hospitalized, will dose escalate to 50 mg on Week 1 Day 2.  After the first dose of 50 mg, 
if no laboratory abnormalities occur, the subject will remain on the 50 mg dose through 
Week 1 (e.g., Week 1 Day 2 – Week 1 Day 7).  If abnormalities are observed, no 
additional venetoclax doses will be administered until resolution.
After the subject has received the 50 mg dose for approximately a week (6 – 7 days), the 
following dose escalation will proceed with weekly dose escalations →100 mg →200 mg 
→400 mg (or additional lead-in steps to designated 400 mg dose), as tolerated.
For all dose escalations, laboratory values for subject management must be reviewed in
real time by the investigator and prior to the subject's next dose to ensure appropriate 
subject management.  Based upon the laboratory values, the subject may continue dosing, 
may need to hold dose until resolution, may require hospitalization for further monitoring 
or may need additional post-dose laboratory checks.  (See Appendix D, Recommendations 
for Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS], for procedures to follow.)
Refer to Section 6.1.8.1, Prophylaxis and Management of Tumor Lysis Syndrome, for 
additional details on TLS prophylaxis.
Safety Expansion Cohort Dosing Schedule
To mitigate the risk for TLS, a lead-in period of 5 weeks will be employed with a 
step wise dose escalation (Figure 2).  For tumor lysis syndrome prophylaxis, all subjects 
will be classified into 3 risk categories based on the risk for developing TLS prior to 


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venetoclax administration (Section 6.1.8.1, Prophylaxis and Management of Tumor Lysis 
Syndrome).
Subjects in the low risk category and medium risk category with CrCl ≥ 80 mL/min 
and low tumor burden will begin the lead-in period in the outpatient setting with an 
initial dose of 20 mg venetoclax on Week 1 Day 1.  
●
If no significant findings suggestive of clinical or laboratory TLS occur within 
24 hours, the same dose will be continued through Week 1 Day 7 in the 
outpatient setting.  Subjects with no laboratory abnormalities suggestive of 
TLS will escalate to a dose of 50 mg venetoclax on Week 2 Day 1 in the 
outpatient setting.
●
If there is indication of laboratory or clinical TLS, the study drug dose will be 
held until resolution of all findings.  TLS management will be implemented as 
appropriate.
Medium risk subjects with CrCl < 80 mL/min and/or higher tumor burden (i.e., ALC 
> 100 × 109/L or multiple bulky nodes) may be admitted to the hospital, at the 
investigator's discretion, to begin the lead-in period with an initial dose of 20 mg 
venetoclax on Week 1 Day 1.  
●
If no significant findings suggestive of clinical or laboratory TLS occur within 
24 hours, the same dose will be continued through Week 1 Day 7 in the 
outpatient setting.  Subjects with no laboratory abnormalities suggestive of 
TLS will escalate to a dose of 50 mg venetoclax on Week 2 Day 1 in the 
outpatient setting.  However, subjects may still be hospitalized prior to the 
first dose escalation at 50 mg if they continue to have CrCl < 80 mL/min 
and/or higher tumor burden (i.e., ALC > 100 × 109/L or multiple bulky nodes), 
at the investigator's discretion.
●
If there is indication of laboratory or clinical TLS, the study drug dose will be 
held until resolution of all findings.  TLS management will be implemented as 
appropriate.


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All high risk subjects will be admitted to the hospital and begin the lead-in period with 
an initial dose of 20 mg venetoclax on Week 1 Day 1. 
●
If no significant findings suggestive of clinical or laboratory TLS occur within 
24 hours, the same dose will be continued through Week 1 Day 7 in the 
outpatient setting.  Subjects will be hospitalized prior to the first dose 
escalation to 50 mg beginning on Week 2 Day 1.  Each subject's risk status 
may be reassessed prior to subsequent dose escalations per the guidelines in 
Section 6.1.8.1, Prophylaxis and Management of Tumor Lysis Syndrome.
●
If no significant findings occur within 24 hours of dose escalation, the study 
drug will be continued at the same dose from Days 2 through 7 in the 
outpatient setting.
●
If there is indication of laboratory or clinical TLS, the study drug dose will be 
held until resolution of all findings.  TLS management will be implemented as 
appropriate.
A lower starting dose and/or modification to the lead-in regimen may be implemented for 
individual subject(s) at particularly high risk for TLS.  For these individual cases, a 
discussion should occur between the investigator and the AbbVie medical monitor.
If a high risk subject has clinical signs of progression during the first week of 20 mg 
dosing, correspondence between the investigator and the AbbVie medical monitor must 
occur.
Figure 2.
Dosing Schematic – Safety Expansion Cohort


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Lead-in Period
Every subject will receive a dose of 20 mg on Week 1, Day 1 of the lead-in period.  If one 
or more electrolyte changes (from the 0 hour measurement prior to dosing) suggestive of 
TLS occur within 24 hours of the 20 mg dose, no additional venetoclax doses will be 
administered until resolution.  If aggressive correction of electrolytes abnormalities is 
performed, the subsequent dose of venetoclax can only be given when electrolytes have 
been stable without any more treatment for at least 24 hours.  See Appendix D, 
Recommendations for Initial Management of Electrolyte Abnormalities and Prevention of 
Tumor Lysis Syndrome (TLS), for additional laboratory assessments and management 
guidelines.  Upon resolution of laboratory abnormalities, the subject will continue on the 
20 mg dose through Week 1 (e.g., Week 1 Day 2 – Week 1 Day 7).
Subjects who had drug interruptions may escalate to 50 mg after they have been on a 
20 mg dose for at least one week (7 days).
After a week at 50 mg, weekly dose escalations will be implemented as follows:  
100 mg →200 mg →400 mg (or additional lead-in steps to designated 400 mg dose) as 
tolerated.
For all dose escalations, laboratory values for subject management must be reviewed in 
real time by the investigator, and prior to the subject's next dose, to ensure appropriate 
subject management.  Based upon the laboratory values, the subject may continue dosing, 
may need to hold dose until resolution, may require hospitalization for further monitoring 
or may need additional post-dose laboratory checks.  See Appendix D, Recommendations 
for Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome (TLS) for additional laboratory assessments and management guidelines.
Refer to Section 6.1.8.1, Prophylaxis and Management of Tumor Lysis Syndrome, 
for additional details on TLS prophylaxis.


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Main and Safety Expansion Cohorts
Dose Interruptions and Dose Reductions
If a subject has a venetoclax dose interruption or reduction, venetoclax may be 
reintroduced or escalated per correspondence between the Investigator and the AbbVie 
medical monitor.
Post-Treatment Follow-Up Visit(s)
For subjects who discontinue venetoclax (e.g., due to toxicity or stem cell/bone marrow 
transplant), post-treatment follow-up visits will be performed every 3 months until 
discontinuation from the study.  Post-Treatment follow-up visits are not required for 
subjects who have discontinued due to disease progression or a subject's refusal of the 
Post-Treatment visits.  This will be for a period of up to 5 years after the last subject has 
enrolled on the study.
Note:  Effective with protocol Amendment 6, subjects being followed in Post-Treatment as 
of 12 May 2017 will switch to being assessed per the Survival Assessments below.  No 
new subjects will enter the Post-Treatment period.
Survival Assessment(s)
Survival information (i.e., the date and cause of death, post treatment cancer therapies, 
etc.) will be collected via telephone calls and/or clinical visits at 3 month (± 7 days) 
intervals after the last study visit for a period of 5 years after the last subject has enrolled 
on the study for subjects who have not withdrawn consent.
Richter's Transformation and Second Primary Malignancies Assessment
Richter's transformation and second primary malignancies information (i.e., confirmation 
if the subject developed Richter's transformation and/or second primary malignancies and 
post treatment cancer therapies, etc.) will be collected via clinic visits or telephone calls at 
3 month intervals after the last study visit for a period of up to 5 years after the last subject 
has been enrolled, for those subjects who have not withdrawn consent.


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Option to Continue Venetoclax Treatment
Subjects may continue receiving study drug for up to 2 years following the date of the last 
subject enrolled provided they continue to tolerate the drug, have no evidence of disease 
progression, and do not meet any of the criteria for subject discontinuation.  Please see 
Section 5.4.1 for additional information.
Survival – Extended Access
For subjects who continue to derive benefit from venetoclax treatment 2 years following 
the date of the last subject enrolled, AbbVie will provide venetoclax for monotherapy use 
until the subject develops disease progression or until 5 years following the date of last 
subject enrolled (12 May 2020).  In countries where venetoclax is commercially available, 
subjects have the option to discontinue receiving venetoclax via the study and switch to 
commercial supply at any time but may be contacted every 12 weeks (± 7 days) to collect 
the Survival information noted above, provided they have not withdrawn consent. 
For subjects continuing into the Survival Extended Access portion of the trial, venetoclax 
will be dispensed at the Final Visit, and Survival visits will begin 12 weeks (± 7 days) 
following the 30-day Safety Follow-Up Visit.  Survival visits will include collection of 
Survival information, AEs/SAEs and concomitant medication information, study drug 
administration, collection and dispensing of subject diaries, and MRD PCR sample 
collection for eligible subjects.  All other procedures for disease assessments will be 
performed as standard of care.
5.2
Selection of Study Population
Subjects will undergo screening procedures within 28 days prior to initial study drug 
administration, with the exception of the CT scan and bone marrow biopsy and aspirate 
which must be completed within 35 days prior to study drug administration.  Adult male 
and female subjects who meet the inclusion criteria and who do not meet any of the 
exclusion criteria will be eligible for enrollment into the study.


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5.2.1
Inclusion Criteria
A subject will be eligible for participation in the safety expansion cohort if he/she meets 
the following criteria:
1.
Subject must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any screening or study specific procedures.
2.
Subject must be ≥ 18 years of age.
3.
Subject must have diagnosis of CLL that meets published 2008 Modified IWCLL 
NCI-WG Guidelines.
●
Subject has an indication for treatment according to the 2008 Modified 
IWCLL NCI-WG Guidelines;
●
Subject has clinically measurable disease (lymphocytosis > 5 × 109/L and/or 
palpable and measurable nodes by physical exam and/or organomegally 
assessed by physical exam);
●
Subject must have relapsed/refractory CLL or previously untreated CLL;
○
Refractory or relapsed CLL subjects must meet the following 
requirements:
●
Refractory or relapsed after receiving at least one prior line of therapy 
(subjects that have progressed after 1 cycle of treatment or have 
completed at least 2 cycles of treatment for a given line of therapy);
○
Previously untreated CLL subjects must meet the following requirements 
(previously untreated chronic lymphocytic leukemia harboring 
17p deletion patients will not be enrolled in Germany):
●
Received no prior chemotherapy or immunotherapy.  Subjects with a 
history of emergency, loco-regional radiotherapy (e.g., for relief of 
compressive signs or symptoms) are eligible.
●
CLL diagnostic criteria above and must have > 5 × 109/L 
B-Lymphocytes in the peripheral blood.


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●
Subjects must have 17p deletion, assessed by local laboratory (in bone marrow 
or peripheral blood) or assessed by central laboratory (peripheral blood).  A 
result obtained prior to study Screening may be used for eligibility.  
Additionally, a confirmatory sample (peripheral blood) will be sent to the 
central laboratory.
4.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance score 
of ≤ 2.
5.
Subject must have adequate bone marrow function at Screening as follows:
●
Absolute Neutrophil Count (ANC) ≥ 1000/μL, or
○
For subjects with an ANC < 1000/μL at Screening and bone marrow 
heavily infiltrated with underlying disease (unless cytopenia is clearly due 
to marrow involvement of CLL), growth factor support may be 
administered after Screening and prior to the first dose of venetoclax to 
achieve the ANC eligibility criteria (≥ 1000/μL);
●
Platelets ≥ 30,000/mm3
○
without transfusion support within 14 days of Screening,
○
without evidence of mucosal bleeding,
○
without known history of bleeding episode within 3 months of Screening, 
and
○
without history of bleeding disorder.
●
Hemoglobin ≥ 8.0 g/dL.
6.
Subject must have adequate coagulation, renal, and hepatic function, per laboratory 
reference range at Screening as follows:
●
aPTT and PT not to exceed 1.5 × the upper limit of normal (ULN);
●
Calculated creatinine clearance > 50 mL/min using 24-hour Creatinine 
Clearance or modified Cockcroft-Gault equation (using Ideal Body Mass 
[IBM] instead of Mass):
eCCr =
(140 – Age) × IBM (kg) × [0.85 if Female]
72 × Serum Creatinine (mg/dL)


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Or, if serum creatinine is in μmol/L:
eCCr =
(140 – Age) × IBM (kg) × [1.23 if Male, 1.04 if Female]
Serum Creatinine (μmol/L)
Ideal Body Mass should be used:
IBM (kg) = [(height cm –154) × 0.9] + (50 if Male, 45.5 if Female)
Note:  For subjects that have BMI of > 30 kg/m2 or < 19 kg/m2, 24-hour measured 
urine creatinine clearance is required.
●
AST and ALT ≤ 3.0 × the upper normal limit (ULN) of institution's normal 
range; Bilirubin ≤ 1.5 × ULN.  Subjects with Gilbert's Syndrome may have a 
bilirubin > 1.5 × ULN, per correspondence between the investigator and 
AbbVie medical monitor.
7.
Female subjects of childbearing potential and non-sterile male subjects must 
practice at least one of the following methods of birth control with partner(s) 
beginning with initial study drug administration and continuing to 30 days after the 
last dose of study drug:
●
Total abstinence from sexual intercourse as the preferred life style of the 
subject; periodic abstinence is not acceptable;
●
Surgically sterile partner(s); acceptable sterility surgeries are:  vasectomy, 
bilateral tubal ligation, bilateral oophorectomy or hysterectomy;
●
Intrauterine device (IUD);
●
Double-barrier method (contraceptive sponge, diaphragm or cervical cap with 
spermicidal jellies or cream AND a condom);


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●
Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months 
prior to study drug administration;
If hormonal contraceptives are used, the specific contraceptive must have been
used for at least 3 months prior to study drug administration.  If the subject is 
currently using a hormonal contraceptive, she should also use a barrier method 
during this study from initial study drug administration to 30 days after the last 
dose of study drug.  Any contraception method must be continued for 30 days 
after the last dose of study drug.
8.
Females of childbearing potential (i.e., not postmenopausal for at least 1 year with 
no alternative medical reason or surgically sterile) must have negative results for 
pregnancy test performed:
●
At Screening with a serum sample obtained within 14 days prior to the 
first study drug administration, and
●
Prior to dosing with a urine sample obtained on Week 1 Day 1 (tested locally), 
if it has been > 7 days since obtaining the serum pregnancy test results.
9.
Male subjects must agree to refrain from sperm donation, from initial study drug 
administration until 90 days after the last dose of study drug.
10.
For high risk subjects (as defined in Section 6.1.8.1) a pre-approval by the AbbVie 
medical monitor is required prior to enrollment.
Rationale for Inclusion Criteria
(2 – 4)  To select the subject population
(5, 6, 10)  For the safety of the subjects
(7 – 9)  The impact of venetoclax on pregnancy in humans is unknown
(1)  In accordance with Harmonized Good Clinical Practice (GCP)


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5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Subject has undergone an allogeneic stem cell transplant.
2.
Subject has developed Richter's transformation confirmed by biopsy.
3.
Subject has prolymphocytic leukemia.
4.
Subject has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to 
Screening), including autoimmune hemolytic anemia (AIHA) and idiopathic 
thrombocytopenic purpura (ITP) despite low dose corticosteroids.
5.
Subject has previously received venetoclax.
6.
Subject is known to be positive for HIV (due to potential drug-drug interactions 
between anti-retroviral medications and venetoclax, as well as anticipated 
venetoclax mechanism based lymphopenia that may potentially increase the risk of 
opportunistic infections).
7.
Subject has received the following within 30 days prior to the first dose of study 
drug:
●
A biologic agent (i.e., monoclonal antibodies) for anti-neoplastic intent. 
8.
Subject has received radiotherapy within 14 days or any of the following within 
5 half-lives as applicable prior to the first dose of study drug, or has not recovered 
to less than CTC grade 2 clinically significant adverse effect(s)/toxicity(s) of the 
previous therapy:
●
Any anti-cancer therapy including chemotherapy, or radiotherapy;
●
Investigational therapy, including targeted small molecule agents.
9.
Subject has received the following within 7 days prior to the first dose of study 
drug:
●
Steroid therapy for anti-neoplastic intent;


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●
CYP3A inhibitors (such as fluconazole, ketoconazole, and clarithromycin);
!
Potent CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine or St. John's 
Wort);
●
Coumarins (vitamin K antagonists) or warfarin or phenprocoumon, or requires 
the use of coumarins (vitamin K antagonists) or warfarin (due to potential 
drug-drug interactions that may potentially increase the exposure of coumarins 
[vitamin K antagonists] or warfarin or phenprocoumon and complications of 
this effect).
10.
Subject has consumed the following within 3 days prior to the first dose of study 
drug.
●
Grapefruit or grapefruit products;
●
Seville oranges (including marmalade containing Seville oranges);
●
Star fruit.
11.
Subject has known allergy to both xanthine oxidase inhibitors and rasburicase.
12.
Subject has a 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.
13.
Subject exhibits 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.  
Note:  Subjects with serologic evidence of prior vaccination to HBV 
(i.e., HBs Ag–, anti-HBs+ and anti-HBc–) and positive anti-HBc from IVIG 
may participate.
●
Febrile neutropenia.
14.
Subject has a significant history of renal, pulmonary, neurologic, psychiatric, 
endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in 
the opinion of the investigator would adversely affect his/her participating in this 


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study.  For subjects who have required an intervention for any above diseases 
within the past 6 months, correspondence with the investigator and the AbbVie 
medical monitor must occur.
15.
A female subject is pregnant or breast-feeding.
16.
Subject has a history of active malignancies other than CLL within the past 2 years 
prior to study entry, with the exception of:
●
Adequately treated in situ carcinoma of the cervix uteri;
●
Adequately treated basal cell carcinoma or localized squamous cell carcinoma 
of the skin;
●
Previous malignancy confined and surgically resected (or treated with other 
modalities) with curative intent.
17.
Subject has malabsorption syndrome or other condition that precludes enteral route 
of administration.
Rationale for Exclusion Criteria
(1 – 3, 5, 16)  To select the appropriate subject population
(4, 6 – 14, 17)  For the safety of the subjects
(15)  The impact of venetoclax on pregnancy in humans is unknown
5.2.3
Prior and Concomitant Therapy
If a subject reports taking any over-the-counter or prescription medications, vitamins 
and/or herbal supplements or if administration of any medication becomes necessary 
beginning with the Screening visit through the end of the study, the name of the 
medication, dosage information including dose, route and frequency, date(s) of 
administration including start and end dates, and reason for use must be recorded on the 
appropriate electronic case report form (eCRF).


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Subjects should receive full supportive care during study participation, including 
hematopoietic growth factors, transfusion of blood products, fluid and electrolyte 
replacement, and antibiotics when appropriate.  Subjects who use oral contraceptives, 
hormone-replacement therapy, or other maintenance therapy should continue their use.
Steroid therapy for anti-neoplastic intent will not be allowed either during or within 
7 days prior to the first dose of study treatment.  Inhalational steroids for the treatment of 
asthma or COPD, topical steroids, replacement corticosteroid therapy for an inherited or 
acquired deficiency are allowable.
In addition, limited corticosteroid treatment (i.e., for approximately 21 days with rapid 
taper) 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.  Eltrombopag, a thrombopoiten receptor 
agonist, is another treatment option for ITP.  However, it is cautionary as it is a BCRP and 
OATP1B1 inhibitor (refer to Appendix C).
For additional guidance regarding medications for management of neutropenia and 
management of lymphopenia, refer to Section 6.1.8.2 and Section 6.1.8.3.
The AbbVie medical monitor identified in Section 7.0 should be contacted if there are any 
questions regarding concomitant or prior therapy(ies).
General guidelines regarding excluded, cautionary and allowed medications are 
summarized in Table 2 and Table 3.


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Table 2.
Excluded and Cautionary Medications/Food Items
Excluded
Grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or 
starfruit
Excluded During Ramp Up Phase and Cautionary Afterwards
!
Strong and Moderate CYP3A inhibitors
o
Excluded during ramp-up phase and consider alternative medications.  If subject requires 
use of these medications after the ramp-up phase, use with caution and reduce the venetoclax 
dose at least by 2-fold for moderate inhibitors and at least by 4-fold for strong inhibitors during 
co-administration.  After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax 
dose is increased back to the initial maintenance/target dose.
!
Strong and Moderate CYP3A inducers
o
Exclude during ramp-up phase and consider alternative medications.  If subject requires 
use of these medications after the ramp-up phase, use with caution and contact AbbVie medical 
monitor for guidance.
Cautionary
!
Coumarins (vitamin K antagonists) or warfarin or phenprocoumon*
!
P-gp substrates**
!
BCRP substrates
!
OATP1B1/1B3 substrates
!
BCRP inhibitors
*
Closely monitor international normalized ratio (INR).
**
If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before venetoclax.
Table 3.
Sample of Permitted Medications
Drug or Therapy
Comments
Colony stimulating factors
e.g., G-CSF, GM-CSF
Permitted; per ASCO guidelines.32  Notify AbbVie medical 
monitor if subject requires use of these medications or human 
erythropoietin.
Best supportive care and treatment
e.g., antiemetics, antibiotics, transfusions, 
nutritional support, pain control, etc.
Permitted
Antiherpes and anti-pneumocystis prophylaxis
Permitted; if clinically indicated.
Autoimmune thrombocytopenia and hemolytic 
anemia medications
Permitted; if clinically indicated.
A sample list of excluded medications and cautionary medications that fall into these 
categories can be found in Appendix C.  It is not possible to produce a 100% exhaustive 


Venetoclax (ABT-199)
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54
list of medications that fall into these categories, so if in question, please refer to the 
appropriate product label.
If the investigator determines that such a medication is medically necessary, the 
investigator will notify the AbbVie medical monitor and discuss the investigator's use of 
these medications and the investigator's plans to medically monitor the study subject.
5.3
Efficacy Pharmacokinetic, Pharmacodynamic, 
Pharmacogenetic, and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart


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55
Table 4.
Study Activities
Activity
Scra
Within 
72 
Hours 
Prior to 
1st Doseb W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-
Day 
Safety 
Visit
Post-
Treatc
Survival 
Follow-
Upt
Informed 
Consent
X
Detection of 
17p Deletiond
X
Medical 
History/ 
Oncology 
History 
Assessment
X
X
Adverse 
Event/ 
Concomitant 
Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Examina-
tione*
X
X
X
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
X
ECOG 
Performance 
Status*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 4.
Study Activities (Continued)
Activity
Scra
Within 
72 
Hours 
Prior to 
1st Doseb W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-
Day 
Safety 
Visit
Post-
Treatc
Survival 
Follow-
Upt
Pregnancy 
Testf
X
X
Hematology/ 
Chemistryg
X
X
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh X** X** X** X** X** X** X**
X**
X**
X**
X**
X**
Coagulation 
Panel**
X
X
X
X
X
X
Urinalysis**
X
X
X
Viral 
Serologies
X
Viral 
Polymerase 
Chain Reaction
X
Quantitative 
Immuno-
globulin**
X
X
X
X
X
Lymphocyte 
Enumera-
tion**
X
X
X
X
X
X
ECG
X
X


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57
Table 4.
Study Activities (Continued)
Activity
Scra
Within 
72 
Hours 
Prior to 
1st Doseb W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-
Day 
Safety 
Visit
Post-
Treatc
Survival 
Follow-
Upt
Echocardio-
gram or a 
Multi Gated 
Acquisition 
Scan 
(MUGA)i
X
CT or MRI 
Scanj***
X
Xk
Xl
X
Xm
Bone Marrow 
Aspirate and 
Biopsy
Xn
Xo
Xo
X
Disease 
Assessments*
Xp
X
X
X
X
X
X
X
X
X
X
X
X
MRD 
Assessment
Xq
Xq
X
Survival 
Assessment†
X
X
Dispense/ 
Collect 
Venetoclax 
and Subject 
Calendars/ 
Diaries
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Venetoclax (ABT-199)
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Table 4.
Study Activities (Continued)
Activity
Scra
Within 
72 
Hours 
Prior to 
1st Doseb W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-
Day 
Safety 
Visit
Post-
Treatc
Survival 
Follow-
Upt
MDASIr
X
X
X
X
X
X
EORTC 
QLQ-C30 and 
EORTC QLQ 
CLL16r
X
X
X
X
X
X
X
EQ-5D-5L 
and 
EQ-5D-VASr
X
X
X
X
X
X
Subject TL 
Surveys
X
Scr = Screening; W, Wk = Week, D = Day, Post-Treat = Post-Treatment; FV = Final Visit
Study Windows:  
*
within 72 hours before or after scheduled visit starting with Week 8 Day 1;
**
within 72 hrs prior to scheduled visit starting with Week 8 Day 1; 
***
within 7 days after scheduled visit.
†
within ± 7 days of scheduled visit.
a.
Subjects will undergo screening procedures within 28 days prior to the first study drug administration, except where otherwise indicated.
b.
All subjects must receive tumor lysis prophylaxis prior to and during treatment.  For details on tumor lysis prophylaxis and management, refer to Section 6.1.8.1, Prophylaxis 
and Management of Tumor Lysis Syndrome and Appendix D – Recommendations for Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome (TLS).
c.
Assessments will be collected at 3 month intervals after the last study visit for a period of 5 years after the last subject has enrolled in the study.


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Table 4.
Study Activities (Continued)
d.
Subjects must have 17p deletion as assessed by local or central laboratory to be considered for enrollment.  A result obtained prior to study Screening may be used for 
eligibility.  A confirmatory sample will be sent to central laboratory at Screening.  Refer to Section 5.3.1.5, Collection and Handling of Biomarker Variables, for more details.
e.
A complete physical examination will be performed at Screening.  A symptom directed physical examination will be performed on Day 1 of Weeks 2 – 4 and the 30-day 
Safety Visit.  All other physical examinations will be targeted.  If during physical examination, signs or symptoms suggestive of Richter's Syndrome are observed, further 
assessments (e.g., lymph node biopsy, PET scan) should be considered to exclude or confirm the transformation.  Refer to Section 5.3.1.1 Physical Examination, for more 
details.
f.
For females of childbearing potential, a urine pregnancy test must be obtained and processed locally at the Week 1 Day 1, if it has been > 7 days since obtaining the serum 
pregnancy results at Screening.
g.
Cholesterol and triglycerides are only required at Screening and Final Visit.
h.
There is no 72 hour window for these samples.  Refer to Section 6.1.8.1, Prophylaxis and Management of Tumor Lysis Syndrome and Appendix D – Recommendations for 
Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS).
i.
Assessment of ejection fraction will be made at screening at the discretion of the investigator.  Subsequent evaluation of Left Ventricular Ejection Fraction (LVEF) will be 
made as clinically indicated for subjects who develop signs of cardiac compromise.
j.
If a subject exhibits clinical signs of possible disease progression (i.e., increased or de novo enlargement of liver, spleen or lymph nodes on physical examination without an 
increase in lymphocytes meeting PD criteria), a CT scan and/or bone marrow biopsy must be performed within 2 weeks to confirm or rule out PD as described in 
Section 5.3.3.2.
k.
Imaging assessments are required for all subjects at Week 36 Day 1.  Assessment to be performed on Week 36 Day 1 only (not every 12 weeks).  The Week 36 scan may be 
performed within 4 weeks before or after the 36 week scheduled visit provided that it has been at least 8 weeks since the subject's last scan.
l.
After a response is determined by clinical criteria, a CT scan will be performed no earlier than 8 weeks for confirmation of response.  For determination of CR/CRi, both the 
CT scan and bone marrow are required to be negative.  It is recommended that the CT scan is performed first, and if it does confirm a CR/CRi, then a BM biopsy should be 
obtained as soon as possible.  
m.
Post-treatment CT or MRI scans to be done only if collected by the site as part of standard of care. 
n.
A bone marrow aspirate and biopsy will be performed and assessed locally at Screening (within 35 days prior to the first dose of study drug).  Bone marrow and aspirate for 
biomarker sample collection should be split from this sample.  Refer to Table 6.
o.
For subjects who meet all criteria for CR/CRi with the exception of a node(s) that is enlarged around 1.5 – 2 cm may also have a bone marrow performed.  If bone marrow 
was not performed at the time of the confirmatory CT, then it should be performed after the Week 36 Day 1 CT scan.


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Table 4.
Study Activities (Continued)
p.
At baseline, all measurable disease must be documented at screening by laboratory testing, physical examination and CT scans (or MRI if CT is medically contraindicated), 
and bone marrow examinations.
q.
Specimens (bone marrow aspirate and peripheral blood) for MRD analysis should be collected at the same time as the bone marrow aspirate and biopsy performed for tumor 
assessments to confirm the CR/CRi.  If MRD negativity is achieved in the bone marrow no further MRD analyses are required.  Otherwise, MRD should be assessed at 
12-week intervals thereafter (in peripheral blood) until MRD negativity is achieved.  Once MRD negativity is achieved and confirmed in peripheral blood (e.g., two MRD 
negative consecutive peripheral blood samples), a bone marrow aspirate specimen will again be collected for analysis of MRD levels to confirm the peripheral blood 
negativity.  Subjects who meet all criteria for CR/CRi with the exception of a node(s) that is enlarged around 1.5 – 2 cm may also have a bone marrow performed and MRD 
assessment.  If a bone marrow and MRD assessment was not performed at the time of the confirmatory CT scan, then they should be performed after the Week 36 Day 1 CT 
scan.  If MRD negativity is achieved in the bone marrow no further MRD analyses are required.  Otherwise, MRD should be assessed at 12-week intervals thereafter (in 
peripheral blood) until MRD negativity is achieved.  Once MRD negativity is achieved and confirmed in peripheral blood (e.g., two MRD negative consecutive peripheral 
blood samples), a bone marrow aspirate specimen will again be collected for analysis of MRD levels to confirm the peripheral blood negativity.
r.
The Health Economic and Patient Reported Outcomes questionnaires should be administered and completed prior to any other study procedures being performed at these 
visits.  Refer to Section 5.3.8, Health Economic and Patient-Reported Outcome Measures, for further information.
s.
For subjects in the United States only:  Subjects in the safety expansion cohort will be asked to complete a survey assessing the information they were provided for the Patient 
Information Card and the Tumor Lysis Syndrome Patient Information Brochure at Week 2 Day 1 or the next scheduled visit.  For subjects participating in the main cohort, the 
survey will be given to the subject at the next scheduled study visit upon signing the Protocol Amendment 2 Informed Consent.  This survey is optional.
t.
For subjects continuing into the Survival Extended Access portion of the trial, Survival vists will include collection of Survival information, AEs/SAEs and concomitant 
medication information, study drug administration, collection and dispensing of subject diaries, and MRD PCR sample collection for eligible subjects.  All other procedures 
for disease assessments will be perfomed as standard of care.


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Table 5.
Schedule of PK Blood Collection for Venetoclax (and Possible Metabolite[s])
Study Visit
Week 1
Day 1
Weeks 2, 3, 4, 5
Day 1
Weeks 8, 12, 16 
Day 1
Week 24 Day 1 and Day 1 of 
Every 12 Weeks thereafter 
(e.g., Weeks 36, 48, 60, etc.)
Collection Times
8 hours post-dose
8 hours post-dose if escalation 
to a new dose level
0 hour
(pre-dose)
0 hour
(pre-dose)
Notes:
1) The PK collection performed 8 hours post-dose after each dose escalation to a new dose level of venetoclax may be taken up to 1 hour prior or up to 20 minutes after 
to allow for processing, if necessary.
2) The date and time (to the nearest minute) of each study drug dose taken and whether or not the dose was taken within 30 minutes after completing breakfast (or the 
subject's first meal of the day) will be recorded on the eCRF for each scheduled venetoclax PK day and for the 2 days prior to every scheduled venetoclax PK day (with 
the exception of Week 1 Day 1 where no medication is given the 2 days prior to dosing).


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Table 6.
Schedule of Biomarkers and Pharmacogenetic Sample Collection
Sample Collections
Screening
Week 1 Day 1
Week 1 Day 2
Week 5 Day 1
Final Visit/
Time of 
Relapseg,h
Comments
Serum Markers
Xa
Xb
Xb
X
3.5 mL Blood
Blood for CD19 Cell Isolation Bcl-2 
Family Analysis
Xa
X
8 mL Blood
Blood for FISH for Detection of 17p 
Deletion
X
4 mL Blood
Bone Marrow Aspirate for Bcl-2 
Protein Analysisc
X
X
1 mL Bone Marrow 
Aspirate
Bone Marrow Aspirate for CD19 Cell 
Isolationc
X
X
6 mL Bone Marrow 
Aspirate
Tissue (Subjects with Richter's 
Transformation)d
X
Biopsy
(FFPE Tissue of LN)
Tissue for IHC/FISH (Optional)
Xa,e
X
FFPE Archival Tissue, 
or Biopsy
Pharmacogenetics (Optional)
Xa,f
4 mL Blood
a.
Perform once at either Screening or prior to dosing on Week 1 Day 1.
b.
Obtain sample prior to dosing.
c.
The aspirate (6 mL) samples should be split from samples obtained for 2008 Modified IWCLL NCI-WG Guidelines for Tumor Response assessment whenever possible.  If 
additional bone marrow aspirates are collected by the site per standard of care, a sample should be provided for this study. Subjects should not be subjected to additional bone 
marrow sampling only for this purpose.
d.
Biopsies to be collected from all subjects whose CLL has undergone a Richter's transformation.  Tumor tissue from accessible site of transformation should be submitted for 
biomarker testing.
e.
Archive sample may be used at Screening if obtained within 35 days of starting study drug without intervening treatment and representative of subject's current disease state.


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Table 6.
Schedule of Biomarkers and Pharmacogenetic Sample Collection (Continued)
f.
If the sample is not collected at either of these visits, the sample can be collected at any visit during the study
g.
Subjects with PD who continue to receive treatment per the discretion of the investigator (per Section 5.4.1) will have biomarker samples collected at both time of relapse and 
their subsequent final visit at discontinuation of venetoclax.
h.
No final visit biomarker specimens are required for subjects that transition to the survival extended assess portion of the study.


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5.3.1.1
Study Procedures
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 study drug.
Informed Consent
Signed informed consent will be obtained from the subject or the subject's legally 
acceptable representative before any study-specific procedures are undertaken or before 
any prohibited medications are withheld from the subject in order to participate in this 
study.  Informed consent is also required for pharmacogenetic (PG) sampling and a 
portion of the pharmacodynamic (PD) sample collections.  Details about how informed 
consent will be obtained and documented are provided in Section 9.3.
Medical and Oncologic History
The following will be collected during the Screening Visit:
●
Complete medical history, including documentation of any clinically 
significant medical condition
●
History of tobacco and alcohol use
●
Detailed oncology history 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)
●
Detailed prior and concomitant medication usage including dates of usage and 
dosing information for all medications and supplements taken


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On Week 1 Day 1, any changes observed from the Screening assessments (prior to
dosing) will be recorded in the subject's medical history.  
Adverse Event and Concomitant Medication Assessment
Medication (prescription or over-the-counter, including vitamins and herbal supplements) 
will be recorded beginning with the Screening Visit through the end of the study.
At each visit, including the Final Visit and the 30-day Safety Follow-Up Visit, the 
subject's medical history will be reviewed and any changes from baseline will be recorded 
on the adverse event eCRF.
Physical Examination
A complete physical examination performed should include the evaluation of head, 
eyes, ears, nose, and throat (HEENT); cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems.
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination.  New or worsened abnormalities should be recorded as AEs if appropriate.
Physical examinations should also include the evaluation of the presence and degree of 
enlarged lymph nodes in two dimension (cervical, supraclavicular, axillary, inguinal and 
femoral nodes), hepatomegaly, and splenomegaly.  These should be noted on all 
examinations irrespective of being present or absent.  Refer to Section 5.3.3.1 for 
additional information pertaining to methods of measurement.
If during physical examination, signs or symptoms suggestive of Richter's Syndrome are 
observed, further assessments (i.e., nodes, biopsy, PET scan) should be considered to 
exclude or confirm the transformation.
At Screening, the subject should have a complete physical examination.


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A targeted physical examination should be limited to systems of primary relevance-that 
is, cardiovascular, respiratory, those associated with symptoms, and those associated with 
disease assessment (lymph nodes, cervical, supraclavicular, axillary, inguinal nodes, liver, 
and spleen).
Targeted physical examinations should also include the evaluation of the presence and 
degree of enlarged lymph nodes in two dimension (cervical, supraclavicular, axillary, 
inguinal and femoral nodes), hepatomegaly, and splenomegaly.  These should be noted on 
all examinations irrespective of being present or absent.  Refer to Section 5.3.3.1 for 
additional information pertaining to methods of measurement.
A physical examination will be performed at:
●
Screening (height will be measured only at Screening, subject should not wear 
shoes)
●
Week 1 Day 1**
●
Week 2 Day 1*
●
Week 3 Day 1*
●
Week 4 Day 1*
●
Week 5 Day 1**
●
Week 8 Day 1**
●
Week 12 Day 1**
●
Week 16 Day 1**
●
Week 20 Day 1**
●
Week 24 Day 1**
●
Week 28 Day 1**
●
Week 32 Day 1**
●
Week 36 Day 1 and Day 1 of every 12 weeks thereafter (e.g., Weeks 48, 60, 
etc.)**
●
No earlier than 8 weeks after the CR, CRi or PR criteria for tumor response are 
first met**


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●
Final Visit**
●
30-Day Safety Follow-Up Visit*
●
Post Treatment Visits**, if applicable
Note: *
indicates symptom directed physical examination and 
** indicates targeted physical examination.
Note: Physical examinations may be performed within 72 hours before or after the 
scheduled visit starting with Week 8 Day 1.
Vital Signs
Body temperature (oral or tympanic), weight, blood pressure and pulse will be measured 
at:
●
Screening 
●
Week 1 Day 1
●
Week 2 Day 1
●
Week 3 Day 1
●
Week 4 Day 1
●
Week 5 Day 1
●
Week 8 Day 1
●
Week 12 Day 1
●
Week 16 Day 1
●
Week 20 Day 1
●
Week 24 Day 1 
●
Week 28 Day 1
●
Week 32 Day 1
●
Week 36 Day 1 and Day 1 of every 12 weeks thereafter (e.g., Weeks 48, 60, 
72, etc.)
●
Final Visit
●
30-Day Safety Follow-Up Visit


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●
Post Treatment Visits, if applicable
Note:  Vital signs may be performed within 72 hours before or after the scheduled visit 
starting with Week 8 Day 1.
Blood pressure and pulse rate will be measured after the subject has been sitting for at 
least 5 minutes on days when study drug is administered in the clinic.
ECOG Performance Status
The ECOG performance status33 will be performed as follows:
●
Screening
●
Week 1 Day 1
●
Week 2 Day 1
●
Week 3 Day 1
●
Week 4 Day 1 
●
Week 5 Day 1
●
Week 8 Day 1
●
Week 12 Day 1
●
Week 16 Day 1
●
Week 20 Day 1
●
Week 24 Day 1 
●
Week 28 Day 1
●
Week 32 Day 1
●
Week 36 Day 1 and Day 1 every 12 weeks thereafter (e.g., Weeks 48, 60, 72, 
etc.)
●
Final Visit
●
30-Day Safety Follow-Up Visit
Note:  ECOG performance status may be performed within 72 hours before or after the 
scheduled visit starting with Week 5 Day 1.


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It is recommended, where possible, that a subject's performance status will be assessed by 
the same person throughout the study.
Grade
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction.
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, 
office work.
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair.
Clinical Laboratory Tests
A central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  The principal investigator or subinvestigator should review, initial, and 
date the Screening laboratory results after receipt from the central laboratory.  For 
subsequent laboratory tests, the principal investigator or subinvestigator will review, 
initial, and date laboratory results used for subject management after receipt from the 
laboratory (i.e., local and/or central).  The central laboratory values will be directly loaded 
to the clinical database from the central laboratory provider.  Laboratory normal ranges 
will be provided to the AbbVie Clinical Team, as requested.  
A laboratory test value that requires a subject to be discontinued from the study, requires a 
subject to receive treatment, meets protocol specific criteria (see Section 6.7 regarding 
toxicity management), and/or the Investigator considers clinically significant will be 
recorded as an adverse event.


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Local Laboratory Tests
Sites must utilize local laboratories to provide results for immediate subject management.  
Duplicate samples should also be sent to the central laboratory for processing for all 
protocol required laboratory samples, with the exception of serial laboratory samples 
collected on the same day (i.e., 4, 8 and 12 hour post dose laboratory collections).  Local 
laboratory results from samples that are also processed by the central laboratory should 
not be input into the eCRF with the exception of calcium, inorganic phosphorus, 
potassium, uric acid, creatinine and LDH, which should be entered through the lead-in 
period, and ALC (or % lymphocytes if ALC is not tested), ANC (or % neutrophils if 
ANC is not tested), WBC, platelets and hemoglobin which should be entered throughout 
the duration of the study.
If a duplicate sample is not able to be provided (e.g., subject in hospital), local laboratory 
values, as requested by AbbVie, 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.
Pregnancy Test
For female subjects of childbearing potential, pregnancy testing must be performed as 
follows:
●
Screening – Serum test
●
Week 1 Day 1: Urine test performed locally, if it has been > 7 days since 
obtaining the Screening serum pregnancy test results.
Pregnancy test results must be reviewed and determined to be negative prior to dosing.  
Subjects considered not of childbearing potential must be documented as being surgically 
sterile or postmenopausal for at least 2 years.
Hematology and Chemistry
Chemistry and hematology samples will be collected at the following time points.


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●
Screening
●
Within 72 hours prior to first dose of venetoclax
●
Weeks 1 – 5:  Refer to Section 6.1.8.1 Prophylaxis and Management of Tumor 
Lysis Syndrome and Appendix D, Recommendations for Initial Management 
of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS), 
for monitoring required during the lead-in period.
●
Week 8 Day 1
●
Week 12 Day 1
●
Week 16 Day 1
●
Week 20 Day 1
●
Week 24 Day 1
●
Week 28 Day 1
●
Week 32 Day 1
●
Week 36 Day 1 and Day 1 of every 12 weeks thereafter (e.g., Weeks 48, 60, 
72, etc.)
●
No earlier than 8 weeks (+1 week) after the CR, CRi or PR criteria for tumor 
response are first met
●
Final Visit
●
30-Day Safety Follow-Up Visit
●
Post Treatment Visits, if applicable
●
As needed throughout study
Note:  Chemistry and hematology samples may be collected within 72 hours prior to the 
scheduled visit starting with Week 8 Day 1.  There is no 72 hour window permitted for 
the chemistry and hematology samples collected Week 1 Day 1 through Week 5 Day 2.
Refer to Table 7 for a special sample handling procedure that must be followed to avoid 
ex vivo uric acid degradation in the presence of rasburicase for samples analyzed locally.
Cholesterol and triglycerides are only required at Screening and Final Visit.


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Additional monitoring as needed based on risk assessment by the investigator and 
correspondence with the AbbVie medical monitor.
Coagulation Panel
PT/aPTT samples will be collected at the following time points:
●
Screening
●
Week 12 Day 1
●
Week 24 Day 1
●
Final Visit
●
30-Day Safety Follow-Up Visit
●
Post Treatment Visits, if applicable
Note:  Coagulation panel may be collected within 72 hours prior to the scheduled visit 
starting with Week 8 Day 1.
Urinalysis
Urinalysis samples will be collected at:
●
Screening
●
Week 24 Day 1
●
Final Visit
Note:  Urinalysis may be collected within 72 hours prior to the scheduled visit starting 
with Week 8 Day 1.
Viral Polymerase Chain Reaction (PCR):  Sample Collection
Approximately 4 mL of blood will be collected by venipuncture into an appropriately 
labeled tube at the following time points:
●
Screening


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●
As needed throughout study
Viral polymerase chain reaction (PCR) samples are to be collected and sent to the central 
laboratory for archiving and will only be analyzed, if needed, due to manifestations of 
possible infections during the treatment period.
Viral Serologies
A sample for viral serologies to identify Hepatitis B (HBsAg, anti-HBs, total anti-HBc, 
IgM anti-HBc), Hepatitis C (HCV) antibody or RNA, cytomegalovirus IgG and IgM, 
varicella zoster virus IgG and IgM, herpes simplex virus IgG and IgM, and Epstein-Barr 
virus IgG and IgM will be collected at the following time points:
●
Screening
●
As needed for suspicion of viral infection
Note:  If during Screening, a subject presents with a positive Hepatitis B core antibody, a 
Hepatitis B Viral DNA PCR test should be performed to rule out an active infection.  
Results will be reviewed by AbbVie.
Quantitative Immunoglobulin
A sample to identify serial immunoglobulin levels of IgA, IgG and IgM will be collected 
at the following time points:
●
Screening
●
Week 12 Day 1
●
Week 24 Day 1
●
Final Visit
●
30-Day Safety Follow-Up Visit
Note:  Quantitative immunoglobulin may be collected within 72 hours prior to the 
scheduled visit starting with Week 8 Day 1.


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Lymphocyte Enumeration
Lymphocyte enumeration to identify B and T-cell lymphocyte subpopulations will be 
performed at:
●
Screening
●
Week 5 Day 1
●
Week 12 Day 1
●
Week 24 Day 1
●
Week 36 Day 1 and Day 1 of every 12 weeks thereafter (e.g., Weeks 48, 60, 
72, etc.)
●
Final Visit
The following B- and T-cell lymphocyte subpopulations will be assessed:
●
T-cells (CD3)
●
B-cells (CD19)
●
B-cells (CD5 + CD19)
●
Natural killer (CD16 + CD56)
●
Helper T-cells (CD4)
●
T-Suppressor or T-Cytotoxic cells (CD8)
●
Other lymphocyte studies
Note:  Lymphocyte enumeration samples may be collected within 72 hours prior to the 
scheduled visit starting with Week 12 Day 1.


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Table 7.
Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not
acceptable)
Mean corpuscular hemoglobin 
(MCH)
Mean corpuscular volume 
(MCV)
Mean corpuscular hemoglobin 
concentration (MCHC)
Reticulocyte count
Coagulation
Prothrombin time (PT)
Activated partial thromboplastin
time (aPTT)
Blood Urea Nitrogen (BUN)
Creatininea
Total bilirubin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST) 
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acidb
Cholesterol (Screening and Final 
Visit)
Total protein
Glucose
Triglycerides (Screening and 
Final Visit)
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Viral Analysis
Viral Polymerase Chain 
Reaction (PCR)c
Viral Serologies
Quantitative Immunoglobulins
IgA, IgG, and IgM
a.
Creatinine clearance should be assessed using Cockcroft-Gault equation or a 24-hour urine collection.
b.
For samples analyzed locally, at room temperature, rasburicase causes enzymatic degradation of the uric acid in 
blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings.  The 
following special sample handling procedure must be followed to avoid ex vivo uric acid degradation.  Uric acid 
must be analyzed in plasma.  Blood must be collected into pre-chilled tubes containing heparin anticoagulant.  
Immediately immerse plasma samples for uric acid measurement in an ice water bath.  Plasma samples must 
be prepared by centrifugation in a pre-cooled centrifuge (4°C).  Finally, the plasma must be maintained in an ice 
water bath and analyzed for uric acid within four hours of collection.
c.
Viral polymerase chain reaction (PCR) samples are to be collected and sent to the central laboratory for archiving 
and will only be analyzed if needed due to manifestations of possible infections during the treatment period.
Electrocardiogram
A resting ECG will be obtained at the following:
●
Screening


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●
Final Visit
●
As clinically indicated
The ECG results will be used by the investigator for subject safety assessments, including 
adverse event determination and management, dose escalation, and termination of 
subjects from the study.  ECG results will be summarized as follows:
●
normal ECG
●
abnormal ECG – not clinically significant
●
abnormal ECG – clinically significant
●
unable to evaluate
Any reports that are abnormal and clinically significant will be faxed to the Oncology 
Safety Management Team via the contact information provided in Section 6.1.6 within 
5 business days of obtaining the results.  The QT interval measurement will be 
documented in the eCRF only if a "prolonged QT" is observed.  Correction by the 
Fridericia formula (QTcF) is preferred; however, correction by other methods may be 
acceptable based on correspondence with the AbbVie medical monitor.  The original ECG 
tracing will be retained in the subject's records at the study site.
Assessment of Left Ventricular Ejection Fraction (LVEF) 
Assessment of ejection fraction will be made at screening by either echocardiogram or a 
Multi Gated Acquisition Scan (MUGA) at the discretion of the investigator.  Subsequent 
evaluation of LVEF will be made as clinically indicated for subjects who develop signs of 
cardiac compromise.
Disease Assessments (2008 Modified IWCLL NCI-WG Guidelines)
Clinical response will be assessed by the investigator based on analysis of laboratory tests 
(hematology laboratory values) and complete physical examination.  In addition, based 
upon the clinical response (CR/CRi/PR), a CT scan of involved anatomic regions (or MRI 
if CT is medically contraindicated), and bone marrow aspirate and biopsy may be 


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performed.  Subjects will be evaluated against the 2008 Modified IWCLL NCI-WG 
Guidelines for Tumor Response34 including CT imaging (or MRI).
Analysis of clinical laboratory values and physical examination will be performed at 
the following visits:
●
Screening
●
Week 5 Day 1
●
Week 8 Day 1
●
Week 12 Day 1
●
Week 16 Day 1
●
Week 20 Day 1
●
Week 24 Day 1
●
Week 28 Day 1
●
Week 32 Day 1
●
Week 36 Day 1 and Day 1 of every 12 weeks thereafter (e.g., Weeks 48, 60, 
72, etc.)
●
No earlier than 8 weeks after the CR ,CRi or PR criteria is first met (if 
applicable)
●
Final Visit
●
Post Treatment Visits, if applicable
Note:  Disease Assessments may be performed within 72 hours prior to or after the 
scheduled visit starting with Week 8 Day 1.
Response criteria definitions are outlined in Section 5.3.3.1.
Computed Tomography (CT) Scans (or Magnetic Resonance Imaging [MRI])
A CT scan with contrast must be performed within 35 days prior to study drug 
administration for all subjects.  CT scans (with contrast) should include neck, chest, 
abdomen, and pelvic sequences.  A contrast-enhanced MRI of the neck, chest, abdomen 


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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 an allergy to CT contrast 
agents or subjects with impaired renal clearance).  Whichever method is used at 
Screening, it should be used consistently through the duration of the study.
When a response (PR or CR) is determined by clinical criteria (e.g., laboratory 
tests/physical exam) at any time during the study, a CT scan must be performed no earlier 
than 8 weeks later for confirmation per 2008 Modified IWCLL NCI-WG Guidelines for 
Tumor Response.  If the CT scan confirms a CR, then a BM biopsy should be performed 
as soon as possible to confirm the CR.  For determination of CR, both the CT scan and
bone marrow are required to be negative.
A CT scan should also be performed at 36 weeks for all subjects.  This scan may be 
performed within 4 weeks before or after the 36 week scheduled visit provided that it has 
been at least 8 weeks since the subject's last scan.  For subjects whose response meets 
criteria for a PR at the time of the Week 36 CT scan, an additional CT scan should be 
performed (no earlier than 8 weeks following the Week 36 scan) if a subsequent clinical 
disease assessment indicates that a CR or CRi has been achieved.
If a subject exhibits clinical signs of possible disease progression (i.e., increased or 
de novo enlargement of liver, spleen or lymph nodes on physical examination) without an 
increase in lymphocytes meeting PD criteria, a CT scan must be performed within 
2 weeks to confirm or rule out PD as described in Section 5.3.3.2 according to Modified 
IWCLL NCI-WG Criteria for Tumor Response.
In addition to being reviewed by the investigator and/or site staff, an independent review 
will be performed to assess tumor response and disease progression.  Clinical data and 
radiographic scans will be interpreted according to 2008 Modified IWCLL NCI-WG
Guidelines for Tumor Response (refer to Table 8).  The independent review facility will 
provide instructions regarding the preparation and shipment of the data.  Interpretations 
from the independent review will not be sent to the site.  Subject treatment management 
will be based on review by the local investigator and/or site staff.


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Note:  Computed Tomography (CT) Scans (or MRI) may be performed up to 7 days after 
the scheduled visit.
Bone Marrow Aspirate and Biopsy
A bone marrow aspirate and biopsy will be performed and assessed locally at Screening 
(within 35 days prior to the first dose of study drug).  Bone marrow aspirate and biopsy 
for biomarker sample collection should be split from this sample.  A portion of the 
baseline aspirate may be used to design primers for ASO-PCR based MRD assessment.  
The bone marrow aspirate and biopsy should be performed after all other eligibility 
criteria have been met, unless otherwise obtained through standard of care.  Bone marrow 
aspirates and biopsies performed as standard of care throughout the study should also be 
captured on an eCRF.
Bone marrow aspirate and biopsy reports will be faxed to the AbbVie primary contact 
listed in Section 6.2 or designee.
If the subject achieves a CR/CRi by both clinical criteria and confirmatory CT scan, a 
bone marrow aspirate and biopsy should be performed as soon as possible to confirm the 
CR/CRi.
Subjects who meet all criteria for CR/CRi with the exception of a node(s) that are 
enlarged around 1.5 – 2 cm may also have a bone marrow performed.  If bone marrow 
was not performed at the time of the confirmatory CT, then it should be performed after 
the Week 36 Day 1 CT scan.  Bone marrow for biomarker sample collection can be split 
from this sample, from the bone marrow used for eligibility criteria, or from any bone 
marrow performed as standard of care throughout the study.
Quantitative Minimal Residual Disease (MRD) Assessment
MRD35 for enumeration of CLL cells using ERIC panel based flow cytometry will be 
assessed by regional laboratories from all available samples.  Additionally, MRD may be 
assessed using a PCR based technique from all available samples. MRD negativity may 


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be defined as the presence of less than one CLL cell per 10,000 leukocytes (or below 104) 
in the peripheral blood and/or bone marrow.
Specimens (bone marrow aspirate and peripheral blood) for MRD analysis should be 
collected at the same time as the bone marrow aspirate and biopsy performed for tumor 
assessments to confirm the CR/CRi.  If MRD negativity is achieved in the bone marrow 
no further MRD analyses are required.  Otherwise, MRD should be assessed at 12-week 
intervals thereafter (in peripheral blood) until MRD negativity is achieved.  Once MRD 
negativity is achieved and confirmed in peripheral blood (e.g., two MRD negative 
consecutive peripheral blood samples), a bone marrow aspirate specimen will again be 
collected for analysis of MRD levels to confirm the peripheral blood negativity.
Subjects who meet all criteria for CR/CRi with the exception of a node(s) that is enlarged 
around 1.5 – 2 cm may also have a bone marrow performed and MRD assessment.  If a 
bone marrow and MRD assessment was not performed at the time of the confirmatory CT 
scan, then they should be performed after the Week 36 Day 1 CT scan.  If MRD 
negativity is achieved in the bone marrow no further MRD analyses are required.  
Otherwise, MRD should be assessed at 12-week intervals thereafter (in the peripheral 
blood) until MRD negativity is achieved.  Once MRD negativity is achieved and 
confirmed in peripheral blood (e.g., two MRD negative consecutive peripheral blood 
samples), a bone marrow aspirate specimen will again be collected for analysis of MRD 
levels to confirm the peripheral blood negativity.
Subjects continuing into the Survival Extended Access portion of the study, and who 
continue to be eligible for MRD testing, will have blood specimens collected for MRD 
PCR collected at 12-week (± 7 days) intervals.  If a subject undergoes a bone marrow 
biopsy as standard of care while on the survival extended access portion, a portion of the 
aspirate is requested to be collected for MRD-PCR.
The Peripheral Blood and Bone Marrow Aspirate for MRD assessment by Flow and/or 
PCR samples will be processed and shipped directly to separate laboratories from the site 
per the current laboratory manual.


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Dispense/Collect Venetoclax and Subject Calendars/Diaries
Subject calendars/diaries will be provided.  Subjects will be instructed to bring their 
calendars/diaries back to the site to be reviewed at:
●
Week 1 Day 1
●
Week 2 Day 1
●
Week 3 Day 1
●
Week 4 Day 1
●
Week 5 Day 1
●
Week 8 Day 1 
●
Week 12 Day 1
●
Week 16 Day 1
●
Week 20 Day 1
●
Week 24 Day 1
●
Week 28 Day 1
●
Week 32 Day 1
●
Week 36 Day 1 and Day 1 of every 12 weeks thereafter (e.g., Weeks 48, 60, 
72, etc.)
Subjects will be instructed to record the date and time each dose of study drug is taken, 
(indicating if any doses of study drug are missed) and whether or not doses were taken 
within 30 minutes after completing breakfast or the subject's first meal of the day.  The 
date and time (to the nearest minute) of each dose taken and whether or not the dose was 
taken within 30 minutes after completing breakfast or the subject's first meal of the day 
will be recorded on the eCRF on the scheduled venetoclax PK days and for the 2 days 
prior to every scheduled venetoclax PK day (with the exception of Week 1 Day 1 where 
no medication is given the 2 days prior to dosing).
Subjects will also be instructed to record adverse events and concomitant medications in 
the subject calendars/diaries.


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The calendars/diaries are to be reviewed at each visit and relevant pages are to be 
photocopied by study staff.  At the end of the subject's participation in the study, the 
calendars/diaries are to be returned to the site and appropriately filed with the subject's 
source documents for this study.
Health Economic and Patient Reported Outcome Measures
The MDASI (measure of subject reported symptoms), the EORTC QLQ-C30 and EORTC 
QLQ CLL16 (a measure of health related quality of life), and the EQ-5D-5L and 
EQ-5D-VAS (measure of general health status) are the measures of quality of life as they 
pertain to symptomology and treatment that will be assessed in the study.
The MDASI assessment will take place at:
●
Week 1 Day 1
●
Week 5 Day 1
●
Week 12 Day 1
●
Week 24 Day 1
●
Week 36 Day 1 and Day 1 of every 12 weeks thereafter
●
Final Visit
The EORTC QLQ-C30 and EORTC QLQ CLL16 assessment will take place at:
●
Week 1 Day 1
●
Week 5 Day 1
●
Week 12 Day 1
●
Week 24 Day 1
●
Week 36 Day 1 and Day 1 of every 12 weeks thereafter (e.g., Weeks 48, 60, 
72, etc.)
●
Final Visit
●
Post Treatment Visits, if applicable


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The EQ-5D-5L and EQ-5D-VAS assessments will take place at:
●
Week 1 Day 1
●
Week 5 Day 1
●
Week 12 Day 1
●
Week 24 Day 1
●
Week 36 Day 1 and Day 1 of every 12 weeks thereafter (e.g., Weeks 48, 60, 
72, etc.)
●
Final Visit
The Health Economic and Patient Reported Outcomes questionnaires should be 
administered and completed prior to any other study procedures being performed at these 
visits.  Refer to Section 5.3.8, Health Economic and Patient-Reported Outcome Measures, 
for further information.
TLS Survey
Subjects participating in the United States will be asked to complete an optional survey 
assessing the information they were provided for the Patient Information Card and the 
Tumor Lysis Syndrome Patient Information Brochure, at their next regularly scheduled 
visit following reconsent if the subject is in the main cohort, or at Week 2 Day 1 or the 
next scheduled visit if the subject is in the safety expansion cohort.
Post-Treatment Follow-Up Visit(s)
For subjects who discontinue venetoclax monotherapy (e.g., due to toxicity or stem 
cell/bone marrow transplant), the following assessments will be performed every 
3 months (post treatment) until discontinuation from the study (e.g., disease progression 
or a subject's refusal of the Post-Treatment visits) for a period of 5 years after the last 
subject has enrolled on the study:
●
Physical Examination
●
Vital Signs


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●
Hematology and Chemistry
●
Coagulation
●
CT scan (or MRI) only if collected by the site as part of standard of care
●
Disease Assessments
●
The EORTC QLQ-C30 and EORTC QLQ CLL16 Assessment
Note:  Effective with protocol Amendment 6, subjects being followed in Post-Treatment as 
of 12 May 2017 will switch to being assessed per the Survival Assessments below.  No 
new subjects will enter the Post-Treatment period.
Survival Assessment(s)
Survival information (i.e., the date and cause of death, post treatment cancer therapies, 
etc.) will be collected via telephone calls and/or clinical visits at 3 month (± 7 days) 
intervals after the last study visit for a period of 5 years after the last subject has enrolled 
on the study for subjects who have not withdrawn consent.
Survival Assessment(s) – Extended Access
For subjects continuing into the Survival Extended Access portion of the trial, venetoclax 
will be dispensed at the Final Visit, and Survival visits will begin 12 weeks (±7 days) 
following the 30-day Safety Follow-Up Visit.  Survival visits will continue every 
12 weeks (±7 days) until disease progression; up to 5 years following last subject enrolled 
(12 May 2020); or until a subject chooses to switch to commercial supply.  Survival visits 
will include: 
●
Collection of Survival information
●
AE/SAE/Con Med assessment
●
Study drug reconciliation and dispensing
●
Collect/Dispense subject diaries 
●
MRD PCR sample collection for eligible subjects


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All other procedures for disease assessments will be performed as standard of care.
Assignment of Subject Numbers
Subjects will be assigned unique consecutive subject numbers at Screening, as described 
in Section 5.5.3.  The results of all screening evaluations must be within clinically 
acceptable limits, upon review by the investigator and AbbVie medical monitor, before a 
subject can be administered study drug.  Subjects will not be enrolled in the study if 
laboratory or other screening results are unacceptable.
5.3.1.2
Confinement
Subjects will not be confined during this study, but all subjects at high risk for TLS will 
be hospitalized for TLS prophylaxis and observation prior to their first dose of venetoclax 
at 20 mg and at 50 mg.  Additionally, subjects who continue to meet the criteria for high 
risk of TLS, or medium risk subjects with low creatinine clearance and/or higher tumor 
burden (i.e., ALC > 100 × 109/L or multiple bulky nodes), may be hospitalized for 
prophylaxis and monitoring at each subsequent dose escalation, at the discretion of the 
investigator.
5.3.1.3
Meals and Dietary Requirements
Each dose of venetoclax will be taken with approximately 240 mL of water within 
30 minutes after the completion of breakfast or the subject's first meal of the day.  On 
days that pre-dose PK sampling is required, dosing will occur in the morning at the clinic 
to facilitate PK sampling.
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 study drug administration and until the last day of treatment is completed 
due to possible CYP3A mediated metabolic interaction.


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5.3.1.4
Blood Samples for Pharmacogenetic Analysis (Optional)
One 4 mL whole blood sample for DNA isolation will be collected at Screening or prior 
to first dose of study drug on Week 1 Day 1 from each subject who consents to provide 
samples for pharmacogenetic analysis.  If the sample is not collected at either of these 
visits, it may be collected at any visit during the study.  The procedure for obtaining and 
documenting informed consent is discussed in Section 9.3.
Whole blood will be collected by standard phlebotomy techniques as described below:
●
Collect approximately 4 mL of blood into an appropriately labeled EDTA 
tube.
●
Immediately invert the collection tube 8 to 10 times to reduce the likelihood of 
clot formation.
●
Within 30 minutes of blood collection, store samples at –20°C or colder until 
shipped to central laboratory on dry ice sufficient to last during transport.
Samples will be shipped frozen to central laboratory.  The central laboratory or AbbVie 
will maintain the samples for DNA extraction and long-term storage.  Samples should not 
be allowed to thaw prior to arrival at the central laboratory.
The sample collection tubes will minimally be labeled with "PG-DNA blood," the drug 
number, protocol number, subject number and the study day.  AbbVie or designee will 
store the DNA samples in a secure space with adequate measures to protect 
confidentiality.  The samples will be retained while research on venetoclax (or drugs of 
this class) continues but no longer than 20 years or per country requirement.
5.3.1.5
Collection and Handling of Biomarker Variables
5.3.1.5.1
Mandatory Collections
Serum Markers
Approximately 3.5 mL of blood will be collected by venipuncture into an appropriately 
labeled 3.5 mL SST (gold top) tube from all subjects at the following time points:


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●
Screening or Week 1 Day 1 pre-dose
●
Week 1 Day 2 pre-dose
●
Week 5 Day 1 pre-dose
●
Final Visit/Time of Relapse
Note:  Subjects with PD who continue to receive treatment per the discretion of the 
investigator (per Section 5.4.1) will have biomarker samples collected at both time of 
relapse and their subsequent final visit at discontinuation of venetoclax.
Serum Marker samples will be processed and shipped to the central laboratory from the 
site per the current laboratory manual.
Blood for CD19 Cell Isolation Bcl-2 Family Analysis
Approximately 8 mL of blood will be collected by venipuncture into one appropriately 
labeled 8.5 mL ACD vacutainer from all subjects at the following time points:
●
Screening or Week 1 Day 1 pre-dose
●
Final Visit/Time of Relapse
Note:  Subjects with PD who continue to receive treatment per the discretion of the 
investigator (per Section 5.4.1) will have biomarker samples collected at both time of 
relapse and their subsequent final visit at discontinuation of venetoclax.
Blood for CD19 Isolation Bcl-2 Family Analysis samples will be processed and shipped 
to the central laboratory from the site per the current laboratory manual.
Blood for FISH for Detection of 17p Deletion
In order to determine subject eligibility, sites may use their local laboratory to test for 
17p deletion in either bone marrow or peripheral blood or provide results previously 
obtained.  For sites that are unable to test locally, the confirmatory sample (peripheral 


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blood) sent to the central laboratory, as described below, may be used to determine 
eligibility.  The results will be provided to the site within 5 to 7 business days.
A confirmatory sample will be collected from all subjects and will be processed by the 
central laboratory.  Approximately 4 mL of blood will be collected by venipuncture into 
an appropriately labeled Sodium Heparin vacutainer at the following time point:
●
Screening
Central Laboratory 17p Deletion Testing Information
17p deletion status is defined using FISH cytogenetic testing, as recommended in ESMO 
guidelines.26  The detection of 17p del, identified by loss of TP53 locus, will be 
determined by FISH study using the Vysis CLL probe kit,36 which is an IUO/PEO labeled 
test assessed by a central laboratory.
The kit uses FISH DNA probe technology to determine deletion status of probe targets for 
locus-specific identifier (LSI) including LSI- TP53 (containing tumor protein p53gene, 
located on the short arm of chromosome 17 (17p).  LSI TP3 probe, approximately 
172 Kilobases in length, is located at 17p13.1 and contains the complete TP53 gene.  A 
normal/abnormal determination for LSI TP53 probe is made by comparing the number of 
nuclei observed (per 200 scoreable nuclei) with the abnormal signal pattern to the normal 
cut-off value, which is > 7% (defined as 14 nuclei observed per 200 nuclei scoreable).36
FISH for Detection of 17p Deletion samples will be processed and shipped directly to the 
testing laboratory from the site per the current laboratory manual.
Bone Marrow Aspirate Bcl-2 Protein Analysis
Approximately 1 mL of bone marrow aspirate will be collected and placed into a sodium 
heparin vacutainer.  Bone marrow aspirate must be split for this analysis from samples 
obtained for 2008 Modified IWCLL NCI-WG Guidelines for Tumor Response whenever 
feasible, but should not require the subject to undergo a second bone marrow collection if 
sample is insufficient.  Samples should be collected at the following time points:


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●
Screening or Week 1 Day 1 pre-dose
●
Final Visit/Time of Relapse
Note:  Subjects with PD who continue to receive treatment per the discretion of the 
investigator (per Section 5.4.1) will have biomarker samples collected at both time of 
relapse and their subsequent final visit at discontinuation of venetoclax.
Bone Marrow Aspirate Bcl-2 Protein Analysis samples will be processed and shipped 
directly to the central laboratory from the site per the current laboratory manual.
Bone Marrow Aspirate for CD19 Isolation
Approximately 6 mL of bone marrow aspirate each will be collected and placed into a 
6 mL ACD vacutainer.  Bone marrow aspirate must be split for this analysis from samples 
obtained for 2008 Modified IWCLL NCI-WG Guidelines for Tumor Response whenever 
feasible, but should not require the subject to undergo a second bone marrow collection if 
sample is insufficient.  Samples should be collected at the following time points:
●
Screening or Week 1 Day 1 pre-dose
●
Final Visit/Time of Relapse
Note:  Subjects with PD who continue to receive treatment per the discretion of the 
investigator (per Section 5.4.1) will have biomarker samples collected at both time of 
relapse and their subsequent final visit at discontinuation of venetoclax.
Bone Marrow Aspirate for CD19 Isolation will be processed and shipped to the central 
laboratory from the site per the current laboratory manual.
Tissue from Subjects with Richter's Transformation
Formalin-fixed core needle biopsies will be obtained for all subjects in the study whose 
CLL has undergone Richter's transformation.  Biopsies will be performed on readily 
accessible lymph node tissue at the following time point:


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●
Time of Relapse (when Richter's transformation is confirmed)
The needle biopsy should be at least 18 gauge in diameter and at least 1 cm in length.  It is 
estimated that there will be between 2 to 5 million cells from each biopsy.  The biopsy 
may be processed according to the institutional standard procedures or per the most 
current version of the laboratory manual for this study.  If a procedure other than what is 
described in the most current version of the Laboratory Manual for this study is used, a 
description of the procedure should be provided to AbbVie.
5.3.1.5.2
Optional Collections
Tissue for IHC and FISH
●
Screening or Week 1 Day 1 pre-dose
●
Final Visit/Time of Relapse, when feasible
Note:  Subjects with PD who continue to receive treatment per the discretion of the 
investigator (per Section 5.4.1) will have biomarker samples collected at both time of 
relapse and their subsequent final visit at discontinuation of venetoclax.
Either archived diagnostic formalin fixed paraffin embedded (FFPE) tissue blocks and/or 
formalin fixed core needle biopsy should be completed at Screening for all subjects who 
provide consent.  A formalin-fixed core needle biopsy should be completed at the Final 
Visit or time of disease progression for all subjects who have consented.  Tissue specimen 
for IHC and FISH testing should be split from samples obtained for 2008 Modified 
IWCLL NCI-WG Guidelines for Tumor Response whenever possible.
Formalin Fixed, Paraffin Embedded Samples (Archived Tissues are Acceptable at 
Screening Only)
Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and/or nucleic 
acid analysis, for example, quantitative polymerase chain reaction (qPCR), or micro RNA 
quantitation may be performed on tissue slides from archived, diagnostic, formalin fixed, 
paraffin embedded FFPE tissue blocks from all subjects who consent in the study.


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The tissue may be processed according to the institutional standard procedures or per the 
most current version of the Laboratory Manual for this study.  If a procedure other than 
what is described in the most current version of the Laboratory Manual for this study is 
used, a description of the procedure should be provided to AbbVie.
Core Needle Biopsy – Formalin Fixed (Prior to Therapy if FFPE Block is Not 
Available or if Investigator Prefers; and at Time of Disease Progression)
Formalin-fixed core needle biopsies will be obtained prior to therapy and at time of 
disease progression, when feasible, for all subjects in the study who consent and who have 
readily accessible tumor tissue.  Biopsies will be performed after consent, prior to study 
drug administration and again after the subject has progressed on therapy.
The needle biopsy should be at least 18 gauge in diameter and at least 1 cm in length.  It is 
estimated that there will be between 2 to 5 million cells from each biopsy.  The biopsy 
may be processed according to the institutional standard procedures or per the most 
current version of the Laboratory Manual for this study.  If a procedure other than what is 
described in the most current version of the Laboratory Manual for this study is used, a 
description of the procedure should be provided to AbbVie.  
Recollection of biopsy samples prior to the first dose of venetoclax may occur as 
necessary due to technical failures, inadequate sampling in screening, etc.
Tissue for IHC and FISH should be shipped to the central laboratory from the site per the 
current laboratory manual.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples (3 mL) for venetoclax (and possible metabolite[s]) assay will be collected 
in K2EDTA containing tubes by venipuncture in appropriately labeled tubes at the 
following times:
●
Week 1 Day 1:  8 hour post dose


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●
Week 2 Day 1:  8 hour post dose (if escalation to a new dose level)
●
Week 3 Day 1:  8 hour post dose (if escalation to a new dose level)
●
Week 4 Day 1:  8 hour post dose (if escalation to a new dose level)
●
Week 5 Day 1:  8 hour post dose (if escalation to a new dose level)
●
Week 8 Day 1:  0 hour (pre-dose)
●
Week 12 Day 1:  0 hour (pre-dose)
●
Week 16 Day 1:  0 hour (pre-dose)
●
Week 24 Day 1 and Day 1 of every 12 weeks thereafter:  0 hour (pre-dose)
A total of up to 9 blood samples (approximately 27 mL) will be collected per subject up to 
Week 24.  After Week 24, additional blood samples will be collected from each subject 
pre-dose at Day 1 of every 12 weeks.  The PK collection performed 8 hours post-dose 
after each dose escalation may be taken up to 1 hour prior or up to 20 minutes after to 
allow for processing, if necessary.
Refer to Table 5 for a schedule of the blood collection for venetoclax (and possible 
metabolite[s]) assay during the study.
The date and time of each blood sample collection will be recorded to the nearest minute 
on the eCRF.  The date and time (to the nearest minute) of each venetoclax dose and 
whether or not the venetoclax dose was taken within 30 minutes after the completion of 
breakfast (or subject's first meal of the day) will be recorded on the scheduled venetoclax 
PK days and for the 2 days prior to every scheduled venetoclax PK day (with the 
exception of Week 1 Days 1 and 2 where no medication is given the 2 days prior to 
dosing).  In addition, on the scheduled venetoclax PK draws days, the subject's meal 
content will be captured on the day of venetoclax first dose and days where venetoclax 
dose escalation to a new dose level has occurred.  Sites will ensure that all information is 
captured through source documents (e.g., subject calendar/diary provided by AbbVie).


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5.3.2.2
Handling/Processing of Samples
Blood and plasma samples must be protected from direct sunlight during collection, 
processing and storage.  Immediately after collection, the blood samples for venetoclax 
will be inverted 8 to 10 times to ensure good mixing of the blood and anticoagulant, and 
will be placed in an ice bath.  The blood samples will be centrifuged using a refrigerated 
centrifuge (2° to 8°C) to separate the plasma at 1100 to 1600 × g for approximately 10 to 
15 minutes.  The plasma samples will be transferred using plastic pipettes into 
screw-capped polypropylene tubes (cryovials) labeled with the drug number name, assay 
type, type of sample (plasma), the protocol number, the subject number, the study week 
and day, and the planned time of sampling relative to dosing and then frozen at –20°C or 
colder.  The entire process should be completed within one hour of draw.  Samples should 
be maintained at –20°C or colder until shipped to the central laboratory.
5.3.2.3
Disposition of Samples
The frozen plasma samples for venetoclax (and possible metabolite[s]) assay will be 
packed in dry ice sufficient to last during transport and shipped from the study site to the 
central laboratory according to instructions included in the Laboratory Manual for this 
study.  An inventory of the samples included will accompany the package.  The central 
laboratory will be responsible for shipping the plasma samples to AbbVie or designated 
laboratory for testing.
5.3.2.4
Measurement Methods
Plasma concentrations of venetoclax (and possible metabolite[s]) will be determined 
under the supervision of the Drug Analysis Department at AbbVie.
5.3.3
Efficacy Variables
The primary objective of the main cohort is to evaluate the efficacy of venetoclax 
monotherapy in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) 
harboring the 17p deletion.  Efficacy will be measured by overall response rate (ORR).  
The secondary objectives are to evaluate CR, PR, duration of overall response, determine 


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progression-free survival (PFS), event free survival, time to progression (TTP), time to 
first response, time to 50% reduction in ALC, overall survival (OS) and percent of 
subjects who move on to stem cell transplant.
For the safety expansion cohort in subjects with relapsed/refractory or previously 
untreated chronic lymphocytic leukemia (CLL) harboring the 17p deletion, efficacy will 
be considered a secondary endpoint.  The secondary objectives are to evaluate ORR, CR, 
PR, duration of overall response, determine progression-free survival (PFS), event free 
survival, time to progression (TTP), time to first response, time to 50% reduction in ALC, 
overall survival (OS), and percent of subjects who move on to stem cell transplant.
Analyses of these endpoints are described in Section 8.0.
5.3.3.1
2008 Modified IWCLL NCI-WG Guidelines for Tumor 
Response
For disease assessments, response will be assessed by the investigator based on analysis 
of clinical laboratory tests (hematology laboratory values), complete physical 
examination, contrast-enhanced CT scan of involved anatomic regions, bone marrow 
aspirate and biopsy.  If a contrast-enhanced CT is medically contraindicated (e.g., subjects 
with an allergy to CT contrast agents or subjects with impaired renal clearance), a 
contrast-enhanced MRI of all involved anatomical regions plus a non-contrast CT of the 
chest should be done.  Subjects will be evaluated against the 2008 Modified IWCLL 
NCI-WG Guidelines for Tumor Response34 with the addition of CT imaging (or MRI).
At Screening, all measurable disease must be documented by laboratory testing 
(hematology laboratory values), physical examination, CT scan, and bone marrow.  All 
baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment with the 
exception of the CT scan and bone marrow biopsy and aspirate which must be completed 
within 5 weeks before the beginning of the treatment.  All other tumor assessments after 
baseline should be performed within 7 days after the scheduled visit.


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Beginning at Week 5 Day 1, disease response will be assessed by the investigator based 
on the analysis of clinical laboratory tests and a complete physical examination.  When a 
response (PR or CR) is determined by clinical criteria (laboratory tests and physical exam) 
at any time during the study, a CT scan must be performed no earlier than 8 weeks later to 
confirm clinical response.  If the CT scan confirms a CR, then a BM biopsy is required as 
soon as possible for confirmation of CR.  For determination of CR, both the CT scan and 
bone marrow are required to be negative.
A CT scan should also be performed at 36 weeks for all subjects.  This scan may be 
performed within 4 weeks before or after the 36 week scheduled visit provided that it has 
been at least 8 weeks since the subject's last scan.  For subjects whose response meets 
criteria for a PR at the time of the Week 36 CT scan, an additional CT scan should be 
performed (no earlier than 8 weeks following the Week 36 scan) if a subsequent clinical 
disease assessment indicates that a CR or CRi has been achieved.
If a subject exhibits clinical signs of possible disease progression (i.e., increased or 
de novo enlargement of liver, spleen or lymph nodes on physical examination) without an 
increase in lymphocytes meeting PD criteria, then additional assessments including 
contrast-enhanced CT scan and/or bone marrow must be performed within 2 weeks to 
confirm or rule out PD.
Methods of Measurement
Disease response and progression will be assessed by analysis of peripheral blood, clinical 
examination, radiographic techniques 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 5.3.1.1, Study Procedures.


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A physical examination should be performed to assess the extent of disease involvement.  
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., palpable lymph nodes).  The diameter, in two planes, of the largest palpable nodes in 
each of the following sites should be measured:  cervical, supraclavicular, axillary, 
inguinal, and femoral.  Evaluation for the presence of hepatomegaly and splenomegaly 
should be performed.
The 12 largest bi-dimensional lesions should be recorded in the eCRF.
●
Target Lesions:  A maximum of 12 target lesions may be selected (up to 
6 nodal and 6 extranodal).  Target nodal lesions must be abnormal (> 1.5 cm in 
LDi at baseline), clearly measurable and suitable for consistent, reproducible 
measurement in at least two perpendicular dimensions.  Target extranodal 
lesions must be > 1 cm in two perpendicular diameters at baseline. 
●
Non-Target Lesions:  A maximum of 10 non-target lesions can be selected.  
Non-target nodal lesions must be abnormal (> 1.5 cm in LDi at baseline).  
Non-target extranodal lesions must be > 1 cm in two perpendicular diameters.  
Nodal and extranodal lesions that were not selected as target lesions at baseline 
can be followed as non-target lesions.
Computed tomography (CT) is the preferred method to measure lesions selected for 
response assessment.  Contrast-enhanced CT scans with anatomical coverage of the neck, 
chest, abdomen, and pelvis should be performed.  CT scans for response assessment may 
be limited to areas of prior involvement only, if required by local regulatory authorities.  
Contrast-enhanced magnetic resonance imaging (MRI) scans with anatomical coverage of 
the neck, chest, abdomen, and pelvis plus a non-contrast CT scan of the chest may be used 
if CT is medically contraindicated (e.g., severe contrast allergy).  Whichever scanning 
method was used at baseline must be used during follow-up.  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.


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For accurate overall response evaluation, ultrasound (US) or PET scans should not be 
used to measure tumor lesions.
Details on bone marrow biopsy and aspirate are provided in Section 5.3.1.1, Study 
Procedures.
In addition to being reviewed by the investigator and/or site staff, an independent review 
will be performed to assess tumor response and disease progression.  Clinical criteria and 
radiographic scans will be evaluated using the 2008 Modified IWCLL NCI-WG 
Guidelines for Tumor Response (refer to Table 8).  The independent review facility will 
provide instructions regarding the preparation and shipment of the data.  Interpretations 
from the independent review will not be sent to the site.  Subject treatment management 
will be based on review by the local investigator and/or site staff.
Disease 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 (absence of 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) and CT scan (if abnormal prior 
to therapy or if physical exam is inconclusive at the time of evaluation)
●
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)


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○
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 as soon as possible after CR/CRi has been 
achieved by laboratory tests, physical exam and CT scan.  If the bone marrow 
is hypocellular, a repeat determination should be made in 4 weeks or when 
peripheral blood counts have recovered.  A marrow biopsy should be 
compared to a pre-treatment marrow if available.  Subjects who are otherwise 
in a complete remission, but bone marrow nodules can be identified 
histologically should be considered to be nodular PR (nPR).  
Immunohistochemistry should be performed to define whether these nodules 
are composed of primarily T cells or lymphocytes other than CLL cells, or 
CLL cells.
Complete Remission with Incomplete Marrow Recovery (CRi)
Subjects who fulfill the criteria for CR (including bone marrow) but who have persistent 
cytopenia (anemia or thrombocytopenia or neutropenia) apparently unrelated to CLL but 
related to drug toxicity will be considered CRi.  The marrow evaluation described above 
should be performed with scrutiny and not show any clonal infiltrate.
Partial Remission (PR)
To be considered a PR at least 2 of the following must be met:
●
≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment
baseline value.
●
≥ 50% reduction in lymphadenopathy.
●
≥ 50% reduction in the enlargement of the liver and/or spleen (if abnormal 
prior to therapy).


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In addition at least one of the following criteria must be met:
●
Neutrophils ∀1,500/#L or ≥50% improvement over baseline.
●
Platelets > l00,000/#L or ≥ 50% improvement over baseline.
●
Hemoglobin > 11.0 g/dL or ≥ 50% improvement over baseline without 
transfusions or exogenous growth factors.


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Table 8.
2008 Modified IWCLL NCI-WG Guidelines 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,e
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%f
Blood Lymphocytes
< 4000/μL
Decrease ≥ 50% from 
baseline
Increase ≥ 50% 
over nadir 
(≥5000/μL)d
Change of –49% to 
+49%
Hepatomegalyg
None
Decrease ≥ 50%
Increase ≥ 50%h
Change of –49% to 
+49%
Splenomegalyg
None
Decrease ≥ 50%
Increase ≥ 50%h
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/μLi
> 100,000/μL or increase 
≥ 50% over baselinei
Decrease of ≥50% 
from baseline 
secondary to CLLe
Change of –49% to 
+49%
Hemoglobin
> 11.0 g/dLi
> 11.0 g/dL or increase 
≥50% over baselinei
Decrease of 
> 2 g/dL from 
baseline secondary 
to CLLe
Increase to 
≤11.0 g/dL over 
baseline, or 
decrease < 2 g/dL
Neutrophils
> 1500/μLi
> 1500/μL or increase 
≥50% over baselinei
Decrease ≥ 50% 
from baseline 
secondary to CLLe
N/A


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Table 8.
2008 Modified IWCLL NCI-WG Guidelines 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,e
Stable Disease 
(SD) All Criteria 
Must be Met
Other Considerations
New Lesions
None
None
Appearance of new 
palpable lymph nodes 
(> 1.5 cm in longest 
diameter) or any new 
extra nodal lesion 
(> 5 mm) or 
transformation to a 
more aggressive 
histology, e.g., 
Richter Syndromed
None
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.  For lymphocyte only, an increase of ≥ 50% AND a value of ≥ 5000 μL are 
necessary to define PD.


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Table 8.
2008 Modified IWCLL NCI-WG Guidelines for Tumor Response 
(Continued)
e.
Worsening of cytopenias cannot define PD unless a bone marrow biopsy is performed to show unequivocal 
progression.
f.
Sum products of up to 12 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.
g.
If enlarged before therapy.
h.
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.
i.
Without the need for exogenous growth factors or transfusions.
To be assigned a status of PR, the response must be confirmed no earlier than 8 weeks 
after the clinical criteria for response are first met.
5.3.3.2
Definition of Disease Progression
Disease progression according to 2008 Modified IWCLL NCI-WG Guidelines for Tumor 
Response is characterized by at least one of the following:
●
Appearance of any new lesion, such as enlarged lymph nodes (> 1.5 cm), 
splenomegaly, hepatomegaly, or other organ infiltrates.  An increase by 50% 
or more in greatest determined diameter of any previous site and > 1.5 cm.
●
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 established 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 only if confirmed by a bone marrow assessment showing 
unequivocal progression.


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5.3.3.3
Definition of Stable Disease
Patients who have not achieved a CR or a PR, or who have not exhibited PD, will be 
considered to have stable disease.
5.3.4
Safety Variables
The following safety evaluations will be performed during the study:  adverse event 
monitoring, vital signs, physical examination, ECG, and laboratory assessments.
5.3.5
Pharmacokinetic Variables
Values for the PK parameters of venetoclax, including the apparent clearance (CL/F), and 
the apparent volume of distribution (V/F), may be determined using a population PK 
approach.  Additional parameters may be calculated if useful in the interpretation of the 
data.
5.3.6
Pharmacogenetic Variables
DNA samples may be analyzed for genetic factors contributing to the subject's response to 
venetoclax in terms of pharmacokinetics, efficacy and safety.  Such genetic factors may 
include, for example, drug metabolizing enzymes, drug transport proteins, CLL 
prognostic markers and Bcl-2 family members.  Some genes currently insufficiently 
characterized or unknown may be understood to be important at the time of analysis.  
These samples may be analyzed as part of a multicenter, multi-study project to identify 
genetic factors involved in the response to study drugs.  The samples may also be used for 
the development of diagnostic tests related to venetoclax (or drugs of this class).  The 
results of pharmacogenetic analyses may not be reported with the study summary.
5.3.7
Biomarker Variables
Several putative biomarkers of efficacy and response may be evaluated in this protocol 
with the goal of defining the relationship between various disease markers and disease 
status.  Biospecimens collected during the course of this study may be banked and used in 
the future to investigate new scientific questions related to this study.  The samples may 


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also be used for diagnostic test development.  AbbVie (or a designated laboratory) will 
store the samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on venetoclax (or drugs of 
this class) continues but no longer than 20 years.
Examination of the serum components of subjects on this venetoclax clinical trial may 
reveal patterns of cell-free nucleic acids, proteins/peptides or metabolites that may be 
further evaluated in future clinical studies to determine any prognostic value and any 
correlation with clinical response.  Serum samples may also be analyzed for predictive or 
drug-responsive markers.  In the event that any serum samples are unused, remaining 
samples may be banked for use in diagnostic test development efforts.
DNA methylation regulates gene expression (inactivates certain genes and their normal 
role); aberrant methylation of specific genes is associated with cancer development and 
poor clinical outcome.  Genes with variable methylation status that are known to have 
prognostic implications may be assessed in the trial.  These analyses may examine 
putative stratification markers for correlation for efficacy.
Venetoclax inhibits the ability of cancer cells to evade cell death, or apoptosis, by 
blocking the activity of the anti-apoptotic protein Bcl-2.  Nonclinical studies have 
demonstrated a pattern of response to venetoclax based on the levels of Bcl-2 family 
proteins.  High levels of Bcl-2 and low levels of Mcl-1 and Bcl-XL are generally 
predictive of response to this drug in vitro.  Therefore, the proteins levels of relevant 
BCL-2 family members may be determined in tumor cells isolated from the bone marrow 
aspirate and examined for correlations with efficacy.
Genetic amplification, chromosomal loss and/or mutational/methylation status of various 
genes represent genetic lesions potentially associated with subject outcome.  Nucleic 
acids, protein expression, and/or mutational/methylation analysis may be conducted on 
CLL cells isolated from blood, bone marrow and/or tumor tissue samples and/or 
DNA/RNA extracted from serum from subjects participating in this study.  Analysis of 
the nucleic acids can be used to identify and track the CLL cells for MRD.  The analysis 


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may include but is not limited to members of the BCL-2 family, p53, Notch-1 and other 
genes/proteins that may be informative to venetoclax mechanism of action or CLL disease 
progression.  Additionally, comprehensive genomic sequencing of CLL cells isolated 
from the blood or bone marrow aspirate may also be performed.  FISH may be conducted 
on tissue from tumor samples and/or CLL cells from subjects participating in this study to 
assess amplifications and translocations in the Bcl-2 gene and other alteration in genes 
associated with CLL, which may prove to be informative.  The potential relationship 
between amplification/loss/mutation/methylation of these genes and the clinical outcome 
in these subjects may be examined as a subject stratification tool.  Biospecimens collected 
during the course of this study may be banked and used in the future to investigate new 
scientific questions related to this study.
5.3.8
Health Economic and Patient-Reported Outcome Measures
MDASI
The MDASI is a multi-symptom PRO measure for clinical and research use.  The 
M.D. Anderson Symptom Inventory37 contains 13 core symptom severity items (pain, 
fatigue, nausea, disturbed sleep, distess [emotional], shortness of breath, lack of appetite, 
drowsiness, dry mouth, sadness, vomiting, difficulty remembering, and numbness or 
tingling), 6 symptom interference items (general activity, mood, walking ability, normal 
work, relations with other people, and enjoyment of life), and 5 chronic lymphocytic 
leukemia specific items (abdominal pain, lymph node pain, night sweating, 
fevers/temperature fluctuation, and frequent infections).
Mean symptom, symptom interference, domain and total scores will be calculated for 
each observation as defined in the MDASI scoring manual and then summarized (mean, 
std. dev., median) at each assessment; in addition mean change in each of these values 
(final assessment versus baseline) will be calculated to identify any statistically significant 
differences versus baseline.38,39


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EORTC QLQ-C30 and EORTC QLQ CLL16
The EORTC QLQ-C30 consists of a Global Health Status/QoL scale, a Financial 
Difficulties scale, five Functional scales (Cognitive Functioning, Social Functioning, 
Physical Functioning, Emotional Functioning, and Role Functioning), and eight Symptom 
scales/items (Fatigue, Insomnia, Appetite Loss, Pain, Constipation, Diarrhea, Dyspnea, 
and Nausea and Vomiting).
Each of these domains will be calculated as per the EORTC scoring manual, and 
summarized (mean, std. dev., median) at each assessment; in addition mean change in 
each of these values (final assessment versus baseline) will be calculated to identify any 
statistically significant differences versus baseline.
The five EORTC QLQ CLL16 domains (Fatigue, Treatment Side Effects and Disease 
Symptoms, Infection, Social Activities, Future Health Worries) will be summarized 
(mean, std. dev., median) at each assessment; in addition mean change in each of these 
values (final assessment versus baseline) will be calculated to identify any statistically 
significant differences versus baseline.40
EQ-5D-5L and EQ-5D-VAS
The EuroQol 5 Dimensions (EQ-5D-5L) is a generic preference instrument that has been 
validated in numerous populations.  The EQ-5D-5L has five dimensions:  mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. These dimensions are 
measured on a five level scale:  no problems, slight problems, moderate problems, severe 
problems, and extreme problems.  The EQ-5D-5L also contains a visual analog scale 
(VAS) to assess the subject's overall health.41
Each of the five dimensions of the EQ-5D-5L, the Visual Analog Scale (VAS) and overall 
utility score will be calculated using the EuroQol scoring manual, and summarized (mean, 
std. dev., median) at each assessment; in addition mean change in each of these values 
(final assessment versus baseline) will be calculated to identify any statistically significant 
differences versus baseline.41


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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator will discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason including:
●
The subject's response to therapy is unsatisfactory, as evidenced by 
progression of disease while on study drug;
●
The subject requires radiotherapy, cancer-related surgery as a result of tumor 
progression, or alternate anti-neoplastic agents during the study period;
●
Noncompliance with the protocol.
Subjects with disease progression may continue to receive treatment when, in the opinion 
of the investigator, it is in the subject's best interest to stay on drug.  Disease progression 
will be captured in EDC per modified IWCLL NCI-WG criteria as described in 
Section 5.3.3.2 of the protocol.  The patient will be monitored per study procedures 
described in Section 5.3.1.1 or more often if the investigator considers it necessary.
Subjects with disease progression who continue to receive venetoclax will also be allowed 
to receive other agents approved to treat CLL in addition to venetoclax.  This will be 
added at the discretion of the investigator, and AbbVie or its partners will not reimburse 
for treatment agents or for the procedures required to monitor subjects other than those 
required per protocol.
The investigator will inform AbbVie prior to discontinuing a subject from the study by 
contacting the Clinical Team Leader as identified in Section 6.2.  All subjects will be 
included for analysis of safety data.  Subjects who withdraw from the study will not be 
replaced.


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In the event that a subject withdraws or is discontinued from the study, the reason(s) for 
the discontinuation from the study will be recorded.  Final visit procedures as listed in 
Table 4 will be performed as soon as possible after discontinuation from the study.
At the end of the subject's participation in the study, the calendars/diaries are to be 
returned to the site and appropriately filed with the subject's source documents for this 
study.
A Safety Follow-Up Visit should be performed for all subjects approximately 30 days 
following discontinuation of study drug and then as clinically appropriate for safety 
assessment.  The subject will be followed until a satisfactory clinical resolution of the 
adverse event is achieved.
A separate Safety Follow-Up Visit does not need to be performed for subjects who had a 
Final Visit conducted > 30 days after discontinuation of study drug and did not require 
additional adverse event follow-up.  If the subject refuses or is unable to attend the Safety 
Follow-Up Visit, this should be noted in the subject's source documentation.
For subjects who discontinue venetoclax (e.g., due to toxicity or stem cell/bone marrow 
transplant), post-treatment follow-up visits will be performed every 3 months until 
discontinuation from the study.  Post-Treatment follow-up visits are not required for 
subjects who have discontinued due to disease progression or a subject's refusal of the 
Post-Treatment visits.  This will be for a period of up to 5 years after the last subject has 
enrolled on the study.
Survival information (i.e., the date and cause of death, post treatment cancer therapies, 
etc.) will be collected via telephone calls and/or clinical visits at 3 month intervals after 
the last study visit for a period of 5 years after the last subject has enrolled on the study 
for subjects who have not withdrawn consent.  Additionally, information regarding 
Richter's Transformation and second primary malignancies will also be collected during 
this period for subjects who have not withdrawn consent.


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In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the study, the administration of study drug must be 
discontinued immediately.  The investigator must report a pregnancy within 1 working 
day of the site being aware to one of the AbbVie representatives listed in Section 6.1.6 or 
Section 6.2.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.
If, in the judgment of the investigator and AbbVie, the continued exposure to the study 
drug represents a significant risk to subjects, the study will be stopped.  The following 
procedures for discontinuation will be followed:
●
If the sponsor has decided to prematurely discontinue the study, the sponsor 
will promptly notify in writing the investigator as well as regulatory authorities 
of the decision and give detailed reasons for the discontinuation.
●
The investigator must promptly notify the IEC/IRB and give detailed reasons 
for the discontinuation.
●
The investigator must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments such as replacement of 
the treatment regimen, if applicable, by other appropriate regimens.
5.5
Treatments
5.5.1
Treatments Administered
Each dose of venetoclax will be taken with approximately 240 mL of water within 
30 minutes after the completion of breakfast or the subject's first meal of the day.


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If the subject vomits after taking venetoclax, no additional dose should be taken that day 
and the next dose should be taken at the usual time the next day.  Any dose of venetoclax 
can be given up to 8 hours after its usual time, in which case the following day's dose 
should be taken at the usual time.  If a dose of venetoclax is missed by more than 8 hours, 
the dose should not be taken that day, and should not be made up.  The next dose should 
be taken at the usual time the next day.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 9.
Table 9.
Identity of Investigational Product
Study Drug
Trademark
Formulation
Route of 
Administration
Manufacturer
Venetoclax (ABT-199)
N/A
10 mg Tablet
Oral
AbbVie/Abbott
Venetoclax (ABT-199)
N/A
50 mg Tablet
Oral
AbbVie/Abbott
Venetoclax (ABT-199)
N/A
100 mg Tablet
Oral
AbbVie/Abbott
5.5.2.1
Packaging and Labeling
The venetoclax tablets will be packaged in high density polyethylene (HDPE) plastic 
bottles or blister packs to accommodate the study design.  Each container will be labeled 
per local regulatory requirements.
Blister Packs will contain study drug for one week plus one extra day.  Subjects will be 
instructed to take the extra day's dose (noted with an "X" on the Blister Pack) only if 
directed by the investigator.
5.5.2.2
Storage and Disposition of Study Drug
The investigational products supplied in this study are for investigational use only, and are 
to be used only within this study.  All clinical supplies must be maintained under adequate 
security and stored under conditions specified on the label.


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The tablets must be stored at 15° to 25°C (59° to 77°F).
5.5.3
Method of Assigning Subjects to Treatment Groups
There is no randomization schedule for this study.  Subjects will be assigned a unique 
consecutive subject number at Screening.  In the main cohort, subject numbers will 
consist of 5 digits (XXX01), with the first three digits denoting site number and the last 
2 digits as the subject number, beginning with 01.  In the safety expansion cohort, subject 
numbers will also consist of 5 digits (XXX50), with the first three digits denoting site 
number and the last 2 digits as the subject number, beginning with 50.  All subjects will 
be enrolled using an IxRS.  Before the study is initiated, each site will be provided with 
the IxRS user instructions, which provides direction on how to use the IxRS via the Web 
or the telephone.  Since this is an open-label study, subjects will maintain the same 
subject number regardless of the number of re-screens and through the duration of the 
study.  The site, in conjunction with the 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
Selection of the dose for this study is discussed in Section 5.6.4.  Each dose of venetoclax 
will be taken with approximately 240 mL of water.  On days that pre-dose PK sampling is 
required, dosing will occur in the morning to facilitate PK sampling.  On all other dosing 
days subjects will be trained to self-administer venetoclax orally QD within 30 minutes 
after the completion of breakfast or the subject's first meal of the day.
5.5.5
Blinding
This is an open-label, 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 


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the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
To document compliance with the treatment regimen, subjects will be instructed to return 
all unused tablets and/or containers, even if empty and any other study related items as 
necessary, to the study coordinator at scheduled study visits.  Compliance will be 
monitored and documented by the study coordinator on the appropriate form.  The study 
coordinator will question the subject regarding adherence to the dosing regimen, record 
the number of tablets and/or containers returned, the date returned and determine 
treatment compliance before dispensing new study drug to the subject.  Compliance below 
80% will require counseling of the subject by study site personnel.
5.5.7
Drug Accountability
Documentation of the receipt of supplies will be supported by a signed and dated Proof of 
Receipt or similar shipping document in IxRS.  A current (running) and accurate 
inventory of study drug will be kept by the site and will include lot number, Proof of 
Receipt number(s), container numbers, blister pack numbers, and the date on which study 
drug is administered to the subject.
An overall accountability of study drug will be performed and verified by AbbVie or the 
designated monitor(s) throughout the study and at the study site closeout visit.  Upon 
completion or termination of the study, all original containers (containing partially used or 
unused study drug) will be returned to AbbVie according to instructions from AbbVie or 
the designated monitor(s).  If pre-arranged between AbbVie and the site, destruction of 
used and unused study drug containers will be performed at the site.  Empty containers 
will be destroyed at the site.  Labels must remain attached to the containers.
5.6
Discussion and Justification of Study Design
There are currently no treatments approved and labeled specifically to meet the need of 
the 17p deletion population and currently available treatments for the broader CLL 
population, such as FCR and BR, are not adequate for this patient population.  Due to the 


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limited effectiveness of available therapies, treatment guidelines recommend enrollment 
in clinical trials as a preferred treatment option for patients with 17p deletion.  Those 
patients who achieve a response to initial therapy should be considered for an allogeneic 
transplant.  For relapsed/refractory patients not eligible for an allogeneic transplant, 
suggested regimens in cases where a clinical trial is not available include alemtuzumab; 
however, alemtuzumab has limited use due to its toxicity profile and its efficacy signals 
are more limited in subjects with bulky disease.
Untreated CLL patients who harbor the 17p deletion have generally a short first remission 
if they respond to conventional chemotherapy such as fludarabine, cyclophosphamide, 
and rituximab (FCR) and alemtuzumab, because 17p deletion is a prognostic marker for 
nonresponse to standard chemotherapy.  Thus, novel treatment strategies, which act 
independently of the p53 signaling pathway are needed.
Antiapoptotic Bcl-2 family members are associated with tumor initiation, disease 
progression, and drug resistance, and thus are compelling targets for antitumor therapy.  
Venetoclax is a first-in-class, orally bioavailable small molecule Bcl-2 family protein 
inhibitor that binds with high affinity to Bcl-2 and with lower affinity to other Bcl-2 
family proteins Bcl-XL and Bcl-w.  The mechanism of action of venetoclax is independent 
of the TP53 pathway.  Briefly, venetoclax inhibits Bcl-2 allowing the release of BIM, 
which includes oligomerization of pro-apoptotic molecules such as BAK and BAX.  This 
triggers rapid apoptosis, bypassing the TP53 pathway.
Preliminary data from the ongoing venetoclax first-in-human study, Study M12-175, had 
indicated a strong efficacy signal in oncology subjects. In the CLL Arm A, 56 subjects 
have been dosed with 54 evaluable. Best response reported for 54 evaluable subjects with 
CLL/SLL was 7 (13%) subjects with complete remission (CR) or CR with incomplete 
marrow recovery (CRi), 39 (72%) with partial remission (PR),4 (7%) with stable disease 
(SD), 0% with progressive disease (PD), and 4 (7%) subjects discontinued prior to 
Week 6. The response rate (CR + PR) was 85%.


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Sixteen (28.6%) of 56 subjects with relapsed/refractory CLL had a 17p deletion, as 
evaluated by FISH. Subjects with the 17p deletion remained on study for a median of 
159 days (range:  33 to 495 days).  Best response in all 16 CLL subjects with a 17p 
deletion was 1 (6%) subject with CR/CRi, 13 (81%) with PR, 1 with SD (6%), 0% with 
PD, and 1 (6%) discontinued prior to Week 6; the response rate was 88%.
Updated safety and efficacy data are described in detail in the Investigator Brochure.10
5.6.1
Discussion of Study Design and Choice of Control Groups
There are no control groups in this study.
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.
5.6.3
Suitability of Subject Population
Subjects with relapsed or refractory CLL who harbor 17p deletion will be selected to 
participate in the main cohort of this study.  In addition, subjects in the main cohort of the 
study must have 17p deletion, assessed by central laboratory and determined by FISH 
using the Vysis CLL probe kit.  Subjects must have relapsed or be refractory after 
receiving at least one prior treatment regimen.  Subjects with relapsed/refractory or 
previously untreated CLL who harbor 17p deletion will be selected to participate in the 
safety expansion cohort of this study.  Subjects in the Safety Expansion Cohort must have 
17p deletion, assessed by local laboratory or by central laboratory.  Pre-clinical and 
clinical findings support the possibility of efficacy in this patient population.  As CLL 
subjects with 17p deletion who relapse have very limited treatment options, it is 
appropriate to enroll such subjects in a clinical trial of an investigational agent.


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5.6.4
Selection of Doses in the Study
The dose of 400 mg was selected on the basis of preliminary data in relapsed/refractory 
CLL/SLL subjects from the ongoing venetoclax first-in-human Study M12-175.  
A time-to-response model and a logistic-regression model were developed using data 
from Study M12-175 to understand the relationship between the response outcome and 
the final target venetoclax dose.  Both models found that a faster response was achieved 
with a higher final target dose.  Further analysis focused on comparing 400 mg and 
600 mg as the final target dose showed a minimum difference on the overall response rate 
(i.e., percentage of subjects with partial response or better).  With doses below 400 mg 
QD, however, a longer (and clinically unfavorable) duration will be needed to achieve the 
same response rate.  Since there is no strong difference between 400 mg and 600 mg as 
the final dose, the 400 mg dose was selected as the minimum effective dose.  This 400 mg 
QD venetoclax dose has been deemed tolerable in Study M12-175.
To mitigate the risk for TLS, a step-wise lead-in period (up to 5 weeks) will be employed 
to escalate venetoclax dose to the treatment dose of 400 mg.
The maximum dose in this study is 400 mg, however currently the established maximum 
clinical dose of venetoclax is not to exceed 1200 mg/day for a duration not to exceed 
48 months based on genotoxicity studies.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.8.  For product complaints, please refer to Section 6.2.


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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 patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 


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medical intervention, meets protocol specific criteria (see Section 6.1.8 regarding toxicity 
management) and/or if the investigator considers them to be adverse events. 
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
A treatment-emergent adverse event is defined as any adverse event reported by a subject 
with onset or worsening from the time that the first dose of venetoclax is administered 
until 30 days have elapsed following discontinuation of study drug administration.
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.


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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).
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.
Hospitalization of a subject to allow observation and management (e.g., for IV hydration) 
for the purpose of TLS prophylaxis will not be captured as a serious adverse event (SAE), 
unless there is an additional reason for hospitalization or an additional criterion for 
seriousness other than hospitalization (e.g., abnormal post-dose TLS laboratories that 
necessitate therapeutic medical intervention, etc.).
Certain adverse events are anticipated to occur in the study population (CLL) at some 
frequency independent of drug exposure.  Such events include known consequences of the 
underlying disease under investigation (e.g., symptoms, disease progression) and events 
unlikely to be related to the underlying disease under investigation but common in the 


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study population independent of drug therapy (e.g., cardiovascular events in an elderly 
population).
These events are listed in Appendix E.
These adverse events may occur alone or in various combinations and are considered 
expected for reporting purposes for this protocol.
An Independent Data Monitoring Committee will monitor the incidence of these expected 
events during the study.  An aggregate report of any clinically relevant imbalances that do 
not favor the test product will be submitted to health authorities.
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 serious adverse event (as defined in Section 6.1.6).  For deaths related 
to disease progression (coded to malignant neoplasm progression), the date and cause of 
death will be recorded on the appropriate case report form, but the event will not be 
expedited as an individual case safety report (ICSR) to regulatory authorities.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4.0).42  If a reported adverse event increases in severity, the initial adverse event 
should be given final outcome date and a new adverse event must be reported to reflect 
the change in severity.  The dates on the AE's cannot overlap.  For all reported serious 
adverse events that increase in severity, the supplemental eCRFs also need to be updated 
to reflect any changes due to the increase in severity.  For adverse events not captured by 
the Common Terminology Criteria, the following should be used:


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Grade 1
The adverse event is transient and easily tolerated by the subject 
(mild).
Grade 2
The adverse event causes the subject discomfort and interrupts 
the subject's usual activities (moderate).
Grade 3
The adverse event causes considerable interference with the 
subject's usual activities and may be incapacitating (moderate to 
severe).
Grade 4
The adverse event is life-threatening requiring urgent 
intervention (severe).
Grade 5
The adverse event resulted in death of the subject (severe).
6.1.3
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 serious adverse event.


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6.1.4
Adverse Events Expected Due to Study Related Endpoints
6.1.4.1
Deaths
For this protocol, overall survival is an efficacy endpoint.  Deaths that occur during the 
protocol specified adverse event reporting period (see Section 6.1.6) that are more likely 
related to disease progression will therefore be an expected adverse event and will not be 
subject to expedited reporting.
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 only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without pre-existing 
heart disease, within 1 hour of the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the patient was last seen alive and stable.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should not be 
replaced by the established cause of death. 
6.1.4.2
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.
6.1.5
Adverse Event Collection Period
All adverse events (serious and nonserious) reported from the time of study drug 
administration until 30 days following discontinuation of study drug administration will 
be collected, whether elicited or spontaneously reported by the subject.


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Serious adverse events occurring after the study-specific informed consent is signed, but 
prior to the first dose of venetoclax, will be collected only if they are considered by the 
investigator to be causally related to the study-required procedures.
Adverse event information will be collected as shown in Figure 3.
Figure 3.
Adverse Event Collection
*
Only if considered by the investigator to be causally related to study required procedures.
6.1.6
Adverse Event Reporting
In the event of a serious adverse event, whether related to study drug or not, the 
investigator will notify Clinical Pharmacovigilance within 24 hours of the site becoming 
aware of the serious adverse event by entering the serious adverse event by email.
In the event of a serious adverse event, whether related to 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 
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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.
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 or any additional reports 
required by local regulations) to the IEC/IRB of any changes that affect the conduct of the 
study and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
6.1.7
Pregnancy
Pregnancy in a study subject must be reported to an AbbVie representative (Section 6.1.6
or Section 6.2) within 1 working day of the site becoming aware of the pregnancy.  
Subjects who become pregnant during the study must be discontinued (Section 5.4.1).
All subjects should be informed that contraceptive measures should be taken throughout 
the study and for 30 days after discontinuing study drug.  Male subjects should be 
informed that contraceptive measures should be taken by their female partner.  
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.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.


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6.1.8
Toxicity Management
6.1.8.1
Prophylaxis and Management of Tumor Lysis Syndrome
There is a potential for tumor lysis syndrome in subjects, affected by hematologic 
malignancies especially in those with bulky disease, elevated pretreatment lactate 
dehydrogenase (LDH) levels, elevated leukocyte count, renal dysfunction, and 
dehydration.
In response to the events of TLS reported in the Phase 1 studies in subjects with diagnosis 
of relapsed or refractory CLL treated with venetoclax monotherapy or in combination 
with an anti-CD20 antibody, an extensive review of the safety data was performed across 
all CLL trials in January of 2013.  These clinical data suggest that subjects with higher 
tumor burden are at increased risk of TLS.  Reduced creatinine clearance could further 
increase the risk among subjects with higher tumor burden.  Data analyses have resulted 
in development of three risk categories, listed below.  The risk category for an individual 
subject is determined upon study entry.
A detailed description of risk factors for developing tumor lysis following treatment with 
venetoclax is available in the current Investigator's Brochure.
The section below describes the management of subjects throughout dosing based on their 
risk factors for developing TLS identified upon study entry.
TLS Prophylaxis and Monitoring Checklist will be completed throughout the lead-in 
period to ensure proper TLS prophylaxis measures.
For tumor lysis syndrome prophylaxis, subjects have been classified in 3 risk categories 
based on the risk for developing medically concerning TLS with venetoclax 
administration.  The tumor burden assessed by the nodal disease and absolute lymphocyte 
count at screening has been used to define each category as described below:


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Risk Categories for Developing TLS
TLS Risk Category
Criteria
Low
All measurable lymph nodes with the largest diameter < 5 cm 
by radiologic assessment AND ALC < 25 × 109/L
Medium
Any measurable lymph node with the largest diameter ≥ 5 cm 
but < 10 cm by radiologic assessment OR ALC ≥ 25 × 109/L
High
Any measurable lymph node with the largest diameter ≥ 10 cm 
by radiologic assessment 
OR
ALC ≥ 25 × 109/L AND any measurable lymph node with the 
largest diameter ≥ 5 cm but < 10 cm by radiologic assessment
First Dose of Venetoclax at 20 mg and at 50 mg
Tumor lysis syndrome prophylaxis must be initiated in all subjects irrespective of their 
TLS risk category prior to the first dose of venetoclax at 20 mg and at 50 mg.  Tumor 
lysis syndrome prophylaxis includes:
●
An oral agent to reduce the uric acid level (e.g., allopurinol) to be initiated at 
least 72 hours prior to dosing.  Treatment may need to be continued for 
approximately 5 weeks based on the ongoing risk of TLS development.  
Subjects allergic to allopurinol must use another uric acid reducer.
●
Oral hydration consisting of fluid intake of 1.5 to 2 L per day starting at least 
48 hours prior to the start of treatment for all subjects prior to first dose and at 
all subsequent dose escalations and continued for at least 24 hours after dosing 
and all of the chemistries laboratory values remain within ULN.  Oral 
hydration is recommended beyond 24 hours post-dose for subjects who 
demonstrate any laboratory changes.  Oral hydration should be maintained, as 
tolerated, even during the days the subjects receive IV hydration.
●
Serum chemistry and hematology laboratory samples (low and medium risk 
subjects) must be drawn anytime within 72 hours prior to first dose at 20 mg 
and at 50 mg, and electrolyte values should be reviewed and not demonstrate 
any clinically significant abnormalities prior to the first dose of venetoclax in 


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order to keep the treatment on schedule.  The investigator's decision to proceed 
with venetoclax treatment initiation may be based on these laboratory values.
●
For subjects demonstrating any clinically significant laboratory abnormalities 
in this baseline laboratory assessment, the first dose of venetoclax at 20 mg 
and at 50 mg must be delayed until resolution and management of the 
laboratory abnormalities should be initiated, per the protocol Appendix D
(Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome [TLS]).  If needed, the subject should 
receive additional treatment prior to the initiation of dosing.
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS 
risk category as follows:
Low Risk Category
Subjects in the Low Risk category can begin the venetoclax lead-in period in the 
outpatient setting if there is no indication to hospitalize.
●
For subjects who are unable to maintain adequate oral hydration, IV hydration 
of 1.5 to 2 L is recommended in the outpatient setting on Day 1 of 20 mg and 
50 mg dose to assure this full amount of hydration is achieved.  In subjects for 
whom volume overload is considered a significant risk, hospitalization should 
be considered.
●
Chemistry and hematology laboratory tests are to be collected within 72 hours 
prior to the first dose of venetoclax at 20 mg and at 50 mg.  These laboratory 
values must be reviewed by the investigator.  The investigator's decision to 
proceed with venetoclax treatment initiation may be based on these laboratory 
values.
●
Chemistry laboratory tests must be performed by local laboratory STAT at 
0 hour (pre-dose, within 4 hours before venetoclax administration), 8, and 
24* hours post-dose after the first dose of venetoclax at 20 mg and at 50 mg.  
These laboratory values must be reviewed in real time by the investigator.  
0 hour (pre-dose) laboratory values will be collected and used as baseline to 
assess potential electrolyte abnormalities occurring post venetoclax 


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administration.  Results from 0 hour (pre-dose) laboratory values are not 
required to be available prior to initiating venetoclax treatment.  Subjects must 
remain at the hospital or clinic until the 8 hour laboratory values have been 
reviewed by the investigator.
●
Day 2 dose should not be administered until the 24 hours post-dose chemistry 
laboratory values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient setting.
●
If any significant laboratory changes are observed within the first 24 hours 
after initiation of dosing, see Appendix D, (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]) for additional laboratory assessments and management 
guidelines.  If aggressive correction of electrolytes abnormalities is performed, 
the subsequent dose of venetoclax can only be given when electrolytes have 
been stable without any more treatment for at least 24 hours.
○
Additional laboratory assessments may be performed per investigator 
discretion.
●
Hematology laboratory tests must be performed 0 hour (pre-dose, within 
4 hours before venetoclax administration), and 24* hours post-dose after the 
first dose of venetoclax at 20 mg and at 50 mg.
*
All 24 hours post-dose laboratory assessments may be taken within a 
2 hour window, if necessary.
Medium Risk Category
●
Subjects in Medium Risk category who have creatinine clearance ≥ 80 mL/min 
will receive their initial doses of venetoclax at 20 and 50 mg as outpatients. 
●
Subjects in the Medium Risk category who have creatinine clearance of 
< 80 mL/min and/or higher tumor burden (i.e., ALC > 100 × 109/L or multiple 
bulky nodes), may be handled as high risk subjects, per investigator discretion, 
for the first dose of venetoclax at 20 mg and 50 mg (Refer to section for high 
risk subjects below).


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●
Subjects in Medium Risk category (independently of their creatinine clearance 
and/or tumor burden) will receive IV hydration of 1.5 to 2 L in the outpatient 
setting on Day 1 of 20 mg and 50 mg dose.  In subjects for whom volume 
overload is considered a significant risk, hospitalization should be considered.
●
Chemistry and hematology laboratory tests are to be collected within 72 hours 
prior to the first dose of venetoclax at 20 mg and at 50 mg.  These laboratory 
values must be reviewed by the investigator.  The investigator's decision to 
proceed with venetoclax treatment initiation may be based on these laboratory 
values.
●
Chemistry laboratory tests must be performed by local laboratory STAT at 
0 hour (pre-dose, within 4 hours before venetoclax administration), 8, and 
24* hours after the first dose of venetoclax at 20 mg and at 50 mg.  These 
laboratory values must be reviewed in real time by the investigator.  0 hour 
(pre-dose) laboratory values will be collected and used as baseline to assess 
potential electrolyte abnormalities occurring post venetoclax administration.  
Results from 0 hour (pre-dose) laboratory values are not required to be 
available prior to initiating venetoclax treatment.  Subjects must remain at the 
hospital, or clinic, until the 8 hour laboratory values have been reviewed by the 
investigator.
●
Day 2 dose should not be administered until the 24 hours post-dose chemistry 
laboratory values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient setting. 
●
If any significant laboratory changes are observed within the first 24 hours 
after initiation of dosing, see Appendix D, (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]) for additional laboratory assessments and management 
guidelines.  If aggressive correction of electrolytes abnormalities is performed, 
the subsequent dose of venetoclax can only be given when electrolytes have 
been stable without any more treatment for at least 24 hours.
○
Additional laboratory assessments may be performed per investigator 
discretion. 


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●
Hematology laboratory tests must be performed 0 hour (pre-dose, within 
4 hours before venetoclax administration), and 24* hours post-dose after the 
first dose of venetoclax at 20 mg and at 50 mg.
*
All 24 hour post-dose laboratory assessments may be taken within a 2 hour 
window, if necessary.
High Risk Category
Hospitalization and monitoring will begin the night before administration of the first dose 
of 20 mg and 50 mg of venetoclax and will continue until at least the 24 hour post-dose 
chemistry laboratory values are reviewed by the investigator.
●
Chemistry and hematology laboratory tests to be collected upon admission the 
night before first dose of venetoclax.  The investigator's decision to proceed 
with venetoclax treatment initiation will be based on these laboratory values.  
●
Nephrology (or other acute dialysis service) consultation should be considered 
upon admission per institutional standards at investigators' discretion to ensure 
emergency dialysis is available and the appropriate staff is aware and prepared 
to handle any necessary intervention for TLS.  Telemetry should also be 
considered.  
●
IV hydration must be started the night before first dose of 20 mg and again the 
night before the first dose of 50 mg, with a target of approximately
1.5 – 2 L/day, or as clinically appropriate, and continue for at least 24 hours 
after dose.
●
Rasburicase will be administered per regional standards or institutional dosing 
guidelines for subjects with elevated uric acid level at baseline (> ULN or 
> Cairo-Bishop threshold of 476 #mol/L) prior to the initial dose of venetoclax 
at 20 mg and 50 mg.  For subjects with a contraindication to rasburicase 
(i.e., glucose-6-phosphate dehydrogenase [G6PD] deficiency), the TLS 
risk-mitigation plan must be reviewed with AbbVie medical monitor.
●
Prophylactic reductions for potassium, inorganic phosphorus and/or uric acid 
above of normal range prior to dosing are recommended.
●
Chemistry laboratory tests must be performed by local laboratory STAT at 
0 (pre-dose, within 4 hours before venetoclax administration), 4, 8, 12 and 


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24* hours after the first dose of venetoclax at 20 mg and 50 mg.  These 
laboratory values must be reviewed in real time by the investigator.  0 hour 
(pre-dose) laboratory values will be collected and used as baseline to assess 
potential electrolyte abnormalities occurring post venetoclax administration.  
Results from 0 hour (pre-dose) laboratory values are not required to be 
available prior to initiating venetoclax treatment.  
●
Day 2 dose should not be administered until the 24 hours post-dose laboratory 
values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient setting.
●
If any significant laboratory changes are observed within the first 24 hours 
after initiation of dosing, see Appendix D, (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]), for additional laboratory assessments and management 
guidelines.  If aggressive correction of electrolytes abnormalities is performed, 
the subsequent dose of venetoclax can only be given when electrolytes have 
been stable without any more treatment for at least 24 hours.
○
Additional laboratory assessments may be performed per investigator 
discretion.
●
Hematology laboratory tests will be performed 0 hour (pre-dose, within 
4 hours before venetoclax administration), and 24* hours post-dose after the 
first dose of venetoclax at 20 mg and 50 mg.
*
All 24 hours laboratory assessments may be taken within 2 hour window, 
if necessary.
●
The 24-hour post-dose laboratory results must be reviewed by the investigator 
prior to the subject leaving the hospital.
First Dose of Venetoclax at Dose Escalation to 100 mg, 200 mg, and 400 mg
All subjects, irrespective of their risk category, must receive the following TLS 
prophylaxis measures prior to subsequent dose increases of venetoclax:
●
Continue administration of an oral uric acid reducer as indicated above.


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●
Oral hydration consisting of fluid intake of approximately 1.5 to 2 L/day 
starting at least 48 hours prior to each dose escalation and continued for at 
least 24 hours after the dose.  IV hydration is encouraged at subsequent dose 
escalations for subjects who are unable to maintain such oral hydration.  
IV hydration will be in the outpatient setting on the day of dose escalation.  In 
subjects for whom volume overload is considered a significant risk, 
hospitalization should be considered.  Oral hydration should be maintained, as 
tolerated, even during the days the subjects receive IV hydration.
●
Chemistry and Hematology laboratory tests for all subjects treated in the 
outpatient setting must be collected within 72 hours prior to the first dose of 
venetoclax of each dose escalation, and results must be reviewed by the 
investigator prior to each escalation. The investigator's decision to proceed 
with venetoclax treatment initiation may be based on these laboratory values.
●
For subjects demonstrating any clinically significant laboratory abnormalities 
in this baseline laboratory assessment, the first dose of venetoclax at 100 mg, 
200 mg and at 400 mg must be delayed until resolution and management of the 
laboratory abnormalities should be initiated, per the protocol Appendix D
(Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome [TLS]).  If needed, the subject should 
receive additional treatment prior to the initiation of dosing.
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS 
risk category as follows:
Low Risk Category
●
Subjects in Low Risk category will receive the subsequent dose escalations 
(100, 200 and 400 mg) as outpatients.
●
Chemistry and Hematology laboratory tests will be collected within 72 hours 
prior to the first dose of venetoclax of each dose escalation.  The investigator's 
decision to proceed with venetoclax treatment initiation may be based on these 
laboratory values.
●
Chemistry laboratory tests will be performed by local laboratory STAT at 
0 hour (pre-dose, within 4 hours before venetoclax administration), 8 and 


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24 hours after dose administration.  These laboratory values must be reviewed 
in real time by the investigator.  0 hour (pre-dose) laboratory values will be 
collected and used as baseline to assess potential electrolyte abnormalities
occurring post venetoclax administration.  Results from 0 hour (pre-dose) 
laboratory values are not required to be available prior to initiating venetoclax 
treatment.  Subjects must remain at the hospital, or clinic, until the 8 hour 
laboratory values have been reviewed by the investigator.
●
Day 2 dose should not be administered until the 24 hours post-dose chemistry 
laboratory values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient setting.
●
If any significant laboratory changes are observed within the first 24 hours 
after initiation of dosing, see Appendix D, (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]) for additional laboratory assessments and management 
guidelines.  If aggressive correction of electrolytes abnormalities is performed, 
the subsequent dose of venetoclax can only be given when electrolytes have 
been stable without any more treatment for at least 24 hours.
○
Additional laboratory assessments may be performed per investigator 
discretion.
●
Hematology laboratory tests will be performed at 0 hour (pre-dose, within 
4 hours before venetoclax administration), and 24* hours post-dose after each 
dose escalation.
*
All 24 hours laboratory assessments may be taken within 2 hour window, 
if necessary.
Medium Risk Category
●
Subjects in Medium Risk category may receive their subsequent dose 
escalations in the outpatient setting. 
●
Subjects with creatinine clearance < 80 mL/min and/or higher tumor burden 
(i.e., ALC > 100 × 109/L or multiple bulky nodes) may be hospitalized per 
investigator's discretion.


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For subjects who receive their subsequent dose escalations in the outpatient 
setting:  
○
Chemistry and Hematology laboratory tests will be collected within 
72 hours prior to the first dose of venetoclax of each dose escalation.  The 
investigator's decision to proceed with venetoclax treatment initiation may 
be based on these laboratory values.
○
Chemistry laboratory tests will be performed by local laboratory at 
0 hour (pre-dose, within 4 hours before venetoclax administration), 8 and 
24 hours post dose administration.  These laboratory values must be 
reviewed in real time by the investigator.  0 hour (pre-dose) laboratory 
values will be collected and used as baseline to assess potential electrolyte 
abnormalities occurring post venetoclax administration.  Results from 
0 hour (pre-dose) laboratory values are not required to be available prior to 
initiating venetoclax treatment.  Subjects must remain at the hospital, or 
clinic, until the 8 hour laboratory values have been reviewed by the 
investigator.
○
Day 2 dose should not be administered until the 24 hours post-dose 
chemistry laboratory values are reviewed by the investigator.
○
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient 
setting.
○
If any significant laboratory changes are observed within the first 24 hours 
after initiation of dosing, see Appendix D, (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]) for additional laboratory assessments and management 
guidelines.  If aggressive correction of electrolytes abnormalities is 
performed, the subsequent dose of venetoclax can only be given when 
electrolytes have been stable without any more treatment for at least 
24 hours.
○
Additional laboratory assessments may be performed per investigator 
discretion.


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○
Hematology laboratory tests will be performed at 0 hour (pre-dose, within 
4 hours before venetoclax administration), and 24* hours post-dose after 
each dose escalation.
*
All 24 hours laboratory assessments may be taken within 2 hour 
window, if necessary.
For subjects who are hospitalized during subsequent dose escalations:
○
Nephrology (or acute dialysis service) consultation may be considered on 
admission (based on investigator discretion) for hospitalized subjects.
○
IV hydration should be started with a target of approximately 1.5 – 2 L per 
day, or as clinically appropriate, for subjects who are hospitalized.
○
Chemistry and Hematology laboratory tests will be collected upon 
admission.
○
Chemistry tests will be performed by local laboratory STAT at 0 hour 
(pre-dose, within 4 hours before venetoclax administration), 4, 8, 12 and 
24 hours post dose.  These laboratory values must be reviewed in real time 
by the investigator.  0 hour (pre-dose) laboratory values will be collected 
and used as baseline to assess potential electrolyte abnormalities occurring 
post venetoclax administration.  Results from 0 hour (pre-dose) laboratory 
values are not required to be available prior to initiating ventoclax 
treatment.
○
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient 
setting.
○
If any significant laboratory changes are observed within the first 24 hours 
after initiation of dosing, see Appendix D, (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]) for additional laboratory assessments and management 
guidelines.  If aggressive correction of electrolytes abnormalities is 
performed, the subsequent dose of venetoclax can only be given when 
electrolytes have been stable without any more treatment for at least 
24 hours.
○
Additional laboratory assessments may be performed per investigator 
discretion.


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○
Hematology laboratory tests will be performed at 0 hour (pre-dose, within 
4 hours before venetoclax administration), and 24* hours post-dose after 
each dose escalation.
*
All 24 hours laboratory assessments may be taken within 2 hour 
window, if necessary.
○
The 24-hour post-dose laboratory results must be reviewed by the 
investigator prior to the subject leaving the hospital or receiving any 
additional doses of the study drug. 
High Risk Category
Re-Assessment of Risk Category for High-Risk Subjects with Lymph Nodes < 10 cm
Subjects in the high-risk TLS category at screening due to an absolute lymphocyte count 
≥ 25 ∃109/L AND a measurable lymph node with the largest diameter ≥ 5 cm but less 
than 10 cm by radiologic assessment may have a re-evaluation of their TLS risk category 
based on their most recent ALC for dose escalations after 50 mg.  Based on those results, 
one of the following two options may be implemented:
1.
Re-categorization to Medium Risk
If the subject's ALC decreases to < 25 × 109/L, the subject may be 
re-categorized as medium-risk for TLS and follow the management guidelines 
for the medium-risk TLS category for subsequent dose escalations of 
venetoclax during the Lead-In Period.
2.
Re-categorization to High Risk
If the subject's ALC remains ≥ 25 × 109/L, the subject will remain in the 
high-risk TLS category and continue to follow management guidelines for 
high-risk TLS subjects for subsequent dose escalations of venetoclax during 
the Lead-In Period.
Re-assessment of the subject's TLS risk category can occur prior to each subsequent dose 
escalation.


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High Risk Category
●
High Risk subjects may receive the subsequent dose increases as outpatients.  
Subjects with creatinine clearance < 80 mL/min, and/or higher tumor burden, 
(i.e., ALC > 100 × 109/L or multiple bulky nodes) may be hospitalized, per 
investigator discretion.  Hospitalization will begin the night before the dose of 
venetoclax and continue for 24 hours after dose administration.
For subjects who are hospitalized during subsequent dose escalations: 
○
Nephrology (or acute dialysis service) consultation may be considered on 
admission (based on investigator discretion) for hospitalized subjects.
○
IV hydration should be started with a target of approximately 1.5 – 2 L per 
day, or as clinically appropriate, for subjects who are hospitalized.
○
Chemistry and Hematology laboratory tests will be collected upon 
admission.
○
Chemistry tests will be performed by local laboratory STAT at 0 hour 
(pre-dose, within 4 hours before venetoclax administration), 4, 8, 12, and 
24 hours post-dose.  These laboratory values must be reviewed in real time 
by the investigator.  0 hour (pre-dose) laboratory values will be collected 
and used as baseline to assess potential electrolyte abnormalities occurring 
post venetoclax administration.  Results from 0 hour (pre-dose) laboratory 
values are not required to be available prior to initiating venetoclax 
treatment.
○
Day 2 dose should not be administered until the 24 hours post dose 
laboratory values are reviewed by the investigator.
○
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient 
setting.
○
If any significant laboratory changes are observed within the first 24 hours 
after initiation of dosing, see Appendix D, (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]) for additional laboratory assessments and management 
guidelines.  If aggressive correction of electrolytes abnormalities is 
performed, the subsequent dose of venetoclax can only be given when 


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electrolytes have been stable without any more treatment for at least 
24 hours.
○
Additional laboratory assessments may be performed per investigator 
discretion.
○
Hematology laboratory tests will be performed 0 hour (pre-dose, within 
4 hours before venetoclax administration), and 24* hours post-dose after 
each dose escalation.
*
All 24 hours laboratory assessments may be taken within 2 hour 
window, if necessary. 
○
The 24-hour post-dose laboratory results must be reviewed by the 
investigator prior to the subject leaving the hospital or receiving any 
additional doses of the study drug. 
For subjects who are not hospitalized:
○
Intravenous hydration (1.5 to 2 L) will be given in the outpatient setting.
○
Chemistry and Hematology laboratory tests will be collected within 
72 hours prior to the first dose of venetoclax of each dose escalation.  The 
investigator's decision to proceed with venetoclax treatment initiation may 
be based on these laboratory values.
○
Chemistry tests will be collected and performed by local laboratory at 
0 hour (pre-dose, within 4 hours before venetoclax administration), 8 and 
24 hours post dose administration.  These laboratory values must be 
reviewed in real time by the investigator.  0 hour (pre-dose) laboratory 
values will be collected and used as baseline to assess potential electrolyte 
abnormalities occurring post venetoclax administration.  Results from 
0 hour (pre-dose) laboratory values are not required to be available prior to 
initiating venetoclax treatment.  Subjects must remain at the hospital, or 
clinic, until the 8 hour laboratory values have been reviewed by the 
investigator.
○
Day 2 dose should not be administered until the 24 hours post-dose 
chemistry laboratory values are reviewed by the investigator.
●
If no significant findings suggestive of clinical or lab TLS occur within 
24 hours, the same dose will be continued until Day 7 in the outpatient 
setting.


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○
If any significant laboratory changes are observed within the first 24 hours 
after initiation of dosing, see Appendix D, (Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]) for additional laboratory assessments and management 
guidelines.  If aggressive correction of electrolytes abnormalities is 
performed, the subsequent dose of venetoclax can only be given when 
electrolytes have been stable without any more treatment for at least 
24 hours.
○
Additional laboratory assessments may be performed per investigator 
discretion.
○
Hematology laboratory tests will be performed at 0 hour (pre-dose, within 
4 hours before venetoclax administration), and 24* hours post-dose after 
each dose escalation.
*
All 24 hours laboratory assessments may be taken within 2 hour 
window, if necessary.
Any subject, who at any dose level develops clinically significant electrolyte 
abnormalities, must have their subsequent venetoclax dose held until the electrolyte 
abnormalities resolve.  Electrolyte changes should undergo aggressive management and 
further monitoring as per Appendix D (Recommendations for Initial Management of 
Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]).  The subject 
may resume dosing based on a risk assessment (including tumor burden status), as 
determined by the investigator.  All subjects must receive the intended dose for at least 
7 days before increasing to the next higher dose.
6.1.8.2
Management of Neutropenia
Based on clinical observations with the 1st generation Bcl-2 inhibitor, navitoclax and in 
vitro colony-forming assays to assess Bcl-2-selective inhibitor effects on granulocyte 
precursors, it is possible that subjects treated with venetoclax might experience 
neutropenia.  Subjects with a history of neutropenia, who have received multiple prior 
therapies and/or have significant bone marrow involvement, may be at particular high 
risk.  If determined to be clinically indicated by the treating physician in compliance with 


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ASCO guidelines,32 G-CSF may be administered during dosing of venetoclax.  The use of 
G-CSF support is strongly recommended for subjects with Grade 4 neutropenia (ANC 
< 500/μL).  If the subject presents with febrile neutropenia or Grade 4 neutropenia for 
more than one week despite the use of optimal G-CSF support, venetoclax dosing should 
be interrupted until ANC recovery to > 500/μL.  Venetoclax may then be re-initiated at a 
lower dose as defined in the following table.  Subjects not responding to G-CSF despite 
venetoclax interruption should undergo further evaluation to determine the etiology of the 
neutropenia.
Table 10.
Dose Reduction Guidelines for Management of Neutropenia
Venetoclax Dose
Reduced Dose
400 mg
300 mg
300 mg
200 mg
200 mg 
100 mg
100 mg
50 mg
50 mg
Re-challenge at 20 mga
a.
Subjects who do not tolerate 20 mg will discontinue venetoclax, but may remain on study to assess for progression.
6.1.8.3
Management of Lymphopenia
There is a potential for clinically significant lymphopenia in this study.  If clinically 
indicated, anti-infective prophylaxis should be implemented at the investigator's 
discretion, including appropriate prophylaxis for viral, fungal, bacterial or Pneumocystis 
infections.  Potential for drug-drug interactions should be considered.  Most anti-fungals 
are excluded and other commonly used agents may be cautionary or prohibited due to 
drug- drug interactions.  Please refer to Table 1, Table 2 and Appendix C for a description 
of excluded and cautionary medications.
6.1.8.4
Management of Decrease in Spermatogenesis
Based on findings in a preclinical study, there is a potential for decreased 
spermatogenesis.  Male subjects should consider sperm banking before treatment with 
venetoclax if they are considering preservation of fertility.


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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 via the Product 
Complaint form.  Product Complaints occurring during 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.


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7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  The 
principal investigator is responsible for complying with all protocol requirements, and 
applicable global and local laws regarding protocol deviations.  If a protocol deviation 
occurs (or is identified) after a subject has been enrolled, the principal investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review 
Board (IRB) regulatory authorities (as applicable), and their assigned CRO Clinical 
Monitor or the following AbbVie Clinical Monitor(s):
Primary Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Office:
Cell:
Fax:
Email:
Medical Monitor:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Cell:
Fax:
Email:
Back-up Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Office:
Cell:
Fax:
Email:
Program Lead:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Contact Information:
Office:
Fax:
Email:


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Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
Efficacy analyses will be performed separately for each cohort (main and safety 
expansion).  Safety analyses will be performed separately for each cohort, and will be 
pooled for assessment of venetoclax.
8.1.1
Statistical and Analytical Plans – Main Cohort
Efficacy and safety analyses will be performed on all subjects who receive at least one 
dose of venetoclax in the main cohort, unless otherwise specified.
For the primary efficacy analyses, statistical significance will be determined by a 
two-sided p value < 0.05 (one-sided < 0.025).
Detailed analysis descriptions for the main cohort will be provided in a statistical analysis 
plan.
8.1.1.1
Baseline Parameters
8.1.1.1.1
Baseline Characteristics
All baseline summary statistics will be based on characteristics prior to the initiation of 
study drug.  Unless otherwise stated, baseline for a given variable will be defined as the 
last value for that variable obtained prior to the first dose of study drug.
8.1.1.1.2
Demographics
Descriptive statistics will be provided for baseline demographic variables.  Age, height 
and weight will be summarized with means, medians, standard errors, standard deviations 
and ranges.  Frequencies and percentages will be provided for gender and race.


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8.1.1.1.3
Medical Histories
Frequencies and percentages will be summarized for each medical history parameter.
8.1.1.2
Primary Efficacy
8.1.1.2.1
Primary Efficacy Analyses in Main Cohort
The primary efficacy endpoint will be overall response rate (ORR) – the proportion of 
subjects with an overall response (complete remission, plus complete remission with 
incomplete bone marrow recovery, plus nodular partial remission, plus partial remission) 
per the NCI-CWG guidelines as assessed by the Independent Review Committee (IRC) in 
the first 70 subjects enrolled treated in the main cohort.
The ORR for venetoclax will be tested to reject the null hypothesis of 40%.  If the null 
hypothesis is rejected and the ORR is higher than 40%, then venetoclax has been shown 
to have an ORR significantly higher than 40%.
In addition, the ninety-five percent (95%) confidence interval for ORR based on binomial 
distribution will be constructed.
The assessment of ORR will be performed once 70 subjects in the main cohort have 
completed the scheduled 36-week disease assessment, have progressed prior to the 
36-week disease assessment, discontinued study drug for any reason, or after all treated 
subjects have discontinued venetoclax, whichever is earlier.  Among these 70 subjects, 
those who have not achieved a CR, CRi, nPR or confirmed PR prior to the cutoff date will 
be considered to be non-responders.
8.1.1.2.2
Secondary Efficacy Analyses in Main Cohort
Secondary efficacy endpoints will include CR rate, PR rate, duration of overall response, 
progression-free survival, event free survival, time to progression, time or response, time 
to 50% reduction in ALC, overall survival, and percent of subjects who move on to stem 
cell transplant.


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CR rate will be defined as the proportion of subjects who achieved a CR or CRi per the 
NCI-CWG criteria (determined by the IRC in the main cohort).  In addition, the 
95% confidence interval based on the binomial distribution will be provided.  Subjects 
who do not achieve a CR or CRi will be considered to be non-responders in the 
calculation of CR rate.
PR rate per the IRC assessment will be defined as the proportion of subjects who achieved 
a nPR or PR per the NCI-CWG criteria (determined by the IRC in the main cohort).  In 
addition, the 95% confidence interval based on the binomial distribution will be provided.  
Subjects who do not achieve a nPR or PR will be considered to be non-responders in the 
calculation of PR rate.
Duration of overall response will be defined as the number of days from the date of 
first response (CR, CRi, nPR, or PR) (determined by the IRC in the main cohort) to the 
earliest recurrence or PD per the IRC assessment.  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 not be 
included in the analysis.  Duration of overall response will be analyzed by Kaplan-Meier 
methodology.  Median duration of response will be calculated and the corresponding 95% 
confidence interval will be presented.
Duration of 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 (determined by the IRC in 
the main cohort) or death.  All disease progression will be included regardless whether the 
event occurred while the subject was taking the study drug or had previously discontinued 
the study drug.  If the subject does not experience disease progression or death, then the 
data will be censored at the date of last disease assessment.  Data for 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.  Median time PFS will 
be calculated and 95% confidence interval for median time PFS will be presented.


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Event-free survival (EFS) is defined as the number of days from the date of first dose to 
the date of earliest disease progression, death, or start of a new anti-leukemic therapy.  If 
the specified event (disease progression, death, start of a new anti-leukemic treatment) 
does not occur, patients will be censored at the date of last disease assessment.  Data for 
subjects without any disease assessments performed after the baseline visit will be 
censored at the date of first dose plus 1 day.  EFS will be analyzed by Kaplan-Meier 
methodology.  EFS will be calculated and 95% confidence interval for median EFS will 
be presented.
Time to progression (TTP) will be defined as the number of days from the date of 
first dose to the date of earliest disease progression (determined by the IRC in the main 
cohort).  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.  Median time TTP will 
be calculated and 95% confidence interval for median time TTP will be presented.
Time to first response will be defined as the number of days from the date of first dose to
the date of the first sign of response (CR, CRi, nPR, or PR) given the subject has had a 
CR, CRi, confirmed nPR or confirmed PR per the 2008 Modified IWCLL NCI-WG 
criteria.  The first response can be an assessment by physical exam as long as the results 
are later confirmed per the NCI-WG criteria.  For subjects who never experience a 
response, the subject's data will not be included in the analysis.  Descriptive statistics 
(mean, standard deviation, median, and range) and the 95% confidence interval of the
mean will be presented.
Time to 50% reduction in ALC will be defined as the number of days (hours if applicable) 
from the date of first dose to the date when the ALC has reduced to 50% of the baseline 


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value (as defined in Section 6.0).  For subjects who never achieve a 50% reduction in 
ALC, the subject's data will not be included in the analysis.  Descriptive statistics (mean, 
standard deviation, median, and range) and the 95% confidence interval of the mean will 
be presented.
Overall survival (OS) will be defined as number of days from the date of first dose to the 
date of death for all dosed subjects.  For subjects who did not die, their data will be 
censored at the date of last study visit or the last known date to be alive, whichever is 
later.  OS will be analyzed by Kaplan-Meier methodology.  Median time survival will be 
estimated and 95% confidence interval for the median time survival will be presented.
The percent of subjects who move on to stem cell transplant will be summarized and the 
95% confidence interval base on the binomial distribution will be provided.
8.1.1.2.3
Supplemental Efficacy in Main Cohort
A supplemental assessment of efficacy will occur when the last subject enrolled in the 
main cohort has completed the 36-week disease assessment.  This assessment will be 
based on the IRC assessment for all treated subjects in the main cohort.
The following analyses will be provided ORR, CR Rate, PR Rate, DoR, PFS, EFS, TTP, 
time to response, time to 50% reduction in ALC and MRD response rate.  The analysis 
will be performed as described above in Section 8.1.1.2.  Confidence intervals will be 
presented for each analysis.  No statistical tests will be performed on the supplemental 
assessment of efficacy.
8.1.1.2.4
Timing of Efficacy and Safety Analyses
The date once 70 subjects in the main cohort have completed the scheduled 36-week 
disease assessment, have progressed prior to the 36-week disease assessment, 
discontinued study drug for any reason, or after all enrolled subjects have discontinued 
venetoclax, whichever is earlier, will be defined as the data "cutoff" date for the primary 
efficacy analyses (ORR, CR rate, PR rate, duration of overall response, PFS, TTP, OS, 


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and additional exploratory efficacy analyses).  Efficacy data (IRC assessment of 
first 70 subjects treated in the main cohort and investigators' assessment on all treated 
subjects in the main cohort) and safety data (all treated subjects in the main cohort) up to 
and including this date will be collected.  Exact data cutoff date for all efficacy and safety 
analyses will be detailed in a statistical analysis plan (SAP) which will be signed off prior 
to the data cut-off date.  During this data collection period, active subjects will continue to 
receive venetoclax, as applicable.  When data collection is complete and all data 
management quality assurance (QA) and quality control (QC) procedures are performed, 
the clinical database data will be extracted for documentation and statistical analyses.
When all subjects treated into the main cohort have completed the scheduled 36-week 
disease assessment, have progressed prior to the 36-week disease assessment, or 
discontinued study drug for any reason, additional supplemental efficacy assessments 
based on the IRC review of response will be performed.  Any active subjects will continue 
to receive venetoclax until they discontinue or for up to 2 years from the date of the last 
subject enrolled in study.
Once the last enrolled subject discontinues/completes the cohort, the cohort will be 
considered complete, and all remaining data will be collected and entered into the clinical 
database.  A final efficacy assessment based on investigator assessment (ORR, CR rate, 
PR rate, duration of overall response, PFS, TTP, OS, and additional exploratory efficacy 
analyses) will be performed once all subjects from the main cohort have 
completed/discontinued.  No statistical tests will be performed; only descriptive statistics 
and the 95% confidence interval will be presented.
Overall survival will be collected on all subjects for up to 5 years from the first subject 
enrolled in the cohort.  After all survival data have been collected and entered into the 
clinical database, a final analysis will be performed on this dataset.
8.1.1.2.5
Pharmacokinetics
Plasma concentrations of venetoclax will be tabulated for each subject by visit.


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An analysis may be performed using a nonlinear mixed-effect population modeling 
approach with NONMEM software to describe the disposition of venetoclax, to identify 
significant covariates and explore relationship between pharmacokinetics and 
pharmacodynamics by combining data from this study with other venetoclax clinical 
studies.  The results from the population pharmacokinetic analysis may not be reported in 
the clinical study report.  Additional analyses may be performed if useful in the 
interpretation of the data.
8.1.1.2.6
Interim Analyses
Independent Data Monitoring Committee (IDMC)
Safety data, after approximately 20 subjects had completed at least 12 weeks of study 
treatment in the main cohort, was reviewed by an Independent Data Monitoring 
Committee (IDMC).  A separate charter had been created to provide detailed descriptions 
of the schedule of the analyses and the IDMC meetings.  The IDMC membership, 
responsibilities and the description of the data coordinating center are documented in the 
charter.  The IDMC received analysis data summary, which included enrollment data, 
subject baseline characteristics and safety data.
8.1.1.2.7
Additional Exploratory Efficacy Analyses
Time to next anti-CLL treatment (TTNT) will be defined as the number of days from the 
date of the first dose of venetoclax to the date of first dose of new non-protocol 
anti-lymphoma therapy (NPT) or death from any cause.  For subjects who did not take 
NPT, the data will be censored at the last known date to be free of NPT.  TTNT will be 
analyzed by Kaplan-Meier methodology using data for all treated subjects.  Median TTNT 
time will be calculated and 95% confidence interval for median TTNT time will be 
presented.
The rate of MRD negativity in subjects will be an exploratory endpoint.  This rate will be 
defined as the proportion of subjects who had MRD negativity status by MRD-flow.  
Ninety-five percent (95%) confidence intervals based on the binomial distribution will be 


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provided.  MRD data for this exploratory analysis was based on the MRD flow cytometry 
data and will not be collected for subjects who continue on in the survival extended access 
portion of the study.  MRD-PCR specimens will be collected and analyzed for subjects 
who are eligible.  This data will not be included in the clinical study report.
Health Economic and Patient Reported Outcome measures will include the MDASI 
(measure of subject reported symptoms), the EORTC QLQ-C30 and QLQ CLL16 (a 
measure of health related quality of life specific to CLL) and the EQ-5D-5L (measure of 
general health status) and EQ-5D-VAS.  Descriptive statistics will be calculated for all 
scales of the MDASI, the EORTC QLQ-C30 and EORTC QLQ CLL16, the EQ-5D-5L 
utility score, and the EQ-5D-VAS score including mean change from baseline to each 
assessment as well as the final visit.  Additionally, the EORTC QLQ-C30 and EORTC 
QLQ CLL16 will be administered through post-treatment.  The results obtained for each 
instrument will be explored for trends and summarized as appropriate.
A sensitivity analysis of overall response rate, CR rate, PR rate, duration of overall 
response, PFS and TTP based on the investigator assessment will be performed using the 
primary subjects analysis set (first 70 subjects treated) and all subjects treated in the main 
cohort.
Alternative statistical analyses may be performed if deemed as necessary and helpful in 
understanding the drug effect.
8.1.1.3
Safety
The safety of venetoclax will be assessed by evaluation study drug exposure, adverse 
events, serious adverse events, all deaths, as well as changes in laboratory values and vital 
sign parameters.
Safety analyses will be performed using subjects who take at least one dose of study drug.  
The safety analysis sets will include all treated subjects in the main cohort, all treated 
subjects in the safety expansion cohort, all treated subjects with 17p deletion CLL, and all 
treated subjects in the study (combination of main cohort and safety expansion cohort).


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8.1.1.3.1
Adverse Events
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the day of the first dose of study drug.
Analyses will not include those that have an onset greater than 30 days after the last dose 
of study drug.
Treatment-emergent adverse events will be summarized by preferred terms within a 
System and Organ Class according to the most current Medical Dictionary for Regulatory 
Activities (MedDRA)43 adverse event coding dictionary.  In addition, the percentage of 
subjects experiencing an adverse event at an NCI CTCAE Version 4.0 toxicity grade, and 
relationship to study drug will be provided.
8.1.1.3.2
Serious Adverse Events
Serious adverse events will be summarized using the same methods as Adverse Events 
described above.
8.1.1.3.3
Deaths
The number of subject deaths will be summarized (1) for deaths occurring within 30 days 
of the last dose of study drug, (2) for deaths occurring more than 30 days of the last dose 
of study drug and (3) for all deaths in this study regardless of the number of days after the 
last dose of study drug.
8.1.1.3.4
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline will be analyzed for each scheduled post-baseline visit and for the 
final visit for blood chemistry and hematology parameters, as well as urinalysis and vital 
sign parameters.  If more than one measurement exists for a subject on a particular day, 
then an arithmetic average will be calculated.  This average will be considered to be that 
subject's measurement for that day.  Post-baseline measurements more than 30 days after 


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the last dose of study drug will not be included.  Subjects that do not have a baseline 
measurement or do not have any post-baseline measurements will not be included.
8.1.1.3.5
Analyses of Laboratory Data Using NCI CTCAE
Where applicable, blood chemistry, hematology and lymphocyte enumeration 
determinations will be categorized according to NCI CTCAE version 4.0 grades, and 
shifts from baseline NCI CTCAE grades to maximum and final post-baseline grades will 
be assessed.
The baseline and final grades will be defined respectively as the grade of the last 
measurement collected prior to the first dose of study drug, and as the last post-baseline 
measurement collected no more than 30 days after the last dose of study drug.  An 
exception will be used for those subjects enrolled with a baseline value of neutrophils less 
than 1000/μL requiring G-CSF support to meet entry criteria.  For these subjects, the last 
value pre-G-CSF administration will be the baseline.  The 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.
8.1.2
Statistical and Analytical Plans for the Safety Expansion 
Cohort
Safety and efficacy analyses will be performed on all subjects who receive at least 
one dose of venetoclax in the safety expansion cohort.  The analyses for the subjects in the 
safety expansion cohort will occur when the last subject enrolled in this cohort has been 
receiving 400 mg of venetoclax for 1 week.


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Secondary efficacy analysis will be performed for subjects with central confirmation of 
17p deletion and all subjects combined in the safety expansion cohort.  All secondary 
efficacy endpoints will be summarized using the investigator assessment of response.  CT 
scans will be collected by the IRC for archival purposes.
No statistical testing will be performed on the safety expansion cohort.
Detailed analysis descriptions for the safety expansion cohort will be provided in a 
statistical analysis plan.
8.1.2.1
Baseline Parameters
8.1.2.1.1
Baseline Characteristics
All baseline summary statistics will be based on characteristics prior to the initiation of 
study drug.  Unless otherwise stated, baseline for a given variable will be defined as the 
last value for that variable obtained prior to the first dose of study drug.
8.1.2.1.2
Demographics
Descriptive statistics will be provided for baseline demographic variables.  Age, height 
and weight will be summarized with means, medians, standard errors, standard deviations 
and ranges.  Frequencies and percentages will be provided for gender and race.
8.1.2.1.3
Medical Histories
Frequencies and percentages will be summarized for each medical history parameter.
8.1.3
Safety
The safety of venetoclax for subject enrolled in the safety expansion will be assessed by 
evaluation of study drug exposure, adverse events, serious adverse events, all deaths, as 
well as changes in laboratory values and vital sign parameters.
Safety analyses will be performed for all subjects who take at least one dose of study 
drug.


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8.1.3.1
Adverse Events
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the day of the first dose of study drug.
Analyses will not include those that have an onset greater than 30 days after the last dose 
of study drug.
Treatment-emergent adverse events will be summarized by preferred terms within a 
System and Organ Class according to the most current Medical Dictionary for Regulatory 
Activities (MedDRA)43 adverse event coding dictionary.  In addition, the percentage of 
subjects experiencing an adverse event at an NCI CTCAE Version 4.0 toxicity grade, and 
relationship to study drug will be provided.
8.1.3.2
Serious Adverse Events
Serious adverse events will be summarized using the same methods as Adverse Events 
described above.
8.1.3.3
Deaths
The number of subject deaths will be summarized (1) for deaths occurring within 30 days 
of the last dose of study drug, (2) for deaths occurring more than 30 days of the last dose 
of study drug and (3) for all deaths in this study regardless of the number of days after the 
last dose of study drug.
8.1.3.4
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline will be analyzed for each scheduled post-baseline visit and for the 
final visit for blood chemistry and hematology parameters, as well as urinalysis and vital 
sign parameters.  If more than one measurement exists for a subject on a particular day, 
then an arithmetic average will be calculated.  This average will be considered to be that 
subject's measurement for that day.  Post-baseline measurements more than 30 days after 


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the last dose of study drug will not be included.  Subjects that do not have a baseline 
measurement or do not have any post-baseline measurements will not be included.
8.1.3.5
Analyses of Laboratory Data Using NCI CTCAE
Where applicable, blood chemistry, hematology and lymphocyte enumeration 
determinations will be categorized according to NCI CTCAE version 4.0 grades, and 
shifts from baseline NCI CTCAE grades to maximum and final post-baseline grades will 
be assessed.
The baseline and final grades will be defined respectively as the grade of the last 
measurement collected prior to the first dose of study drug, and as the last post-baseline 
measurement collected no more than 30 days after the last dose of study drug.  An 
exception will be used for those subjects enrolled with a baseline value of neutrophils less 
than 1000/μL requiring G-CSF support to meet entry criteria.  For these subjects, the last 
value pre-G-CSF administration will be the baseline.  The 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.
8.1.3.6
Assessment of TLS
Analyses of the TLS measures implemented in Safety Expansion Cohort will be 
performed.  Analyses will be performed by risk category and overall for the following 
analyses:
●
TLS-associated adverse events
●
TLS-associated adverse events leading to discontinuation, interruption or drug 
delay


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●
Laboratory changes (see Appendix F Cairo-Bishop and Howard Definitions of 
Tumor Lysis Syndrome)
8.1.4
Efficacy Endpoints
The secondary efficacy endpoint for the safety expansion cohort will be ORR, CR rate, 
PR rate, duration of overall response, event free survival, progression-free survival, time 
to response, time to 50% reduction in ALC, time to progression, overall survival, time to 
next anti-CLL treatment (TTNT), MRD negativity rate, and Health Economic and Patient 
Reported Outcome measures.  Determination of disease progression will be based on 
investigator assessment.
ORR rate will be defined as the proportion of subjects who achieved a CR, CRi, nPR, or 
PR per the NCI-CWG guidelines.  In addition, the 95% confidence interval based on the 
binomial distribution will be provided.  Subjects who do not achieve a CR, CRi, nPR, or 
PR will be considered to be non-responders in the calculation of ORR rate.
CR rate will be defined as the proportion of subjects who achieved a CR or CRi per the 
NCI-CWG guidelines.  In addition, the 95% confidence interval based on the binomial 
distribution will be provided.  Subjects who do not achieve a CR or CRi will be 
considered to be non-responders in the calculation of CR rate.
PR rate will be defined as the proportion of subjects who achieved a nPR or PR per the 
NCI-CWG guidelines.  In addition, the 95% confidence interval based on the binomial 
distribution will be provided.  Subjects who do not achieve a nPR or PR will be 
considered to be non-responders in the calculation of PR rate.
Duration of overall response will be defined as the number of days from the date of 
first response (CR or PR) to the earliest recurrence or PD.  If a subject is still responding, 
then the subject's data will be censored at the date of the subject's last available disease 
assessment.  For subjects who never experience response, the subject's data will not be 
included in the analysis.  Duration of overall response will be analyzed by Kaplan-Meier 


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methodology using data for all treated subjects who responded.  Median duration of 
response will be calculated and the corresponding 95% confidence interval will be 
presented.
Duration of progression-free survival (PFS) will be defined as the number of days from 
the date of first dose to the date of earliest disease progression or death.  All disease 
progression will be included regardless whether the event occurred while the subject was 
taking the study drug or had previously discontinued the study drug.  If the subject does 
not experience disease progression or death, then the data will be censored at the date of 
last disease assessment.  Data for 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 treated.  Median time 
PFS will be calculated and 95% confidence interval for median time PFS will be 
presented.
Event-free survival (EFS) is defined as the number of days from the date of first dose to 
the date of earliest disease progression, death, or start of a new anti-leukemic therapy.  If 
the specified event (disease progression, death, start of a new anti-leukemic treatment) 
does not occur, patients will be censored at the date of last disease assessment.  Data for 
subjects without any disease assessments performed after the baseline visit will be 
censored at the date of first dose plus 1 day.  EFS will be analyzed by Kaplan-Meier 
methodology.  EFS will be calculated and 95% confidence interval for median EFS will 
be presented.
Time to progression (TTP) will be defined as the number of days from the date of 
first dose to the date of earliest disease progression.  All disease progression will be 
included regardless whether the event occurred while the subject was taking the study 
drug or had previously discontinued the study drug.  If the subject does not experience 
disease progression, then the data will be censored at the date of last available disease 
assessment.  Data for subjects who receive non-protocol, CLL therapy prior to disease 


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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 treated.  Median time TTP will be 
calculated and 95% confidence interval for median time TTP will be presented.
Time to first response will be defined as the number of days from the date of first dose to 
the date of the first sign of response (CR, CRi, nPR, or PR) given the subject has had a 
CR, CRi, confirmed nPR or confirmed PR per the 2008 Modified IWCLL NCI-WG
criteria.  The first response can be an assessment by physical exam as long as the results 
are later confirmed per the NCI-WG criteria.  For subjects who never experience a 
response, the subject's data will not be included in the analysis.  Descriptive statistics 
(mean, standard deviation, median, and range) and the 95% confidence interval of the 
mean will be presented.
Time to 50% reduction in ALC will be defined as the number of days (hours if applicable) 
from the date of first dose to the date when the ALC has reduced to 50% of the baseline 
value (as defined in Section 6.0).  For subjects who never achieve a 50% reduction in 
ALC, the subject's data will not be included in the analysis.  Descriptive statistics (mean, 
standard deviation, median, and range) and the 95% confidence interval of the mean will 
be presented.
Overall survival (OS) will be defined as number of days from the date of first dose to the 
date of death for all dosed subjects.  For subjects who did not die, their data will be 
censored at the date of last study visit or the last known date to be alive, whichever is 
later.  OS will be analyzed by Kaplan-Meier methodology using data from all treated 
subjects.  Median time survival will be estimated and 95% confidence interval for the 
median time survival will be presented.
The percent of subjects who move on to stem cell transplant will be summarized and the 
95% confidence interval base on the binomial distribution will be provided.


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8.1.4.1
Additional Exploratory Efficacy Analyses
Time to next anti-CLL treatment (TTNT) will be defined as the number of days from the 
date of the first dose of venetoclax to the date of first dose of new non-protocol 
anti-lymphoma therapy (NPT) or death from any cause.  For subjects who did not take 
NPT, the data will be censored at the last known date to be free of NPT.  TTNT will be 
analyzed by Kaplan-Meier methodology using data for all treated subjects.  Median TTNT 
time will be calculated and 95% confidence interval for median TTNT time will be 
presented.
The rate of MRD negativity in subjects will be an exploratory endpoint.  This rate will be 
defined as the proportion of subjects who had MRD negativity status.  Ninety-five percent 
(95%) confidence intervals based on the binomial distribution will be provided.  MRD 
data for this exploratory analysis was based on the MRD-Flow specimens and will not be 
collected for subjects who continue on in the survival extended access portion of the 
study.  MRD-PCR specimens will be collected and analyzed for subjects who are eligible.  
This data will not be included in the final clinical study report.
Health Economic and Patient Reported Outcome measures will include the MDASI 
(measure of subject reported symptoms), the EORTC QLQ-C30 and QLQ CLL16 (a 
measure of health related quality of life specific to CLL) and the EQ-5D-5L (measure of 
general health status) and EQ-5D-VAS.  Descriptive statistics will be calculated for all 
scales of the MDASI, the EORTC QLQ-C30 and EORTC QLQ CLL16, the EQ-5D-5L 
utility score, and the EQ-5D-VAS score including mean change from baseline to each 
assessment as well as the final visit.  Additionally, the EORTC QLQ-C30 and EORTC 
QLQ CLL16 will be administered through post-treatment.  The results obtained for each 
instrument will be explored for trends and summarized as appropriate.
8.1.4.2
Timing of Safety Evaluations and Secondary Efficacy 
Endpoints
The date once all subjects in the safety expansion cohort have completed the dose 
escalation, or have discontinued venetoclax, whichever is earlier, will be defined as the 


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data "cutoff" date for the safety analyses.  Safety Data up to and including this date will 
be collected.  During this data collection period, active subjects will continue to receive 
venetoclax, as applicable.  When data collection is complete and all data management 
quality assurance (QA) and quality control (QC) procedures are performed, the clinical 
database data will be extracted for documentation and statistical analyses.  Any active 
subjects will continue to receive venetoclax until they discontinue or for up to 2 years 
from the date of the last subject enrolled in this cohort.
Once the last enrolled subject discontinues/completes the cohort, the cohort will be 
considered complete, and all remaining data will be collected and entered into the clinical 
database.  A final safety and efficacy assessment on the subjects treated in the safety 
expansion cohort will be performed once all subjects have completed/discontinued from 
the cohort.  No statistical testing procedures will be performed and only descriptive 
statistics and the 95% confidence interval will be presented.
Overall survival will be collected on all subjects for up to 5 years from the first subject 
enrolled on the cohort.  After all survival data have been collected and entered into the 
clinical database, a final analysis will be performed on this dataset.
8.1.4.3
Pharmacokinetics
Plasma concentrations of venetoclax will be tabulated for each subject by visit.
An analysis may be performed using a nonlinear mixed-effect population modeling 
approach with NONMEM software to describe the disposition of venetoclax, to identify 
significant covariates and explore relationship between pharmacokinetics and 
pharmacodynamics by combining data from this study with other venetoclax clinical 
studies.  The results from the population pharmacokinetic analysis may not be reported in 
the clinical study report.  Additional analyses may be performed if useful in the 
interpretation of the data.


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8.1.4.4
Independent Data Monitoring Committee
Interim analysis results will be reviewed by the IDMC after approximately 20 subjects 
have completed approximately 2 – 3 weeks of the lead-in period in the safety expansion 
cohort.  
8.2
Determination of Sample Size
Approximately 100 subjects will be enrolled in the main cohort to assess the safety and 
efficacy of venetoclax in subjects with relapsed or refractory chronic lymphocytic 
leukemia (CLL) harboring the 17p deletion.  With this sample size, if a rare adverse event 
occurs at a rate of 2%, then the probability of observing at least 1 event in a trial with 
100 subjects is 86%.
Assuming a peak enrollment rate of 0.11 subjects/site/month, it is anticipated that 
approximately 100 subjects will be enrolled during the 14 month enrollment phase.  The 
primary assessment of the efficacy of venetoclax will occur around Month 19 at which 
time 70 subjects should have had their 36-week disease assessment.  The final efficacy 
summary will occur around Month 38 (two years after last subject enrolled).
Overall response rates for CLL subjects with 17p deletion range from approximately 7% 
to 77% with the higher responses in alternative but also more toxic regimens such as 
alemtuzumab + steroids.24  Conventional therapies such as FCR and BR, demonstrated 
ORRs of 35% and 7%, respectively.  Therefore, a therapy providing significant benefit in 
overall response rate over a standard rate of 40% would be considered clinically 
meaningful.
Performing the efficacy analyses at 70 subjects provides at least 90% power (at 2-sided 
alpha of 5%) to reject the null hypothesis of 40% ORR in favor of an alternative 
hypothesis of 60% ORR.  The power calculations for a range of different sample sizes are 
presented in Table 11.


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Table 11.
Sample Size Calculation
Subjects (N)
Power (%)
50
76
60
82
70
90
80
93
90
96
For the safety expansion cohort, an additional 50 subjects with relapsed/refractory or 
previously untreated chronic lymphocytic leukemia (CLL) harboring the 17p deletion will 
be enrolled to assess the modifications made to the initial dosing of venetoclax for the 
management of TLS.  With this sample size, if a TLS event occurs at a rate of 2%, then 
the probability of observing at least 1 event in this cohort of 50 subjects is 64%.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.


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Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix 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.
Pharmacogenetic analysis and a portion of the pharmacodynamic analyses will only be 
performed if the subject has voluntarily signed and dated the informed consent, approved 
by an IRB/IEC, after the nature of the testing has been explained and the subject has had 
an opportunity to ask questions.  The informed consent must be signed before 
pharmacogenetic and/or pharmacodynamic testing is performed.  If the subject does not 


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consent to pharmacogenetic and/or the optional pharmacodynamic testing, it will not 
impact the subject's participation in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Electronic Case Report Forms
Electronic case report forms (eCRF) must be completed for each subject enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The eCRF 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 (Medidata).  The EDC 
system and the study specific electronic case report forms will be in compliance with 
Title 21 CFR Part 11.  The documentation related to the validation of the EDC system is 
available through the vendor, Medidata, while the validation of the study-specific eCRFs 
will be conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  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.


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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 an audit trail that 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/her electronic signature and date to the eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from the 
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
Prior to enrolling any subject in the study, a Site Initiation Visit will be held with AbbVie 
personnel (and/or their representatives), the investigators, and the appropriate site 
personnel.  This meeting will include a detailed discussion and review of the protocol and 
essential documents, performance of study procedures, eCRF completion, and specimen 
collection methods.  The personnel at the study site will be trained on the study 
procedures, when applicable, by an AbbVie monitor or designee.
The AbbVie monitor or designee will monitor the study site throughout the study.  A 
source document review will be performed against entries on the eCRFs and a quality 
assurance check will be performed to ensure that the investigator is complying with the 
protocol and regulations.  In addition, ongoing review of the data will be conducted by a 
physician or representative at AbbVie.


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


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The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name and subject number.  This list will be 
maintained at the study site with other study records under adequate security and 
restricted access, and will not be retrieved by AbbVie.
Any pharmacogenetic research that may be done using DNA samples and/or any research 
performed on the biomarker samples from this study will be experimental in nature.  
Hence, neither the investigator, the subject nor the subject's physician (if different than the 
investigator) will be informed of individual subject pharmacogenetic or biomarker results, 
should analyses be performed, nor will anyone not directly involved in this research.  
Correspondingly, genetic and biomarker researchers will have no access to subject 
identifiers.  Individual results will not be reported to anyone not directly involved in this 
research other than for regulatory purposes.  Aggregate pharmacogenetic and exploratory 
research information from this study may also be used in scientific publications or 
presented at medical conventions.  Pharmacogenetic and biomarker information will be 
published or presented only in a way that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 


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significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Medicines Agency (EMA) 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 last 
follow-up contact, whichever is later.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for venetoclax.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Phase 2 Open-Label Study of the Efficacy of ABT-199 
(GDC-0199) in Subjects with Relapsed/Refractory or Previously 
Untreated Chronic Lymphocytic Leukemia Harboring the 
17p Deletion
Protocol Date:
28 February 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
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Borner C.  The Bcl-2 protein family:  sensors and checkpoints for life-or-death 
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Cory S, Huang DCS, Adam JM.  The Bcl-2 family:  roles in cell survival and 
oncogenesis.  Oncogene.  2003;22:8590-8607.
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Cimmino A, Calin GA, Fabbri M, et al.  miR-15 and miR-16 induce apoptosis by 
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BCL-2 inhibitor, achieves antitumor activity while sparing platelets.  Nat Med.  
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AbbVie.  ABT-199 Investigator's Brochure Edition 8.  15 February 2017.
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Zwiebel JA, Cheson BD.  Chronic lymphocytic leukemia:  staging and prognostic 
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13.
Ries LAG, Harkins D, Krapcho M, et al.  SEER Cancer Statistics Review, 
1975-2003.  Bethesda, MD:  National Cancer Institute [based on November 2005 
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Sant M, Allemani C, Tereanu C, et al.  Incidence of hematologic malignancies in 
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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.  
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Francis S, Karanth M, Pratt G, et al.  The effect of immunoglobulin VH gene 
mutation status and other prognostic factors on the incidence of major infections in 
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Geisler CH, Phillip P, Christensen BE, et al.  In B-cell chronic lymphocytic 
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Byrd JC, Gribben JG, Peterson BL, et al.  Select high-risk genetic features predict 
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Badoux XC, Keating MJ, Wang X, et al.  Fludarabine, cyclophosphamide, and 
rituximab chemoimmunotherapy is highly effective treatment for relapsed patients 
with CLL.  Blood.  2011;117(11):3016-24.


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22.
Wierda WG, Kipps TJ, Mayer J.  Ofatumumab as single-agent CD20 
immunotherapy in fludarabine-refractory chronic lymphocytic leukemia.  J Clin 
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Stilgenbauer S, Zenz T, Winkler D.  German Chronic Lymphocytic Leukemia 
Study Group.  Subcutaneous alemtuzumab in fludarabine-refractory chronic 
lymphocytic leukemia:  clinical results and prognostic marker analyses from the 
CLL2H study of the German Chronic Lymphocytic Leukemia Study Group.  J Clin 
Oncol.  2009;27(24):3994-4001.
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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.
Fischer K, Cramer P, Busch R, et al.  Bendamustine combined with rituximab in 
patients with relapsed and/or refractory chronic lymphocytic leukemia:  a 
multicenter Phase II trial of the German Chronic Lymphocytic Leukemia Study 
Group.  J Clin Oncol.  2011;29:3559-66.
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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.
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National Comprehensive Cancer Network.  Available from:  
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Schnaiter A, Stilgenbauer S.  17p deletion in chronic lymphocytic leukemia:  risk 
stratification and therapeutic approach.  Hematol Oncol Clin North Am.  
2013;27(2):289-301.
29.
Zhu HJ, Liu L, Fan L, et al.  The BH3-only protein Puma plays an essential role in 
p53-mediated apoptosis of chronic lymphocytic leukemia cells.  Leuk Lymphoma.  
2013;54(12):2712-9.


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30.
Mackus WJ, Kater AP, Grummels A, et al.  Chronic lymphocytic leukemia cells 
display p53-dependent drug-induced Puma upregulation.  Leukemia.  
2005;19(3):427-34.
31.
Badoux XC, Keating M, O'Brien S, et al.  Patients with relapsed CLL and 17p 
deletion by FISH have very poor survival outcomes.  In:  Abstracts of the 
American Society of Hematology 51st Annual Meeting, December 5-8, 2009; New 
Orleans, Louisiana, USA.  Blood.  2009;114(22):3-1587.  Abstract 1248.
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Smith TJ, Khatcheressian J, Lyman GH, et al.  2006 update of recommendations 
for the use of white blood cell growth factors:  an evidence-based clinical practice 
guideline.  J Clin Oncol.  2006;24(19):3187-205.
33.
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.
34.
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.
35.
Böttcher S, Ritgen M, Fischer K, et al.  Minimal residual disease quantification is 
an independent predictor of progression-free and overall survival in chronic 
lymphocytic leukemia:  a multivariate analysis from the randomized GCLLSG 
CLL8 trial.  J Clin Oncol.  2012;30(9):980-8.
36.
Vysis CLL CDx FISH Kit List No. 07N67-020.
37.
MDASI; Cleeland et al., 2000.
38.
MDASI-CLL:  http://www3.mdanderson.org/depts/symptomresearch.
39.
http://www.mdanderson.org/education-and-research/departments-programs-and-
labs/departments-and-divisions/symptom-research/symptom-assessment-tools/m-d-
anderson-symptom-inventory.html.
40.
EORTC QLQ-C30 and EORTC QLQ CLL16:  http://groups.eortc.be/qol.
41.
EQ-5D-5L and EQ-5D-VAS:  http://www.euroqol.org.


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42.
National Cancer Institute.  Common Terminology Criteria for Adverse Events 
(CTCAE), v4.0, NCI, NIH, DHHS.  28 May 2009.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
Accessed on:  09 September 2010.
43.
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Research and Development (GPRD), Global Pharmacovigilance and Clinical 
Project Team, current version on file at AbbVie.


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


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


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Statistics
Clinical
Clinical
Global Drug Supply Management
Clinical
Biomarkers
Pharmacokinetics
Bioanalysis


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


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


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Appendix D.
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS)
Section 1:  First Dose of Venetoclax or Dose Escalation
!
Within the first 24 hours after either the first dose or dose escalation, if any 
laboratory criteria below are met, the patient should be hospitalized for 
monitoring and the investigator notified.  No additional venetoclax doses 
should be administered until resolution.  A rapidly rising serum potassium is a 
medical emergency.
!
Nephrology (or other acute dialysis service) 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.


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


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Abnormality
Management Recommendations
Hyperkalemia (Including Rapidly Rising Potassium) (continued)
Potassium ≥ 6.0 mmol/L 
(6.0 mEq/L) and/or symptomatic 
(e.g., muscle cramps, weakness, 
paresthesias, nausea, vomiting, 
diarrhea)
!
Perform STAT ECG and commence telemetry.
!
Nephrology (or other acute dialysis service) assessment 
with consideration of initiating dialysis.
!
Administer Kayexalate 60 g (or Resonium A 60 g).
!
Administer furosemide 20 mg IV × 1.
!
Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV.
!
Administer sodium bicarbonate 1 to 2 mEq 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.


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Abnormality
Management Recommendations
Hypocalcemia
Calcium ≤ 7.0 mg/dL 
(1.75 mmol/L)
AND
Patient symptomatic (e.g., muscle 
cramps, hypotension, tetany, 
cardiac arrhythmias)
!
Administer calcium gluconate 50 to 100 mg/kg IV 
slowly with ECG monitoring.
!
Telemetry.
!
Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hr STAT.
o
If calcium normalized 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 
4 hrs., later, if no other evidence of tumor lysis.
!
Calculate corrected calcium and check ionized calcium if 
albumin low.
Hyperphosphatemia
Phosphorus ≥ 5.0 mg/dL
(1.615 mmol/L) with ≥0.5 mg/dL 
(0.16 mmol/L) increase
!
Administer a phosphate binder (e.g., aluminum 
hydroxide, calcium carbonate, sevelamer hydroxide, or 
lanthanum carbonate).
!
Nephrology (or other acute dialysis service) notification 
(dialysis required for phosphorus ≥10 mg/dL).
!
Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hr STAT.
o
If phosphorus < 5.0 mg/dL 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hrs., later, if no other evidence of 
tumor lysis.
Creatinine
Increase ≥ 25% from baseline
!
Start or increase rate of IV fluids.
!
Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 to 2 hours STAT.


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Section 2:  Ongoing Dosing of Venetoclax
Management of electrolyte changes from last value at intervals > 24 hours after either the 
first dose or dose escalation (e.g., 48 or 72 hours) are as below.
Note:  If the patient is hospitalized, no additional venetoclax doses should be administered 
until resolution.
●
For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or 
any level > upper limit of normal.
○
Refer to the management guidelines for electrolyte changes observed 
within the first 24 hours after either the first dose or dose escalation 
(see prior table).
●
If a smaller potassium increase is observed that does not meet the criteria for 
admission above, recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 24 hours and confirm no evidence of tumor lysis prior to further 
venetoclax dosing.
●
For uric acid, calcium, phosphorus and creatinine, refer to the management 
guidelines for electrolyte changes observed within the first 24 hours after 
either the first dose or dose escalation (see prior table).


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Appendix E.
Adverse Events Commonly Associated with CLL Study Population 
and/or Progression of CLL
Disease-Related Events – CLL
Lymphadenopathy
Splenomegaly
Hepatomegaly
Leukemia cutis (macules, papules, plaques, nodules, ulcers, or blisters)
Lymphocytosis
Cytopenias (neutropenia, anemia and thrombocytopenia)
Febrile neutropenia
Autoimmune hemolytic anemia
Autoimmune thrombocytopenia
Hypogammaglobulinemia
Infections (bacterial, viral, and fungal)
Second primary cancers, all types
Fatigue
Unexplained weight loss
Pyrexia
Bruising
Minor hemorrhages
Pain, all types
Malignant neoplasm progression, including death
Population-Related Comorbidities
Hypertension
Rheumatoid arthritis/osteoarthritis
Hyperlipidemia
Peptic ulcer
Inflammatory bowel disease
Coronary artery disease


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


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Appendix F.
Cairo-Bishop and Howard Definitions of Tumor Lysis Syndrome
Table 12.
Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and 
Grading
Complication
Grade
0
1
2
3
4
5
Creatinine*,†
≤ 1.5 × 
ULN
1.5 × 
ULN
1.5 – 3.0 × 
ULN
> 3.0 – 6.0 × 
ULN
> 6.0 ×
ULN
Death
Cardiac 
Arrhythmia*
None
Intervent
ion not 
indicated
Non-urgent 
medical 
intervention 
indicated
Symptomatic 
and
incompletely 
controlled 
medically or 
controlled with 
device (e.g., 
defibrillator)
Life-
threatening 
(e.g., 
arrhythmia 
associated 
with CHF, 
hypotension, 
syncope, 
shock)
Death
Seizure*
None
–
One brief, 
generalized 
seizure; 
seizure(s) well 
controlled by 
anticonvulsants 
or infrequent 
focal motor 
seizures not 
interfering with 
ADL
Seizure in 
which 
consciousness 
is altered; 
poorly 
controlled 
seizure 
disorder; with 
breakthrough 
generalized 
seizures despite 
medical 
intervention
Seizure of any 
kind which are 
prolonged, 
repetitive or 
difficult to 
control 
(e.g., status 
epilepticus, 
intractable 
epilepsy)
Death
ULN = upper limit of normal; CHF = congestive heart failure; ADL = activities of daily living
*
Not directly or probably attributable to therapeutic agent.
†
If no institutional ULN is specified, age/sex ULN creatinine may be defined as follows:  Cairo-Bishop Clinical 
Tumor Lysis Syndrome Definition and Grading.
Note:
Laboratory tumor lysis syndrome and at least one clinical complication.


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Table 13.
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome
This definition comprises ≥ 2 of the following metabolic abnormalities occurring within 
7 days from first dose at initial dosing or at dose escalation.
Element
Value
Change from Baseline
Uric Acid
≥ 476 μmol/L or 8 mg/dL
25% increase
Potassium
≥ 6.0 mmol/L or 6 mEq/L
25% increase
Inorganic Phosphorus
≥ 1.45 mmol/L
25% increase
Calcium
≤ 1.75 mmol/L
25% decrease
Table 14.
Howard Definition of Laboratory Tumor Lysis Syndrome
This definition comprises ≥ 2 of the following metabolic abnormalities.
Element
Value
Uric Acid
≥ 476 μmol/L or 8 mg/dL
Potassium
≥ 6.0 mmol/L or 6 mEq/L
Inorganic Phosphorus
≥ 1.45 mmol/L
Calcium
≤ 1.75 mmol/L


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Appendix G.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Sponsor/Emergency
  Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Cell:
Fax:
Has been changed to read:
Sponsor/Emergency
  Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Cell:
Fax:
Section 1.2  Synopsis
Subsection Exploratory objectives (both main and safety expansion cohorts):
Add:  new last paragraph
Note:  All study objectives, with the exception of Safety and MRD analyses, will cease to 
be evaluated beyond 2 years after last subject first dose.
Section 1.2  Synopsis
Subsection Survival Assessments:
Previously read:
Survival information will be collected every 3 months for up to 5 years after the last 
subject has been enrolled for subjects who have not withdrawn consent.


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Has been changed to read:
Survival information will be collected every 3 months (± 7 days) for up to 5 years after 
the last subject has been enrolled for subjects who have not withdrawn consent.
Section 1.2  Synopsis
Subsection Survival – Extended Access:
Add:  new subsection title and text
Survival – Extended Access:  For subjects who continue to derive benefit from 
venetoclax treatment 2 years following the date of the last subject enrolled, AbbVie will 
provide venetoclax until the subject develops disease progression or until 5 years 
following the date of last subject enrolled (12 May 2020).
Section 3.0  Introduction
Subsection Venetoclax Clinical Exposure
First paragraph previously read:
As of 28 November 2015, on the basis of data available in the AbbVie and 
Genentech/Roche clinical databases, a total of 1662 subjects have been exposed to at least 
1 dose of venetoclax in the oncology and immunology development programs.  A total of 
1498 oncology subjects had data available in AbbVie and Genentech/Roche studies as of 
28 November 2015.  Of these 1498, 935 subjects had CLL/small lymphocytic leukemia 
(SLL), 346 subjects had NHL, 115 subjects had MM, 102 had AML.  An additional 
66 subjects were healthy volunteers.  A total of 564 oncology subjects received the drug 
as monotherapy, 933 received the drug in combination with other therapies, and 1 subject 
received venetoclax as a single dose in a DDI study and did not re-enroll into a 
subsequent monotherapy study.  Additionally, 98 subjects were exposed to at least 1 dose 
of venetoclax in the AbbVie immunology study, Study M13-093, as of 
28 November 2015.
Has been changed to read:
As of 28 November 2016, on the basis of data available in the AbbVie and 
Genentech/Roche clinical databases, a total of 2573 subjects have been exposed to at least 


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1 dose of venetoclax in the oncology development programs.  Of these 2573, 
1429 subjects had CLL/small lymphocytic leukemia (SLL), 637 subjects had NHL, 
180 subjects had MM, and 327 had AML.  An additional 114 subjects were healthy 
volunteers.  A total of 749 oncology subjects received the drug as monotherapy, and 
1922 received the drug in combination with other therapies.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Main and Safety Expansion Cohorts
Heading "Post-Treatment Follow-Up Visit(s)"
Add:  new last paragraph
Note:  Effective with protocol Amendment 6, subjects being followed in Post-Treatment as 
of 12 May 2017 will switch to being assessed per the Survival Assessments below.  No 
new subjects will enter the Post-Treatment period.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Main and Safety Expansion Cohorts
Heading "Survival Assessment(s)" previously read:
Survival information (i.e., the date and cause of death, post treatment cancer therapies, 
etc.) will be collected via telephone calls and/or clinical visits at 3 month intervals after 
the last study visit for a period of 5 years after the last subject has enrolled on the study 
for subjects who have not withdrawn consent.
Has been changed to read:
Survival information (i.e., the date and cause of death, post treatment cancer therapies, 
etc.) will be collected via telephone calls and/or clinical visits at 3 month (±7 days) 
intervals after the last study visit for a period of 5 years after the last subject has enrolled 
on the study for subjects who have not withdrawn consent.


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Section 5.1  Overall Study Design and Plan:  Description
Subsection Main and Safety Expansion Cohorts
Heading "Option to Continue Venetoclax Treatment" previously read:
Heading title and text previously read:
Option to Continue Venetoclax Treatment
Subjects may continue receiving study drug for up to 2 years following the date of the last 
subject enrolled provided they continue to tolerate the drug, have no evidence of disease 
progression, and do not meet any of the criteria for subject discontinuation (Section 5.4.1).  
For subjects that continue to derive benefit after 2 years of treatment following the date of 
the last subject enrolled, AbbVie will work with the investigator to evaluate options for 
continuation of venetoclax.  In countries where venetoclax is not commercially available, 
the Study M13-982 will be extended to provide subjects with the opportunity to continue 
on venetoclax until alternative options become available.
Has been changed to read:
Option to Continue Venetoclax Treatment
Subjects may continue receiving study drug for up to 2 years following the date of the last 
subject enrolled provided they continue to tolerate the drug, have no evidence of disease 
progression, and do not meet any of the criteria for subject discontinuation.  Please see 
Section 5.4.1 for additional information.
Survival – Extended Access
For subjects who continue to derive benefit from venetoclax treatment 2 years following 
the date of the last subject enrolled, AbbVie will provide venetoclax for monotherapy use 
until the subject develops disease progression or until 5 years following the date of last 
subject enrolled (12 May 2020).  In countries where venetoclax is commercially available, 
subjects have the option to discontinue receiving venetoclax via the study and switch to 
commercial supply at any time but may be contacted every 12 weeks (± 7 days) to collect 
the Survival information noted above, provided they have not withdrawn consent. 


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For subjects continuing into the Survival Extended Access portion of the trial, venetoclax 
will be dispensed at the Final Visit, and Survival visits will begin 12 weeks (± 7 days) 
following the 30-day Safety Follow-Up Visit.  Survival visits will include collection of 
Survival information, AEs/SAEs and concomitant medication information, study drug 
administration, collection and dispensing of subject diaries, and MRD PCR sample 
collection for eligible subjects.  All other procedures for disease assessments will be 
performed as standard of care.
Table 2.  Excluded and Cautionary Medications/Food Items
Previously read:
Excluded
Grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or 
starfruit
Excluded During Ramp Up Phase and Cautionary Afterwards
!
Strong and Moderate CYP3A inhibitors
o
Exclude during ramp-up phase and consider alternative medications.  If subject requires use 
of these medications after the ramp-up phase, use with caution and reduce the venetoclax 
dose at least by 2-fold for moderate inhibitors and at least by 4-fold for strong inhibitors 
during co-administration.  After discontinuation of CYP3A inhibitor, wait for 3 days before 
venetoclax dose is increased back to the initial maintenance/target dose.
!
Strong and Moderate CYP3A inducers
o
Exclude during ramp-up phase and consider alternative medications.  If subject requires use 
of these medications after the ramp-up phase, use with caution and contact AbbVie medical 
monitor for guidance.
Cautionary
!
Coumarins (vitamin K antagonists) or warfarin or phenprocoumon*
!
Weak CYP3A inducers
!
Weak CYP3A inhibitors
!
P-gp substrates
!
BCRP substrates
!
OATP1B1/1B3 substrates
!
P-gp inhibitors
!
BCRP inhibitors
!
OATP1B1/B3 inhibitors
*
Closely monitor international normalized ratio (INR).


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Has been changed to read:
Excluded
Grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or 
starfruit
Excluded During Ramp Up Phase and Cautionary Afterwards
!
Strong and Moderate CYP3A inhibitors
o
Excluded during ramp-up phase and consider alternative medications.  If subject requires 
use of these medications after the ramp-up phase, use with caution and reduce the venetoclax 
dose at least by 2-fold for moderate inhibitors and at least by 4-fold for strong inhibitors during 
co-administration.  After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax 
dose is increased back to the initial maintenance/target dose.
!
Strong and Moderate CYP3A inducers
o
Exclude during ramp-up phase and consider alternative medications.  If subject requires 
use of these medications after the ramp-up phase, use with caution and contact AbbVie medical 
monitor for guidance.
Cautionary
!
Coumarins (vitamin K antagonists) or warfarin or phenprocoumon*
!
P-gp substrates**
!
BCRP substrates
!
OATP1B1/1B3 substrates
!
BCRP inhibitors
*
Closely monitor international normalized ratio (INR).
**
If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before venetoclax.


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Table 4.  Study Activities
Previously read:
Activity
Scra
Within 
72 
Hours 
Prior to 
1st
Doseb
W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-Day 
Safety 
Visit
Post-
Treatc
Informed 
Consent
X
Detection of 
17p Deletiond
X
Medical 
History/ 
Oncology 
History 
Assessment
X
X
Adverse 
Event/ 
Concomitant 
Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Examina-
tione*
X
X
X
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
X
ECOG 
Performance 
Status*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Activity
Scra
Within 
72 
Hours 
Prior to 
1st
Doseb
W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-Day 
Safety 
Visit
Post-
Treatc
Pregnancy 
Testf
X
X
Hematology/ 
Chemistryg
X
X
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh X** X** X** X** X** X** X**
X**
X**
X**
X**
X**
Coagulation 
Panel**
X
X
X
X
X
X
Urinalysis**
X
X
X
Viral 
Serologies
X
Viral 
Polymerase 
Chain Reaction
X
Quantitative 
Immuno-
globulin**
X
X
X
X
X
Lymphocyte 
Enumera-
tion**
X
X
X
X
X
X
ECG
X
X


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Activity
Scra
Within 
72 
Hours 
Prior to 
1st
Doseb
W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-Day 
Safety 
Visit
Post-
Treatc
Echocardio-
gram or a 
Multi Gated 
Acquisition 
Scan 
(MUGA)i
X
CT or MRI 
Scanj***
X
Xk
Xl
X
Xm
Bone Marrow 
Aspirate and 
Biopsy
Xn
Xo
Xo
X
Disease 
Assessments*
Xp
X
X
X
X
X
X
X
X
X
X
X
X
MRD 
Assessment
Xq
Xq
Survival 
Assessment
X


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Activity
Scra
Within 
72 
Hours 
Prior to 
1st
Doseb
W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-Day 
Safety 
Visit
Post-
Treatc
Dispense/ 
Collect 
Venetoclax 
and Subject 
Calendars/ 
Diaries
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MDASIr
X
X
X
X
X
X
EORTC 
QLQ-C30 and 
EORTC QLQ 
CLL16r
X
X
X
X
X
X
X
EQ-5D-5L 
and 
EQ-5D-VASr
X
X
X
X
X
X
Subject TL 
Surveys
X
Scr = Screening; W, Wk = Week, D = Day, Post-Treat = Post-Treatment; FV = Final Visit
Study Windows:  
*
within 72 hours before or after scheduled visit starting with Week 8 Day 1;
**
within 72 hrs prior to scheduled visit starting with Week 8 Day 1; 
***
within 7 days after scheduled visit.
a.
Subjects will undergo screening procedures within 28 days prior to the first study drug administration, except where otherwise indicated.


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b.
All subjects must receive tumor lysis prophylaxis prior to and during treatment.  For details on tumor lysis prophylaxis and management, refer to Section 6.8.1, Prophylaxis 
and Management of Tumor Lysis Syndrome and Appendix D – Recommendations for Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome (TLS).
c.
Assessments will be collected at 3 month intervals after the last study visit for a period of 5 years after the last subject has enrolled in the study.
d.
Subjects must have 17p deletion as assessed by local or central laboratory to be considered for enrollment.  A result obtained prior to study Screening may be used for 
eligibility.  A confirmatory sample will be sent to central laboratory at Screening.  Refer to Section 5.3.1.5, Collection and Handling of Biomarker Variables, for more details.
e.
A complete physical examination will be performed at Screening.  A symptom directed physical examination will be performed on Day 1 of Weeks 2 – 4 and the 30-day 
Safety Visit.  All other physical examinations will be targeted.  If during physical examination, signs or symptoms suggestive of Richter's Syndrome are observed, further 
assessments (e.g., lymph node biopsy, PET scan) should be considered to exclude or confirm the transformation.  Refer to Section 5.3.1.1 Physical Examination, for more 
details.
f.
For females of childbearing potential, a urine pregnancy test must be obtained and processed locally at the Week 1 Day 1, if it has been > 7 days since obtaining the serum 
pregnancy results at Screening.
g.
Cholesterol and triglycerides are only required at Screening and Final Visit.
h.
There is no 72 hour window for these samples.  Refer to Section 6.8.1, Prophylaxis and Management of Tumor Lysis Syndrome and Appendix D – Recommendations for 
Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS).
i.
Assessment of ejection fraction will be made at screening at the discretion of the investigator.  Subsequent evaluation of Left Ventricular Ejection Fraction (LVEF) will be 
made as clinically indicated for subjects who develop signs of cardiac compromise.
j.
If a subject exhibits clinical signs of possible disease progression (i.e., increased or de novo enlargement of liver, spleen or lymph nodes on physical examination without an 
increase in lymphocytes meeting PD criteria), a CT scan and/or bone marrow biopsy must be performed within 2 weeks to confirm or rule out PD as described in 
Section 5.3.3.2.
k.
Imaging assessments are required for all subjects at Week 36 Day 1.  Assessment to be performed on Week 36 Day 1 only (not every 12 weeks).  The Week 36 scan may be 
performed within 4 weeks before or after the 36 week scheduled visit provided that it has been at least 8 weeks since the subject's last scan.
l.
After a response is determined by clinical criteria, a CT scan will be performed no earlier than 8 weeks for confirmation of response.  For determination of CR/CRi, both the 
CT scan and bone marrow are required to be negative.  It is recommended that the CT scan is performed first, and if it does confirm a CR/CRi, then a BM biopsy should be 
obtained as soon as possible.  
m.
Post-treatment CT or MRI scans to be done only if collected by the site as part of standard of care. 
n.
A bone marrow aspirate and biopsy will be performed and assessed locally at Screening (within 35 days prior to the first dose of study drug).  Bone marrow and aspirate for 
biomarker sample collection should be split from this sample.  Refer to Table 6.


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o.
For subjects who meet all criteria for CR/CRi with the exception of a node(s) that is enlarged around 1.5 – 2 cm may also have a bone marrow performed.  If bone marrow 
was not performed at the time of the confirmatory CT, then it should be performed after the Week 36 Day 1 CT scan.
p.
At baseline, all measurable disease must be documented at screening by laboratory testing, physical examination and CT scans (or MRI if CT is medically contraindicated), 
and bone marrow examinations.
q.
Specimens (bone marrow aspirate and peripheral blood) for MRD analysis should be collected at the same time as the bone marrow aspirate and biopsy performed for tumor 
assessments to confirm the CR/CRi.  If MRD negativity is achieved in the bone marrow no further MRD analyses are required.  Otherwise, MRD should be assessed at 
12-week intervals thereafter (in peripheral blood) until MRD negativity is achieved.  Once MRD negativity is achieved and confirmed in peripheral blood (e.g., two MRD 
negative consecutive peripheral blood samples), a bone marrow aspirate specimen will again be collected for analysis of MRD levels to confirm the peripheral blood 
negativity.  Subjects who meet all criteria for CR/CRi with the exception of a node(s) that is enlarged around 1.5 – 2 cm may also have a bone marrow performed and MRD 
assessment.  If a bone marrow and MRD assessment was not performed at the time of the confirmatory CT scan, then they should be performed after the Week 36 Day 1 CT 
scan.  If MRD negativity is achieved in the bone marrow no further MRD analyses are required.  Otherwise, MRD should be assessed at 12-week intervals thereafter (in 
peripheral blood) until MRD negativity is achieved.  Once MRD negativity is achieved and confirmed in peripheral blood (e.g., two MRD negative consecutive peripheral 
blood samples), a bone marrow aspirate specimen will again be collected for analysis of MRD levels to confirm the peripheral blood negativity.
r.
The Health Economic and Patient Reported Outcomes questionnaires should be administered and completed prior to any other study procedures being performed at these 
visits.  Refer to Section 5.3.8, Health Economic and Patient-Reported Outcome Measures, for further information.
s.
For subjects in the United States only:  Subjects in the safety expansion cohort will be asked to complete a survey assessing the information they were provided for the Patient 
Information Card and the Tumor Lysis Syndrome Patient Information Brochure at Week 2 Day 1 or the next scheduled visit.  For subjects participating in the main cohort, the 
survey will be given to the subject at the next scheduled study visit upon signing the Protocol Amendment 2 Informed Consent.  This survey is optional.


Venetoclax (ABT-199)
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Has been changed to read:
Activity
Scra
Within 
72 
Hours 
Prior to 
1st Doseb W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-
Day 
Safety 
Visit
Post-
Treatc
Survival 
Follow-
Upt
Informed 
Consent
X
Detection of 
17p Deletiond
X
Medical 
History/ 
Oncology 
History 
Assessment
X
X
Adverse 
Event/ 
Concomitant 
Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Examina-
tione*
X
X
X
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
X
ECOG 
Performance 
Status*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Venetoclax (ABT-199)
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Activity
Scra
Within 
72 
Hours 
Prior to 
1st Doseb W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-
Day 
Safety 
Visit
Post-
Treatc
Survival 
Follow-
Upt
Pregnancy 
Testf
X
X
Hematology/ 
Chemistryg
X
X
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh X** X** X** X** X** X** X**
X**
X**
X**
X**
X**
Coagulation 
Panel**
X
X
X
X
X
X
Urinalysis**
X
X
X
Viral 
Serologies
X
Viral 
Polymerase 
Chain Reaction
X
Quantitative 
Immuno-
globulin**
X
X
X
X
X
Lymphocyte 
Enumera-
tion**
X
X
X
X
X
X
ECG
X
X


Venetoclax (ABT-199)
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Activity
Scra
Within 
72 
Hours 
Prior to 
1st Doseb W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-
Day 
Safety 
Visit
Post-
Treatc
Survival 
Follow-
Upt
Echocardio-
gram or a 
Multi Gated 
Acquisition 
Scan 
(MUGA)i
X
CT or MRI 
Scanj***
X
Xk
Xl
X
Xm
Bone Marrow 
Aspirate and 
Biopsy
Xn
Xo
Xo
X
Disease 
Assessments*
Xp
X
X
X
X
X
X
X
X
X
X
X
X
MRD 
Assessment
Xq
Xq
X
Survival 
Assessment†
X
X
Dispense/ 
Collect 
Venetoclax 
and Subject 
Calendars/ 
Diaries
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Venetoclax (ABT-199)
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Activity
Scra
Within 
72 
Hours 
Prior to 
1st Doseb W1
D1b
W1
D2
W2
D1b
W2
D2
W3
D1b
W3
D2
W4
D1
W4
D2
W5
D1
W5 
D2
W8
D1
W
12
D1
W
16
D1
W
20
D1
W
24
D1
W
28
D1
W
32
D1
Every 
12 Wks 
Starting 
with 
Wk 36
8 Wks 
After 
1st CR, 
CRi, or 
PR
FV
30-
Day 
Safety 
Visit
Post-
Treatc
Survival 
Follow-
Upt
MDASIr
X
X
X
X
X
X
EORTC 
QLQ-C30 and 
EORTC QLQ 
CLL16r
X
X
X
X
X
X
X
EQ-5D-5L 
and 
EQ-5D-VASr
X
X
X
X
X
X
Subject TL 
Surveys
X
Scr = Screening; W, Wk = Week, D = Day, Post-Treat = Post-Treatment; FV = Final Visit
Study Windows:  
*
within 72 hours before or after scheduled visit starting with Week 8 Day 1;
**
within 72 hrs prior to scheduled visit starting with Week 8 Day 1; 
***
within 7 days after scheduled visit.
†
within ± 7 days of scheduled visit.
a.
Subjects will undergo screening procedures within 28 days prior to the first study drug administration, except where otherwise indicated.
b.
All subjects must receive tumor lysis prophylaxis prior to and during treatment.  For details on tumor lysis prophylaxis and management, refer to Section 6.1.8.1, Prophylaxis 
and Management of Tumor Lysis Syndrome and Appendix D – Recommendations for Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome (TLS).
c.
Assessments will be collected at 3 month intervals after the last study visit for a period of 5 years after the last subject has enrolled in the study.
d.
Subjects must have 17p deletion as assessed by local or central laboratory to be considered for enrollment.  A result obtained prior to study Screening may be used for 
eligibility.  A confirmatory sample will be sent to central laboratory at Screening.  Refer to Section 5.3.1.5, Collection and Handling of Biomarker Variables, for more details.


Venetoclax (ABT-199)
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EudraCT 2012-004027-20
205
e.
A complete physical examination will be performed at Screening.  A symptom directed physical examination will be performed on Day 1 of Weeks 2 – 4 and the 30-day 
Safety Visit.  All other physical examinations will be targeted.  If during physical examination, signs or symptoms suggestive of Richter's Syndrome are observed, further 
assessments (e.g., lymph node biopsy, PET scan) should be considered to exclude or confirm the transformation.  Refer to Section 5.3.1.1 Physical Examination, for more 
details.
f.
For females of childbearing potential, a urine pregnancy test must be obtained and processed locally at the Week 1 Day 1, if it has been > 7 days since obtaining the serum 
pregnancy results at Screening.
g.
Cholesterol and triglycerides are only required at Screening and Final Visit.
h.
There is no 72 hour window for these samples.  Refer to Section 6.1.8.1, Prophylaxis and Management of Tumor Lysis Syndrome and Appendix D – Recommendations for 
Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS).
i.
Assessment of ejection fraction will be made at screening at the discretion of the investigator.  Subsequent evaluation of Left Ventricular Ejection Fraction (LVEF) will be 
made as clinically indicated for subjects who develop signs of cardiac compromise.
j.
If a subject exhibits clinical signs of possible disease progression (i.e., increased or de novo enlargement of liver, spleen or lymph nodes on physical examination without an 
increase in lymphocytes meeting PD criteria), a CT scan and/or bone marrow biopsy must be performed within 2 weeks to confirm or rule out PD as described in 
Section 5.3.3.2.
k.
Imaging assessments are required for all subjects at Week 36 Day 1.  Assessment to be performed on Week 36 Day 1 only (not every 12 weeks).  The Week 36 scan may be 
performed within 4 weeks before or after the 36 week scheduled visit provided that it has been at least 8 weeks since the subject's last scan.
l.
After a response is determined by clinical criteria, a CT scan will be performed no earlier than 8 weeks for confirmation of response.  For determination of CR/CRi, both the 
CT scan and bone marrow are required to be negative.  It is recommended that the CT scan is performed first, and if it does confirm a CR/CRi, then a BM biopsy should be 
obtained as soon as possible.  
m.
Post-treatment CT or MRI scans to be done only if collected by the site as part of standard of care. 
n.
A bone marrow aspirate and biopsy will be performed and assessed locally at Screening (within 35 days prior to the first dose of study drug).  Bone marrow and aspirate for 
biomarker sample collection should be split from this sample.  Refer to Table 6.
o.
For subjects who meet all criteria for CR/CRi with the exception of a node(s) that is enlarged around 1.5 – 2 cm may also have a bone marrow performed.  If bone marrow 
was not performed at the time of the confirmatory CT, then it should be performed after the Week 36 Day 1 CT scan.
p.
At baseline, all measurable disease must be documented at screening by laboratory testing, physical examination and CT scans (or MRI if CT is medically contraindicated), 
and bone marrow examinations.


Venetoclax (ABT-199)
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206
q.
Specimens (bone marrow aspirate and peripheral blood) for MRD analysis should be collected at the same time as the bone marrow aspirate and biopsy performed for tumor 
assessments to confirm the CR/CRi.  If MRD negativity is achieved in the bone marrow no further MRD analyses are required.  Otherwise, MRD should be assessed at 
12-week intervals thereafter (in peripheral blood) until MRD negativity is achieved.  Once MRD negativity is achieved and confirmed in peripheral blood (e.g., two MRD 
negative consecutive peripheral blood samples), a bone marrow aspirate specimen will again be collected for analysis of MRD levels to confirm the peripheral blood 
negativity.  Subjects who meet all criteria for CR/CRi with the exception of a node(s) that is enlarged around 1.5 – 2 cm may also have a bone marrow performed and MRD 
assessment.  If a bone marrow and MRD assessment was not performed at the time of the confirmatory CT scan, then they should be performed after the Week 36 Day 1 CT 
scan.  If MRD negativity is achieved in the bone marrow no further MRD analyses are required.  Otherwise, MRD should be assessed at 12-week intervals thereafter (in 
peripheral blood) until MRD negativity is achieved.  Once MRD negativity is achieved and confirmed in peripheral blood (e.g., two MRD negative consecutive peripheral 
blood samples), a bone marrow aspirate specimen will again be collected for analysis of MRD levels to confirm the peripheral blood negativity.
r.
The Health Economic and Patient Reported Outcomes questionnaires should be administered and completed prior to any other study procedures being performed at these 
visits.  Refer to Section 5.3.8, Health Economic and Patient-Reported Outcome Measures, for further information.
s.
For subjects in the United States only:  Subjects in the safety expansion cohort will be asked to complete a survey assessing the information they were provided for the Patient 
Information Card and the Tumor Lysis Syndrome Patient Information Brochure at Week 2 Day 1 or the next scheduled visit.  For subjects participating in the main cohort, the 
survey will be given to the subject at the next scheduled study visit upon signing the Protocol Amendment 2 Informed Consent.  This survey is optional.
t.
For subjects continuing into the Survival Extended Access portion of the trial, Survival vists will include collection of Survival information, AEs/SAEs and concomitant 
medication information, study drug administration, collection and dispensing of subject diaries, and MRD PCR sample collection for eligible subjects.  All other procedures 
for disease assessments will be perfomed as standard of care.


Venetoclax (ABT-199)
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EudraCT 2012-004027-20
207
Table 6.  Schedule of Biomarkers and Pharmacogenetic Sample Collection
Header row, column "Final Visit/Time of Relapseg" previously read:
Final Visit/Time of Relapseg
Has been changed to read:
Final Visit/Time of Relapseg,h
Table 6.  Schedule of Biomarkers and Pharmacogenetic Sample Collection
Add:  table note "h."
No final visit biomarker specimens are required for subjects that transition to the survival 
extended assess portion of the study.
Section 5.3.1.1  Study Procedures
Subsection Quantitative Minimal Residual Disease (MRD) Assessment
Add:  new fourth paragraph
Subjects continuing into the Survival Extended Access portion of the study, and who 
continue to be eligible for MRD testing, will have blood specimens collected for MRD 
PCR collected at 12-week (± 7 days) intervals.  If a subject undergoes a bone marrow 
biopsy as standard of care while on the survival extended access portion, a portion of the 
aspirate is requested to be collected for MRD-PCR.
Section 5.3.1.1  Study Procedures
Subsection Post-Treatment Follow-Up Visit(s)
Add:  new last paragraph
Note:  Effective with protocol Amendment 6, subjects being followed in Post-Treatment as 
of 12 May 2017 will switch to being assessed per the Survival Assessments below.  No 
new subjects will enter the Post-Treatment period.


Venetoclax (ABT-199)
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Section 5.3.1.1  Study Procedures
Subsection Survival Assessment(s)
Previously read:
Survival information (i.e., the date and cause of death, post treatment cancer therapies, 
etc.) will be collected via telephone calls and/or clinical visits at 3 month intervals after 
the last study visit for a period of 5 years after the last subject has enrolled on the study 
for subjects who have not withdrawn consent.
Has been changed to read:
Survival information (i.e., the date and cause of death, post treatment cancer therapies, 
etc.) will be collected via telephone calls and/or clinical visits at 3 month (± 7 days) 
intervals after the last study visit for a period of 5 years after the last subject has enrolled 
on the study for subjects who have not withdrawn consent.
Section 5.3.1.1  Study Procedures
Subsection Survival Assessment(s) – Extended Access
Add:  new subsection title and text
Survival Assessment(s) – Extended Access
For subjects continuing into the Survival Extended Access portion of the trial, venetoclax 
will be dispensed at the Final Visit, and Survival visits will begin 12 weeks (± 7 days) 
following the 30-day Safety Follow-Up Visit.  Survival visits will continue every 
12 weeks (±7 days) until disease progression; up to 5 years following last subject enrolled 
(12 May 2020); or until a subject chooses to switch to commercial supply.  Survival visits 
will include: 
●
Collection of Survival information
●
AE/SAE/Con Med assessment
●
Study drug reconciliation and dispensing
●
Collect/Dispense subject diaries 
●
MRD PCR sample collection for eligible subjects


Venetoclax (ABT-199)
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209
All other procedures for disease assessments will be performed as standard of care.
Section 5.4.1  Discontinuation of Individual Subjects
Add:  new third paragraph
Subjects with disease progression who continue to receive venetoclax will also be allowed 
to receive other agents approved to treat CLL in addition to venetoclax.  This will be 
added at the discretion of the investigator, and AbbVie or its partners will not reimburse 
for treatment agents or for the procedures required to monitor subjects other than those 
required per protocol.
Section 6.0  Complaints
Add:  new section title and text
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.  For product complaints, please refer to Section 6.2.
Section 6.0 through 6.8.4
Section number and title previously read:
6.0
Adverse Events
6.1
Definitions
6.1.1
Adverse Event
6.1.2
Serious Adverse Events
6.2
Adverse Event Severity


Venetoclax (ABT-199)
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6.3
Adverse Events Expected Due to Study Related Endpoints
6.3.1
Deaths
6.3.2
Lack of Efficacy or Worsening of Disease
6.4
Relationship to Study Drug
6.5
Adverse Event Collection Period
6.6
Adverse Event Reporting
6.7
Pregnancy
6.8
Toxicity Management
6.8.1
Prophylaxis and Management of Tumor Lysis Syndrome
6.8.2
Management of Neutropenia
6.8.3
Management of Lymphopenia
6.8.4
Management of Decrease in Spermatogenesis
Has been changed to read:
6.0
Complaints
6.1
Medical Complaints
6.1.1
Definitions
6.1.1.1
Adverse Event
6.1.1.2
Serious Adverse Events
6.1.2
Adverse Event Severity
6.1.3
Relationship to Study Drug
6.1.4
Adverse Events Expected Due to Study Related Endpoints
6.1.4.1
Deaths


Venetoclax (ABT-199)
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6.1.4.2
Lack of Efficacy or Worsening of Disease
6.1.5
Adverse Event Collection Period
6.1.6
Adverse Event Reporting
6.1.7
Pregnancy
6.1.8
Toxicity Management
6.1.8.1
Prophylaxis and Management of Tumor Lysis Syndrome
6.1.8.2
Management of Neutropenia
6.1.8.3
Management of Lymphopenia
6.1.8.4
Management of Decrease in Spermatogenesis
Section 6.1.3  Relationship to Study Drug
Add:  new section title and text
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, 


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AbbVie will consider the event associated.  If an investigator's opinion of no reasonable 
possibility of being related to study drug is given, an "Other" cause of event must be 
provided by the investigator for the serious adverse event.
Section 6.4  Relationship to Study Drug
Delete:  section title and text
6.4
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.
Section 6.6  Adverse Event Reporting
Third paragraph
Delete:  "Safety Phone:"
Safety Phone: (847) 935-2609


Venetoclax (ABT-199)
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213
Section 6.6  Adverse Event Reporting
Fourth paragraph previously read:
For any subject safety concerns, please contact the AbbVie medical monitor:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Cell:
Fax:
Email:
Has been changed to read:
For any subject safety concerns, please contact the AbbVie medical monitor:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Cell:
Fax:
Email:


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Section 6.2  Product Complaint
Add:  new section and text, renumber subsequent sections
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 via the Product 
Complaint form.  Product Complaints occurring during 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.


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Section 7.0  Protocol Deviations
"Medical Monitor:" previously read:
Medical Monitor:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Cell:
Fax:
Email:
Has been changed to read:
Medical Monitor:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Cell:
Fax:
Email:


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Section 7.0  Protocol Deviations
"Associate Director:" previously read:
Associate Director:
Program Lead II
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Contact Information:
Office:
Fax:
Email:
Has been changed to read:
Program Lead:
Program Lead II
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Contact Information:
Office:
Fax:
Email:
Section 8.1.1.2.7  Additional Exploratory Efficacy Analyses
Second paragraph previously read:
The rate of MRD negativity in subjects will be an exploratory endpoint.  This rate will be 
defined as the proportion of subjects who had MRD negativity status.  Ninety-five percent 
(95%) confidence intervals based on the binomial distribution will be provided.


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Has been changed to read:
The rate of MRD negativity in subjects will be an exploratory endpoint.  This rate will be 
defined as the proportion of subjects who had MRD negativity status by MRD-flow.  
Ninety-five percent (95%) confidence intervals based on the binomial distribution will be 
provided.  MRD data for this exploratory analysis was based on the MRD flow cytometry 
data and will not be collected for subjects who continue on in the survival extended access 
portion of the study.  MRD-PCR specimens will be collected and analyzed for subjects 
who are eligible.  This data will not be included in the clinical study report.
Section 8.1.4.1  Additional Exploratory Efficacy Analyses
Second paragraph previously read:
The rate of MRD negativity in subjects will be an exploratory endpoint.  This rate will be 
defined as the proportion of subjects who had MRD negativity status.  Ninety-five percent 
(95%) confidence intervals based on the binomial distribution will be provided.
Has been changed to read:
The rate of MRD negativity in subjects will be an exploratory endpoint.  This rate will be 
defined as the proportion of subjects who had MRD negativity status.  Ninety-five percent 
(95%) confidence intervals based on the binomial distribution will be provided.  MRD 
data for this exploratory analysis was based on the MRD-Flow specimens and will not be 
collected for subjects who continue on in the survival extended access portion of the 
study.  MRD-PCR specimens will be collected and analyzed for subjects who are eligible.  
This data will not be included in the final clinical study report.
Section 15.0  Reference List
Reference 10 previously read:
AbbVie.  ABT-199 Investigator's Brochure Edition 7.  15 February 2016.
Has been changed to read:
AbbVie.  ABT-199 Investigator's Brochure Edition 8.  15 February 2017.


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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Statistics
Clinical
Clinical
Global Drug Supply Management
Clinical
Biomarkers
Pharmacokinetics
Bioanalysis
Has been changed to read:
Name
Title
Functional Area
Statistics
Clinical
Clinical
Global Drug Supply Management
Clinical
Biomarkers
Pharmacokinetics
Bioanalysis


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Appendix C.  Sample List of Excluded and Cautionary Medications
Previously read:
Excluded During Ramp-Up Phase and Cautionary Afterwards:  (Additional Guidance Noted):
Strong CYP3A inducers –––^–– avasimibe, carbamazepine (Tegretol®), phenytoin (Dilantin®), 
rifampin (Rifadin®), St. John's wort
Moderate CYP3A inducers^ – bosentan, efavirenz, etravirine, modafinil, nafcillin
Strong CYP3A inhibitors† – Boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, 
ketoconazole, mibefradil, lopinavir/ritonavir, nefazodone, nelfinavir, ritonavir, posaconazole, saquinavir,
telaprevir, telithromycin, voriconazole
Moderate CYP3A inhibitors†† – Amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib*, 
darunavir/ritonavir, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, imatinib*, 
verapamil
Cautionary
Coumarins (vitamin K antagonists):
  Warfarin (Coumadin)**
  phenprocoumon (Marcumar)**
Weak CYP3A inducers
Amprenavir, aprepitant, armodafinil, clobazamechinacea, pioglitazone, prednisone, rufinamide, 
vemurafenib*
Weak CYP3A inhibitors
Alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide*, cilostazol, cimetidine, cyclosporine*, 
fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, nilotinib*, oral contraceptives, pazopanib*, 
ranitidine, ranolazine, tipranavir/ritonavir, ticagrelor, zileuton
P-gp substrates
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus*, fexofenadine, lapatinib*, 
loperamide, maraviroc, nilotinib*, ranolazine, saxagliptin, sirolimus*, sitagliptin, talinolol, tolvaptan, 
topotecan*
BCRP substrates
Methotrexate*, mitoxantrone*, irrinotecan*, lapatinib*, rosuvastatin, sulfasalazine, topotecan*
OATP1B1/1B3 substrates
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, rosuvastatin, simvastatin acid, pitavastatin, 
pravastatin, repaglinide, telmisartan, valsartan, olmesartan
P-gp inhibitors
Amiodarone, azithromycin, captopril, carvedilol, felodipine, quercetin, ronalzine, quinidine, ronalzine, 
ticagrelor
BCRP inhibitors
Geftinib*, cyclosporine*
OATP1B1/B3 inhibitors
Gemfibrozil, eltrombopag, cyclosporine*, tipranavir


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Note that this is not an exhaustive list.  For an updated list, see the following link:  
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm08049
9 htm
In addition to the medications listed in this table, subjects receiving venetoclax should not consume grapefruit, 
grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruits.
*
These are anticancer agents; contact AbbVie medical monitor before use.
**    Closely monitor international normalized ratio (INR).
^
If subject requires use of these medications, use with caution and contact AbbVie Primary TA MD or designee for 
guidance.
†
If subject requires use of these medications, use with caution and reduce the venetoclax dose at least by 4-fold.  
After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose is increased back to the target 
dose.
††
If subject requires use of these medications, use with caution and reduce the venetoclax dose at least by 2-fold.  
After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose is increased back to the target 
dose.


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


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

SAP_001.pdf: 
Venetoclax (ABT-199)
M13-982 – Statistical Analysis Plan
Version 3.0 – 27 April 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M13-982
A Phase 2 Open-Label Study of the Efficacy of
ABT-199 in Subjects with Relapsed or Refractory 
Chronic Lymphocytic Leukemia Harboring the 
17p Deletion
Date:  27 April 2018
Version 3.0
NCT01889186


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Study Design and Plan............................................................................ 6
4.3
Sample Size............................................................................................ 7
4.4
Interim Analysis..................................................................................... 9
4.4.1
Independent Data Monitoring Committee (IDMC) ................................. 9
4.5
Timing of Efficacy Analyses and Safety Evaluations.............................. 9
5.0
Analysis Populations ........................................................... 16
5.1
Definition for Analysis Populations ...................................................... 16
5.2
Variables Used for Stratification of Randomization .............................. 17
6.0
Analysis Conventions .......................................................... 17
7.0
Patient Disposition............................................................... 22
8.0
Demographics, Baseline Characteristics, Medical 
History, and Previous Concomitant Medications..............23
8.1
General Consideration.......................................................................... 23
8.2
Demographic and Baseline Characteristics ........................................... 23
8.3
Medical History.................................................................................... 24
8.4
Previous Treatment and Concomitant Medications ............................... 25
9.0
Venetoclax Exposure and Compliance............................... 26
10.0
Efficacy Analysis .................................................................26
10.1
General Considerations......................................................................... 26
10.2
Main Cohort Analysis........................................................................... 27
10.2.1
Primary Efficacy Analysis.................................................................... 27
10.2.2
Secondary Efficacy Analyses ............................................................... 27
10.2.3
Additional Exploratory Efficacy Analyses............................................ 30
10.3
Safety Expansion Cohort ...................................................................... 33
10.3.1
Efficacy Analyses................................................................................. 33
10.3.2
Additional Exploratory Efficacy Analyses............................................ 33


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10.4
Handling of Multiplicity....................................................................... 33
10.5
Efficacy Subgroup Analysis ................................................................. 33
10.6
Efficacy Data Conventions ................................................................... 34
11.0
Safety Analysis.....................................................................35
11.1
Analysis of Treatment-Emergent Adverse Events................................. 36
11.2
Deaths.................................................................................................. 38
11.3
Analysis of Laboratory and Vital Signs Data ........................................ 38
11.3.1
Analysis of Mean Changes from Baseline in Clinical Laboratory 
Data...................................................................................................... 38
11.3.2
Analyses of Shift from Baseline in Clinical Laboratory Data ................ 39
11.3.3
Assessment of Potentially Clinically Significant Laboratory 
Values .................................................................................................. 40
11.3.4
Assessment of Mean Changes from Baseline in Vital Signs 
Variables.............................................................................................. 43
11.3.5
Assessment of Potentially Clinically Significant Vital Signs 
Values .................................................................................................. 43
11.4
ECG/2D Echocardiogram..................................................................... 44
12.0
Pharmacokinetic Analyses..................................................44
12.1
Tabulations and Summary Statistics ..................................................... 44
12.2
Attainment of Steady State ................................................................... 45
13.0
Summary of Changes .......................................................... 45
13.1
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP ................................................................................... 45
14.0
References............................................................................46
List of Tables
Table 1.
Sample Size Calculation......................................................................... 8
Table 2.
Efficacy and Safety Analyses for the 1st Interim CSR 
(R&D/14/1067)‡................................................................................... 10
Table 3.
Efficacy and Safety Analyses for the 2nd Interim CSR 
(R&D/16/0801)‡................................................................................... 12
Table 4.
Efficacy and Safety Analyses for the 3rd Interim CSR 
(R&D/17/1065)‡................................................................................... 14


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Table 5.
Analysis Populations for Efficacy and Safety Analyses ........................ 17
Table 6.
Time Windows for Analysis of Hematology, Chemistry 
Parameters, Vital Signs, and Performance Status.................................. 20
Table 7.
Time Windows for Analysis of Urinalysis ............................................ 21
Table 8.
Time Windows for Quality of Life ....................................................... 22
Table 9.
Adverse Events of Special Interest........................................................ 37
Table 10.
Clinical Laboratory Tests ..................................................................... 39
Table 11.
Criteria for Potentially Clinically Significant Laboratory Values –
Chemistry Variables ............................................................................. 41
Table 12.
Criteria for Potentially Clinically Significant Laboratory Values –
Hematology Variables .......................................................................... 42
Table 13.
Howard Criteria for TLS ...................................................................... 42
Table 14.
Criteria for Potentially Clinically Significant Laboratory Values –
Vital Signs Variables............................................................................ 44
List of Figures
Figure 1.
Dosing Schematic – Main Cohort........................................................... 7
Figure 2.
Dosing Schematic – Safety Expansion Cohort ........................................ 7
List of Appendices
Appendix A.
List of Abbreviations............................................................................ 47


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3.0
Introduction
This statistical analysis plan (SAP) describes the full statistical analyses for Venetoclax 
(ABT-199) original protocol and all protocol amendments for Study M13-982.  The latest 
Protocol Amendment 6 is dated 28 February 2017.  It will provide details of statistical 
methods and describe analysis conventions to guide the statistical programming work.
Unless noted otherwise, all analyses will be performed using SAS® version 9.3 (SAS 
Institute Inc., Cary, NC  27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
Main Cohort
The primary objective of this cohort is to evaluate the efficacy of Venetoclax 
monotherapy in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) 
harboring the 17p deletion.  Efficacy will be measured by overall response rate (ORR) 
based on an independent review committee (IRC) assessment.
The secondary objectives are to evaluate the ORR by investigator assessment, complete 
remission rate (CR rate), partial remission rate (PR rate), duration of overall response 
(DoR), progression-free survival (PFS), event free survival (EFS), time to progression 
(TTP), time to first response, time to 50% reduction in absolute lymphocyte count (ALC), 
overall survival (OS) and percent of subjects who move on to stem cell transplant.  The 
safety and tolerability of Venetoclax in subjects with relapsed or refractory CLL 
harboring 17p deletion will also be evaluated.
Safety Expansion Cohort
The primary objective of the safety expansion cohort is to evaluate the safety of 
Venetoclax in approximately 50 subjects with relapsed or refractory CLL harboring 
17p deletion treated per the updated TLS prophylaxis and management measures based on 


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the analysis conducted on 58 subjects utilizing the TLS prophylaxis and management 
procedures.
The secondary objectives are to evaluate ORR, CR rate, PR rate, DoR, PFS, EFS, TTP, 
time to first response, time to 50% reduction in absolute lymphocyte count (ALC), OS, 
and percent of subjects who move on to stem cell transplant.
Exploratory Objectives
The exploratory objectives which will be evaluated in both cohorts include time to next 
anti-leukemia treatment (TTNT) and minimal residual disease (MRD) response rate, 
assessed in the peripheral blood and/or bone marrow (BM).  Pharmacokinetics, 
pharmacogenetics and biomarkers will also be evaluated as exploratory objectives.  
Health Economic and Patient-Reported Outcome Measures will include the MDASI 
(measure of subject reported symptoms), the EORTC QLQ-C30 and EORTC 
QLQ-CLL16 (a measure of health related quality of life specific to CLL) and the 
EQ-5D-5L (measure of general health status) and EQ-5D-VAS.
4.2
Study Design and Plan
This is an open-label, single arm, multicenter, global study to determine the efficacy and 
safety of Venetoclax monotherapy in subjects with relapsed or refractory chronic 
lymphocytic leukemia harboring 17p deletion sponsored by AbbVie in collaboration with 
Genentech/Roche.
Subjects in this study were enrolled at 56 research sites.
After the first 21 subjects had completed 12 weeks of study treatment in the Main Cohort, 
a safety analysis was conducted by an Independent Data Monitoring Committee (IDMC).  
In the safety expansion cohort, interim safety analysis results will be reviewed by the 
IDMC after approximately 20 subjects have completed approximately 5 weeks of the 
lead-in period.


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Dosing Schedule Overview
Venetoclax was administered orally once daily (QD), continuously.  To mitigate the risk 
for TLS, a lead-in period (up to 5 weeks) was employed to evaluate a step wise dose 
escalation as specified in the protocol, and Figure 1 and Figure 2.
Figure 1.
Dosing Schematic – Main Cohort
Figure 2.
Dosing Schematic – Safety Expansion Cohort
4.3
Sample Size
Approximately 100 subjects were planned to be enrolled in the main cohort to assess the 
safety and efficacy of Venetoclax in subjects with relapsed or refractory chronic 
lymphocytic leukemia (CLL) harboring the 17p deletion.  With this sample size, if a rare 


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adverse event occurs at a rate of 2%, then the probability of observing at least 1 event in a 
trial with 100 subjects is 86%.
Reported overall response rates (ORR) for CLL subjects with 17p deletion range from 
approximately 7% to 77% with the higher responses in more novel but also more toxic 
regimens such as alemtuzumab + steroids.1  Conventional therapies such as FCR and BR, 
demonstrated ORRs of 35% and 7%, respectively.  Therefore, a therapy providing a 
significant benefit in overall response rate over a standard rate of 40% would be 
considered clinically meaningful.
Performing the efficacy analyses at 70 subjects provides at least 90% power (at two-sided 
alpha of 5%) to reject the null hypothesis of 40% ORR in favor of an alternative 
hypothesis of 60% ORR.  The power calculations for a range of different sample sizes are 
presented in Table 1.
Table 1.
Sample Size Calculation
Subjects (N)
Power (%)
50
76
60
82
70
90
80
93
90
96
For the safety expansion cohort, an additional 50 subjects will be enrolled to assess the 
modifications made to the initial dosing of Venetoclax for the management of TLS.  With 
this sample size, if a TLS event occurs at a rate of 2%, then the probability of observing at 
least 1 event in this cohort of 50 subjects is 64%.


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4.4
Interim Analysis
4.4.1
Independent Data Monitoring Committee (IDMC)
In the Main Cohort, the safety data from the first 21 subjects who had completed at least 
12 weeks of study treatment was reviewed by an Independent Data Monitoring 
Committee (IDMC).  A separate charter was created to provide detailed descriptions of 
the anticipated schedule of the interim analyses and the IDMC meetings.  The IDMC 
membership, responsibilities and the description of the data coordinating center were 
documented in the charter.  The IDMC received a data summary, which included 
enrollment data, subject baseline characteristics and safety data.
The IDMC recommended the continuation of the study.
An additional interim analysis of safety data will be reviewed by the IDMC after 
approximately 20 subjects have completed approximately 5 weeks of the lead-in period in 
the safety expansion cohort.
4.5
Timing of Efficacy Analyses and Safety Evaluations
To support regulatory submissions and post-approval requirements of Venetoclax for the 
treatment of relapsed/refractory CLL, interim CSRs were written using efficacy and safety 
analyses based on the database version and data cutoff dates illustrated in below Table 2, 
Table 3, and Table 4.  Descriptions of the analysis datasets for the analyses are provided 
in Section 5.1. 
There were two IRC assessments in the study.  The first IRC assessment was done for the 
107 subjects in the main cohort after they completed 36-week disease assessment.  The 
second IRC assessment was done separately at a later date for the 5 frontline subjects 
from the expansion cohort after they completed 36-week disease assessment.  The 
107 subjects from the main cohort were not evaluated again in the second IRC 
assessment.


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Table 2.
Efficacy and Safety Analyses for the 1st Interim CSR (R&D/14/1067)‡
Cutoff Date&
30APR2015
Database Version&
M13982Y
Number of Subjects
N = 107
N = 145
Efficacy Summaries
Assessment
Safety Summaries
ORR (CR + CRi + nPR + PR Rates)
IRC
Yes
Adverse Events
Yes (N = 107 + 38**)
Investigator
Yes
SAEs/Deaths/AEs leading to discontinuation
Yes (N = 107 + 38**)
DoR
IRC
Yes
Labs (Hematology, Chemistry, and Urinalysis)
Yes (N = 107 + 38**)
Investigator
Yes
Vital Signs
Yes (N = 107 + 38**)
PFS
IRC
Yes
Investigator
Yes
EFS
IRC
Yes
Investigator
Yes
TTP
IRC
Yes
Investigator
Yes
Time to First Response
IRC
Yes
Investigator
Yes
Time to 50% Reduction in ALC
Yes
OS
Yes
Percent of Subjects Who Move to Stem 
Cell Transplant
Yes
Time to Next Anti-Leukemia Treatment
Yes
MRD Response Rate
IRC
Yes
Investigator
Yes


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Table 2.
Efficacy and Safety Analyses for the 1st Interim CSR (R&D/14/1067)‡ (Continued)
Cutoff Date&
30APR2015
Database Version&
M13982Y
Number of Subjects
N = 107
N = 145
Efficacy Summaries
Assessment
Safety Summaries
MDASI, HEOR (EORTC QLQ-C30, 
EORTC QLQ CLL16, EQ-5D-5L, EQ-
5D-VAS)
Yes
&
All data will be included up to the date specified for the identified summaries.
**
Subjects from the safety expansion cohort receiving at least one dose of Venetoclax will be included in the safety analyses. The final subject number was determined at the 
time of the data cutoff.
‡
1st CSR report was used for the original R/R 17p del CLL NDA.  An efficacy and safety analysis will occur when all subjects enrolled in the Main Cohort have completed the 
36-week disease assessment.


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Table 3.
Efficacy and Safety Analyses for the 2nd Interim CSR (R&D/16/0801)‡
Description
30APR2015 (IRC), 10JUN2016 (INV)*
10JUN2016
Database Version&
M13982Y (IRC), M13982AH (INV)
M13982AH
Number of Subjects
N = 107 (IRC), 158 (INV)†
N = 158†
Efficacy Summaries
Assessment
Safety Summaries
ORR (CR + CRi + nPR + PR Rates)
IRC
Yes (N = 107)
Adverse Events
Yes (N = 107 (main) + 51 (expansion)†
Investigator
Yes (N = 107 (main) + 51 (expansion)†
SAEs/Deaths/AEs leading to 
discontinuation
Yes (N = 107 (main) + 51 (expansion)†
DoR
IRC
Yes (N = 107)
Labs (Hematology, 
Chemistry, and Urinalysis)
Yes (N = 107 (main) + 51 (expansion)†
Investigator
Yes (N = 107 (main) + 51 (expansion)†
Vital Signs
Yes (N = 107 (main) + 51 (expansion)†
PFS
IRC
Yes (N = 107)
Investigator
Yes (N = 107 (main) + 51 (expansion)†
EFS
IRC
Yes (N = 107)
Investigator
Yes (N = 107 (main) + 51 (expansion)†
TTP
IRC
Yes (N = 107)
Investigator
Yes (N = 107 (main) + 51 (expansion)†
Time to First Response
IRC
Yes (N = 107)
Investigator
Yes (N = 107)
Time to 50% Reduction in ALC
Yes (N = 107)
OS
Yes (N = 107 (main) + 51 (expansion)†


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Table 3.
Efficacy and Safety Analyses for the 2nd Interim CSR (R&D/16/0801)‡ (Continued)
Description
30APR2015 (IRC), 10JUN2016 (INV)*
10JUN2016
Database Version&
M13982Y (IRC), M13982AH (INV)
M13982AH
Number of Subjects
N = 107 (IRC), 158 (INV)†
N = 158†
Efficacy Summaries
Assessment
Safety Summaries
Percent of Subjects Who Move to 
Stem Cell Transplant
Yes (N = 107)
Time to Next Anti-Leukemia 
Treatment
Yes (N = 107)
No
MRD Response Rate
IRC
Yes (N = 107)
Investigator
Yes (N = 107 (main) + 51 (expansion) †
MDASI, HEOR (EORTC QLQ-
C30, EORTC QLQ CLL16, EQ-5D-
5L, EQ-5D-VAS)
Yes (N = 107)
&
All data will be included up to the date specified for the identified summaries.
†
N = 107 from the main cohort and N = 51 from expansion cohort.
*
10JUN2016 is the Investigator cutoff date; 30APR2015 is the IRC cutoff date.
‡
The 2nd interim CSR was submitted for the FDA expanded monotherapy sNDA for patients with chronic lymphocytic leukemia (CLL) with or without 17p deletion, who have 
received at least one prior therapy.


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Table 4.
Efficacy and Safety Analyses for the 3rd Interim CSR (R&D/17/1065)‡
Data Cutoff Date&
30APR2015 (IRC-Main Cohort) #
29JAN2016 (IRC-5 Frontline Subjects) #
15JUN2017 (INV) #
15JUN2017
(Database Version)&
M13982Y (IRC-Main Cohort)
M13982AE (IRC-5 Frontline Subjects)
M13982AL (INV)
M13982AL
Number of Subjects
N = 112 (IRC)**, 158 (INV)†
N = 158†
Efficacy Summaries
Assessment
Safety Summaries
ORR (CR + CRi + nPR + PR Rates)
IRC
Yes (N = 107 + 5)**
Adverse Events
Yes (N = 107 (main) + 51 (expansion)↑
Investigator
Yes (N = 107 (main) + 51 (expansion)†
SAEs/Deaths/AEs leading to 
discontinuation
Yes (N = 107 (main) + 51 (expansion)↑
DoR
IRC
Yes (N = 107 + 5) **
Labs (Hematology, Chemistry, 
and Urinalysis)
Yes (N = 107 (main) + 51 (expansion)↑
Investigator
Yes (N = 107 (main) + 51 (expansion)†
Vital Signs
Yes (N = 107 (main) + 51 (expansion)↑
PFS
IRC
Yes (N = 107 + 5) **
Investigator
Yes (N = 107 (main) + 51 (expansion)†
EFS
IRC
Yes (N = 107 + 5)**
Investigator
Yes (N = 107 (main) + 51 (expansion)†
Description
TTP
IRC
Yes (N = 107 + 5) **
Investigator
Yes (N = 107 (main) + 51 (expansion)†
Time to First Response
IRC
Yes (N = 107 + 5) **
Investigator
Yes (N = 107 (main) + 51 (expansion)†
Time to 50% Reduction in ALC
Yes (N = 107 (main) + 51 (expansion)†


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Table 4.
Efficacy and Safety Analyses for the 3rd Interim CSR (R&D/17/1065)‡ (Continued)
Data Cutoff Date&
30APR2015 (IRC-Main Cohort) #
29JAN2016 (IRC-5 Frontline Subjects) #
15JUN2017 (INV) #
15JUN2017
(Database Version)&
M13982Y (IRC-Main Cohort)
M13982AE (IRC-5 Frontline Subjects)
M13982AL (INV)
M13982AL
Number of Subjects
N = 112 (IRC) **, 158 (INV)†
N=158†
Efficacy Summaries
Assessment
Safety Summaries
OS
Yes (N = 107 (main) + 51 (expansion)†
Percent of Subjects Who Move to 
Stem Cell Transplant
Yes (N = 107 (main) + 51 (expansion)†
Time to Next Anti-Leukemia 
Treatment
Yes (N = 107 (main) + 51 (expansion)†
MRD Response Rate
IRC
Yes (N = 107 + 5)**
Investigator
Yes (N = 107 (main) + 51 (expansion)†
MDASI, HEOR (EORTC QLQ-C30, 
EORTC QLQ CLL16, EQ-5D-5L, 
EQ-5D-VAS)
Yes (N = 107 (main) + 51 (expansion)†
&
All data will be included up to the date specified for the identified summaries.
†
N = 107 from the main cohort and N = 51 from expansion cohort.
**
N = 107 from the main cohort and N = 5 from expansion cohort are IRC evaluated.
#
15JUN2017 is the Investigator cutoff date; 30APR2015 is the IRC cutoff date for the main cohort; 29JAN2016 is the IRC cutoff for the 5 frontline subjects.
‡
The 3rd interim CSR will be submitted to a health authority.


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5.0
Analysis Populations
5.1
Definition for Analysis Populations
Efficacy and/or safety analyses will be performed for the following analysis sets.  More 
details about analyses populations for efficacy and safety are shown in Table 5.
All Treated Subjects:
This analysis set contains all subjects who received at least one dose of Venetoclax in 
either the Main Cohort or Safety Expansion Cohort.
All Treated Subjects in Main Cohort:
This analysis set contains all subjects who received at least one dose of Venetoclax in the 
Main Cohort.
All Treated Subjects in Main Cohort with 17p Deletion CLL:
This analysis set contains all subjects who received at least one dose of Venetoclax in the 
Main Cohort and have a confirmation of 17p deletion based on the central laboratory.
Primary Efficacy Subjects:
This analysis set contains the first 70 subjects who received at least one dose of 
Venetoclax in the Main Cohort and have a confirmation of 17p deletion based on the 
central laboratory.
Safety Expansion Subjects:
This analysis set contains all subjects who received at least one dose of Venetoclax in the 
Safety Expansion Cohort.
Frontline CLL Subjects
This analysis set contains all frontline CLL subjects in the study who received at least 
one dose of Venetoclax.  This analysis set will be used for efficacy assessments.


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BCRi Failure CLL Subjects
This analysis set contains all BCRi failure subjects who received at least one dose of
Venetoclax.  This analysis set will be used for efficacy assessments.
Table 5.
Analysis Populations for Efficacy and Safety Analyses
Analysis Population
1st Interim CSR
2nd Interim CSR
3rd Interim CSR
Efficacy
Safety
Efficacy
Safety
Efficacy
Safety
All Treated Subjects
X*
X
X
X
X
All Treated Subjects in
Main Cohort
X
X
X
All Treated Subjects in
Main Cohort with 17p
Deletion CLL
X
X
X
Primary Efficacy Subjects
X
X
X
Safety Expansion Subjects
X
X
Frontline CLL Subjects
X
X
BCRi Failure CLL Subjects
X
X
X
*
Subjects from the safety expansion cohort receiving at least one dose of Venetoclax will be included in the safety 
analyses.  The final subject number was determined at the time of the data cutoff.
5.2
Variables Used for Stratification of Randomization
There is no randomization for this trial.
6.0
Analysis Conventions
Definition of Baseline
The baseline value (except for laboratory variables) is defined as the last non-missing 
measurement collected before the first dose of Venetoclax.  The baseline value for 
laboratory variables will be defined as:
●
For subject hospitalized for TLS prophylaxis, the baseline value will be the lab 
value taken at hospital admission prior to the subject receiving hydration for 
TLS prophylaxis (the day prior to the first dose of Venetoclax).


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●
For subject not hospitalized for TLS prophylaxis, the baseline value will be the 
0 hour lab draw prior to the first dose of study drug on Day 1.
Definition of Final Observation
The final observation (Final Visit) is defined as the last non-missing observation collected 
within 30 days following the last dose of Venetoclax.
Definition of Rx Days (Days Relative to the First Dose of Venetoclax)
Rx days are calculated for each time point relative to the first dose date of Venetoclax.  
They are defined as the number of days between the day of the first dose of Venetoclax 
and the specific time point.  Rx days are negative values when the time point of interest is 
prior to the first Venetoclax dose day.  Rx days are positive values when the time point of 
interest is after the first Venetoclax dose day.  The day of the first dose of Venetoclax is 
defined as Rx Day 1, while the day prior to the first Venetoclax dose is defined as Rx 
Day –1 (there is no Rx Day 0).
Definition of Analysis Windows
For visit wise analyses including quality of life and performance status, and visit wise 
safety analyses, the time windows specified in Table 6, Table 7, and Table 8 describe how 
efficacy and safety data are assigned to protocol specified visits respectively.  Analysis 
time windows are constructed using the following algorithm:
●
Determine the nominal study Rx day for each scheduled visit.
●
Determine the window around a specific nominal study Rx day as in Table 6, 
Table 7 and Table 8.
●
If more than one assessment is included in a time window the assessment 
closest to the nominal day should be used.  If there are two observations equal 
distant to the nominal day the latest one will be used in analyses.
●
For laboratory variables with both central and local lab results, the mean 
change analyses will be performed using the central lab result.  For missing 
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available.  For the lab parameters of white blood cell (WBC) counts, 
neutrophil count, platelet count, and hemoglobin an additional analysis of the 
local result will be provided due to discrepancies observed during the trial 
between the central and local lab results.  These discrepancies between the 
central result and the local result will be discussed in the CSR.  Except for 
laboratory measurements for TLS, if more than one measurement exists for a 
subject on a particular day from the central lab, an arithmetic average is 
calculated and used as the subject's measurement for that day.  For TLS 
laboratory variables where multiple values were collected over the course of a 
day (4 hours, 8 hours, 12 hours and 24 hours post dose of Venetoclax) all 
values will be used and no averages will be taken.  For the shift tables, all 
values will be used from both the central and local labs.  The highest National 
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) 
grade will be used.  For potentially clinically significant lab listing, all values 
from both the central and local labs that meet the NCI CTCAE grade 3 or 
higher will be reported.


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Table 6.
Time Windows for Analysis of Hematology, Chemistry Parameters, 
Vital Signs, and Performance Status
Scheduled Visit
Nominal Day
Time Window (Study Rx Day Range)
Screening
Screening
Screening Visit
Baseline
≤ 1
See the baseline definition (Section 6.0)
Week 1 Day 1
1
[1]*
Week 1 Day 2
2
[2]*
Week 1 Day 3
3
[3]
Week 1 Day 4
4
[4]
Week 1 Day 5
5
[5 – 6]
Week 2 Day 1
8
[7 – 8]*
Week 2 Day 2
9
[9 – 10]
Week 3 Day 1
15
[11 – 15]
Week 3 Day 2
16
[16 – 17]
Week 4 Day 1
22
[18, 22]
Week 4 Day 2
23
[23, 25]
Week 5 Day 1
29
[26, 29]
Week 5 Day 2
30
[30, 39]
Week 8 Day 1
50
[40, 64]
Week 12 Day 1
78
[65, 92]
Week 16 Day 1
106
[93, 120]
Week 20 Day 1
134
[121, 148]
Week 24 Day 1
162
[149, 176]
Week 28 Day 1
190
[177, 204]
Week 32 Day 1
218
[205, 232]
Week 36 Day 1
246
[233, 288]
Every 12 Weeks from 
Week 36 Day 1
Rx day of Week X Day 1
[Rx day of Week (X) Day 1 – 6 weeks to 
Rx day of Week (X) Day 1 + 6 weeks]
Final Observation
Last value within 30 days of last dose of 
Venetoclax
Post Treatment
3 month intervals after last study visit


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Table 6.
Time Windows for Analysis of Hematology, Chemistry Parameters, 
Vital Signs, and Performance Status (Continued)
*
TLS lab draws could occur at 4 hours, 8 hours, 12 hours and 24 hours post dose of Venetoclax for both the 20 mg 
and 50 mg dosing.
Note:
Hematology and chemistry samples will be collected at the Screening Visit, on Week 1 Days –1, 1, 2, 3, 4 and 
5 (when applicable), Weeks 2, 3, 4 Days 1 and 2, Week 5 Days 1 and 2 (when applicable), Week 8 Day 1, 
Week 12 Day 1, Week 16 Day 1, Week 20 Day 1, Week 24 Day 1, Week 28 Day 1, Week 32 Day 1, every 
12 weeks starting with Week 36, at least 8 weeks after the CR, CRi or PR criteria for tumor response are 
first met, at the Final Visit, and every 3 months post treatment.  Physical exam will be assessed at the 
Screening Visit, on Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1, Week 5 Day 1 (when 
applicable), Week 8 Day 1, Week 12 Day 1, Week 16 Day 1, Week 20 Day 1, Week 24 Day 1, Week 28 
Day 1, Week 32 Day 1, every 12 weeks starting with Week 36, at least 8 weeks after the CR, CRi or PR 
criteria for tumor response are first met, at the Final Visit, and every 3 month post treatment.  Vital Signs and 
ECOG Performance Status will be assessed at the Screening Visit, on Week 1 Day 1, Week 2 Day 1, Week 3 
Day 1, Week 4 Day 1, Week 5 Day 1 (when applicable), Week 8 Day 1, Week 12 Day 1, Week 16 Day 1, 
Week 20 Day 1, Week 24 Day 1, Week 28 Day 1, Week 32 Day 1, every 12 weeks starting with Week 36, and 
every 3-month post treatment (for vital signs only).
Table 7.
Time Windows for Analysis of Urinalysis
Scheduled Visit
Nominal Day
Time Window (Study Rx Day Range)
Screening
Screening
See the baseline definition
Week 24 Day 1
162
[149, 176]
Final Observation
Last value within 30 days of last dose of Venetoclax
Note:
Urinalysis will be collected at Screening, on Week 24 Day 1, and at the Final Visit.


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Table 8.
Time Windows for Quality of Life
Scheduled Visit
Nominal Day
Time Window (Study Rx Day Range)
Week 1 Day 1
Baseline
See the baseline definition
Week 4 Day 1
22
[17, 25]
Week 12 Day 1
78
[65, 92]
Week 24 Day 1
162
[149, 176]
Week 36 Day 1
246
[233, 288]
Every 12 Weeks from 
Week 36 Day 1
Rx day of Week X Day 1
[Rx day of Week (X) Day 1 – 6 weeks to Rx 
day of Week (X) Day 1 + 6 weeks]
Final Observation
Last value within 30 days of last dose of 
Venetoclax
Post Treatment
3 month intervals after last study visit
Note:
MDASI, EQ-5D-5L and EQ-5D-VAS will be assessed at Week 1 Day 1, Week 4 Day 1, Week 12 Day 1, 
Week 24 Day 1, every 12 weeks starting with Week 36, and at the Final Visit.  EORTC QLQ-C30 and 
EORTC QLQ-CLL16 will be assessed at Week 1 Day 1, Week 4 Day 1, Week 12 Day 1, Week 24 Day 1, 
every 12 weeks starting with Week 36, at the Final Visit, and every 3 months post treatment.
7.0
Patient Disposition
The number and percentage of subjects will be summarized for each of the following 
categories, for overall and by country:
●
Subjects enrolled into the study.
●
Subjects who discontinued Venetoclax – overall and for each reported primary 
reason.
These analyses will be performed on the All Treated Subjects analysis set, All Treated 
Subjects in the Main Cohort analysis set, and Safety Expansion Subjects analysis set.


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8.0
Demographics, Baseline Characteristics, Medical 
History, and Previous Concomitant Medications
8.1
General Consideration
All demographic, baseline characteristics, medical history, prior and concomitant 
medication summaries will be performed on the analysis sets specified in each section 
below.
8.2
Demographic and Baseline Characteristics
All baseline summary statistics and analyses are based on characteristic prior to the 
first dose of Venetoclax.  The following demographic and baseline characteristics will be 
summarized:
●
age
●
gender
●
race
●
region [US, EU, ROW]
●
tobacco use
●
alcohol use
●
ECOG performance status
●
LDH
●
prior number of oncology therapies
●
17p deletion status
●
17p central laboratory testing center
●
staging at diagnosis
●
IgVH status
●
ZAP-70
●
CD-38
●
Beta 2-microglobulin (≤ 3 mg/L, > 3 mg/L)
●
P53 mutation


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●
11q
●
13q
●
12q trisomy
●
bulky disease [nodes > 5 cm and nodes > 10 cm]
●
Absolute Lymphocyte count [ ≥ 25 × 109/L and ≥ 100 × 109/L]
●
Fludarabine refractory
●
TLS risk category [low, medium, or high]
The distributions of the continuous demographic and baseline variables will be 
summarized with the number of non-missing observations, mean, standard deviation, and 
median, as well as the minimum and maximum values.
For the categorical variables, the frequencies and percentages of subjects within each 
outcome will be summarized.  The number of subjects with missing information will also 
be summarized.
These analyses will be performed on the All Treated Subjects analysis set, All Treated 
Subjects in the Main Cohort analysis set, All Treated Subjects in the Main Cohort with 
17p Deletion CLL analysis set, and Safety Expansion Subjects analysis set.
8.3
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the CRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized.  Subjects reporting more than 
one condition/diagnosis within a body system will be counted only once for that body 
system.


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These analyses will be performed on the All Treated Subjects analysis set, All Treated 
Subjects in the Main Cohort analysis set, All Treated Subjects in the Main Cohort with 
17p Deletion CLL analysis set, and Safety Expansion Subjects analysis set.
8.4
Previous Treatment and Concomitant Medications
A prior medication is defined as any medication taken prior to the first dose of 
Venetoclax.  A concomitant medication is defined as any medication that started prior to 
the first dose of Venetoclax and continued to be taken after the first dose of Venetoclax or 
any medication that started after the first dose of Venetoclax, but not after the last dose of 
Venetoclax.  The number and percentage of subjects who have taken medications will be 
summarized by generic drug name for prior medications, concomitant medication, and 
prior oncology therapies.  In addition, the number and percentage of subjects who have 
taken zero, one, two, three, four, five and six or more drugs will be summarized for prior 
medications, concomitant medications, and prior oncology therapies.
For summaries of concomitant medications, if an incomplete start date was collected for a 
medication, the medication will be assumed to be a concomitant medication unless there 
is evidence that confirms that the medication was not a concomitant medication (e.g., the 
medication end date was prior to the first dose of Venetoclax).
A subject who reports the use of two or more medications will be counted only once in the 
summary of "Any Concomitant Medication."  A subject who reports two or more uses of 
the same medication will be counted only once in the total for the associated generic drug 
name.  Similar rules apply to prior medications as well.
These analyses will be performed on the All Treated Subjects analysis set, All Treated 
Subjects in the Main Cohort analysis set, All Treated Subjects in the Main Cohort with 
17p Deletion CLL analysis set, and Safety Expansion Subjects analysis set.


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9.0
Venetoclax Exposure and Compliance
The duration of exposure to Venetoclax will be summarized.  Duration of exposure is 
defined for each subject as (last dose date – first dose date) + 1.  Duration of exposure will 
be summarized using the following statistics:  sample size (N), mean, standard deviation, 
median, and range.  In addition, the number and percentage of subjects exposed to 
Venetoclax will be summarized for the following categories of exposure duration:  0 to 
5 weeks, > 5 weeks to 8 weeks, > 8 weeks to 12 weeks, > 12 weeks to 16 weeks, 
> 16 weeks to 20 weeks, > 20 weeks to 24 weeks, > 24 weeks to 28 weeks, > 28 weeks to 
32 weeks, > 32 weeks to 36 weeks, > 36 weeks to 48 weeks, > 48 weeks to 60 weeks, and 
> 60 weeks.
The compliance based on investigator opinion for each subject will be provided in the 
listing.
These analyses will be performed on the All Treated Subjects analysis set, All Treated 
Subjects in the Main Cohort analysis set, All Treated Subjects in the Main Cohort with 
17p Deletion CLL analysis set, and Safety Expansion Subjects analysis set.
10.0
Efficacy Analysis
10.1
General Considerations
Main Cohort
Further details on the analysis sets used will be specified in each description of efficacy 
analyses to be performed below.
For the primary efficacy analysis of ORR based on IRC assessment in the first 70 subjects 
treated in the Main Cohort, statistical significance will be determined by a two-sided 
P value < 0.05 (one-sided < 0.025 where applicable).  No other efficacy endpoints will 
have statistical testing performed.  Descriptive statistics and the ninety-five percent (95%) 
confidence interval will be presented, where applicable.


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Safety Expansion Cohort
No statistical testing will be performed for the efficacy endpoints in the Safety Expansion 
Cohort.  Descriptive statistics with 95% confidence intervals will be presented, where 
applicable.
10.2
Main Cohort Analysis
10.2.1
Primary Efficacy Analysis
The primary efficacy endpoint will be overall response rate (ORR) – the proportion of 
subjects with an overall response (complete remission [CR] + complete remission with 
incomplete marrow recovery [CRi] + nodular partial remission [nPR] + partial remission 
[PR]) per the 2008 Modified IWCLL NCI-CWG criteria as assessed by the Independent 
Review Committee (IRC) in the first 70 subjects treated in the Main Cohort (Primary 
Efficacy Subject Analysis Set).
The ORR (based on the IRC assessment) for Venetoclax will be tested to reject the null 
hypothesis of ORR = 40%.  If the null hypothesis is rejected and the ORR is higher than 
40%, then Venetoclax has been shown to have an ORR significantly higher than 40%.
In addition, the 95% confidence interval for ORR based on the binomial distribution 
(Clopper-Pearson exact method) will be constructed.
Among these 70 subjects, those who have not achieved a CR, CRi, confirmed nPR, or 
confirmed PR prior to the data cutoff date will be considered to be non-responders.
10.2.2
Secondary Efficacy Analyses
Secondary efficacy endpoints will include all 107 subjects for ORR, complete remission 
rate (CR + CRi), partial remission rate (nPR + PR), duration of overall response (DoR), 
progression-free survival (PFS), event-free survival (EFS), time to progression (TTP), 
time to 50% reduction in absolute lymphocyte count (ALC), overall survival (OS) and 
percent of subjects who move on to stem cell transplant.


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Secondary efficacy analyses will be performed for both the IRC assessment of response 
and the investigator assessment of response, as applicable, for the All Treated Subjects in 
the Main Cohort analysis set and the All Treated Subjects in the Main Cohort with 
17p Deletion CLL analysis set.  Description of the secondary efficacy analyses are as 
follows:
CR rate will be defined as the proportion of subjects who achieved a CR or CRi per the 
2008 Modified IWCLL NCI-CWG criteria.  In addition, the 95% confidence interval 
based on the binomial distribution (Clopper-Pearson exact method) will be provided.  
Subjects who do not achieve a CR or CRi will be considered to be non-responders in the 
calculation of CR rate.
PR rate will be defined as the proportion of subjects who achieved a nPR or PR per the 
2008 Modified IWCLL NCI-CWG criteria.  In addition, the 95% confidence based on the 
binomial distribution (Clopper-Pearson exact method) will be provided.  Subjects who do 
not achieve a nPR or PR will be considered to be non-responders in the calculation of PR 
rate.
Duration of overall response (DoR) will be defined as the number of days from the date of 
first response (CR, CRi, nPR, or PR) by either CT scan or physical exam determination to 
the earliest recurrence (PD) or death per the IRC assessment.  For subjects who have a PR 
before CR, CRi, or nPR in subsequent visits, the DoR is computed from the earliest PR.  
If a subject is still responding, then the subject's data will be censored at the date of the 
subject's last available disease assessment.  To be included in the DoR analysis, subjects 
must have had a response per the 2008 Modified IWCLL NCI-WG criteria (CR, CRi, 
confirm nPR, or confirmed PR).  For subjects who never experience response, the 
subject's data will not be included in the analysis.  Duration of overall response will be 
analyzed by Kaplan-Meier methodology.  Median duration of response will be calculated 
and the corresponding 95% confidence interval will be presented.
Duration of 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 


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progression will be included regardless of whether the event occurred while the subject 
was taking the Venetoclax or had previously discontinued the Venetoclax.  If the subject 
does not experience disease progression or death, then the data will be censored at the 
date of last disease assessment.  Data for subjects without any disease assessments 
performed after the baseline visit will be censored at the date of first dose plus 1 day.  PFS 
will be analyzed by Kaplan-Meier methodology.  Median duration of PFS will be 
calculated and 95% confidence interval for median duration of PFS will be presented.
Event-free survival (EFS) is defined as the number of days from the date of first dose to 
the date of earliest disease progression, death, or start of a new anti-leukemic therapy.  If 
the specified event (disease progression, death, start of a new anti-leukemic treatment) 
does not occur, patients will be censored at the date of last disease assessment.  Data for 
subjects without any disease assessments performed after the baseline visit will be 
censored at the date of first dose plus 1 day.  EFS will be analyzed by Kaplan-Meier 
methodology.  EFS will be calculated and 95% confidence interval for median EFS will 
be presented.
Time to progression (TTP) will be defined as the number of days from the date of 
first dose to the date of earliest disease progression.  All disease progression will be 
included regardless of whether the event occurred while the subject was taking the 
Venetoclax or had previously discontinued the Venetoclax.  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 without any disease assessments performed after 
the baseline visit will be censored at the date of first dose plus 1 day.  TTP will be 
analyzed by Kaplan-Meier methodology.  Median TTP will be calculated and 95% 
confidence interval for median TTP will be presented.
Time to first response will be defined as the number of days from the date of first dose to 
the date of the first sign of response (CR, CRi, nPR, or PR) given the subject has had a 
CR, CRi, confirmed nPR, or confirmed PR per the 2008 Modified IWCLL NCI-WG 
criteria.  The first response can be an assessment by physical exam as long as the results 
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never experience a response, the subject's data will not be included in the analysis.  
Descriptive statistics (mean, standard deviation, median, and range) and the 95% 
confidence interval of the mean will be presented.
Time to 50% reduction in ALC will be defined as the number of days (hours if applicable) 
from the date of first dose to the date when the ALC has reduced to 50% of the baseline 
value (as defined in Section 6.0).  Only subjects with a baseline of ALC > 5 × 109/L will 
be included in the analysis.  For subjects who never achieve a 50% reduction in ALC, the 
subject's data will not be included in the analysis.  Descriptive statistics (mean, standard 
deviation, median, and range) and the 95% confidence interval of the mean will be 
presented.
Overall survival (OS) will be defined as number of days from the date of first dose to the 
date of death.  For 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.  Median survival time will be estimated and 95% confidence 
interval for the median survival time will be presented.
The percent of subjects who move on to stem cell transplant will be summarized and the 
95% confidence interval based on the binomial distribution (Clopper-Pearson exact 
method) will be provided.
10.2.3
Additional Exploratory Efficacy Analyses
The additional exploratory efficacy analyses will be performed on the Treated Subjects in 
the Main Cohort analysis set, and All Treated Subjects in the Main Cohort with 
17p Deletion CLL analysis set.
Descriptions of the additional efficacy endpoints are as follows:
Time to next anti-leukemia treatment will be defined as the number of days from the date 
of the first dose to the date of first dose of new non-protocol anti-leukemia therapy (NPT) 
or death from any cause.  For subjects who did not take NPT, the data will be censored at 


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the last known date to be free of NPT.  TTNT will be analyzed by Kaplan-Meier 
methodology.  Median TTNT time will be calculated and 95% confidence interval for 
median TTNT time will be presented.
The rate of MRD response in subjects will be defined as the proportion of subjects who 
had MRD negative status.  Only subjects with an MRD assessment (negative or positive), 
as required per protocol, will be used in calculation of MRD response rate, indeterminate 
samples will not be included in the denominator for the calculation.  Ninety-five percent 
(95%) confidence intervals based on the binomial distribution (Clopper-Pearson exact 
method) will be provided.
Health Economic and Patient Reported Outcome measures will include the MDASI 
(measure of patient reported symptoms), the EORTC QLQ-C30 and QLQ-CLL16 (a 
measure of health related quality of life specific to CLL) and the EQ-5D-5L (measure of 
general health status) and EQ-5D-VAS.
The MDASI is a multi-symptom PRO measure for clinical and research use.  The MD 
Anderson Symptom Inventory Core Items contains 13 symptom severity items (pain, 
fatigue, nausea, disturbed sleep, distress [emotional], shortness of breath, lack of appetite, 
drowsiness, dry mouth, sadness, vomiting, difficulty remembering, and numbness or 
tingling), and 6 symptom interference items (general activity, mood, walking ability, 
normal work, relations with other people, and enjoyment of life).
Mean symptom severity and symptom interference scores will be calculated for each 
observation as defined in the MDASI scoring manual and then summarized at each 
assessment; in addition mean change in each of these values (final assessment versus 
baseline) will be calculated to identify any statistically significant differences versus 
baseline.
The EORTC QLQ-C30 consists of a Global Health Status/QoL scale, five Functional 
scales (Cognitive Functioning, Social Functioning, Physical Functioning, Emotional 
Functioning, and Role Functioning), and nine Symptom scales/items (Fatigue, Insomnia, 


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Appetite Loss, Pain, Constipation, Diarrhea, Dyspnea, Financial Difficulties, and Nausea 
and Vomiting).
Each of these scales will be calculated as per the EORTC scoring manual, and 
summarized (mean, standard deviation, median) at each assessment; in addition mean 
change in each of these values (final assessment versus baseline) will be calculated to 
identify any statistically significant differences versus baseline.
The five EORTC QLQ-CLL16 domains (Fatigue, Treatment Side Effects and Disease 
Symptoms, Infection, Social Activities, Future Health Worries) will be summarized 
(mean, standard deviation, and median) at each assessment; in addition mean change in 
each of these values (final assessment versus baseline) will be calculated to identify any 
statistically significant differences versus baseline.
The EORTC QLQ-C30 and EORTC QLQ-CLL16 will also be administered through 
post treatment.  To explore the trend of time, a repeated measures analysis will be 
performed for the scheduled times of measurement without imputation of missing values.
The EuroQol 5 Dimensions (EQ-5D-5L) is a generic preference instrument that has been 
validated in numerous populations.  The EQ-5D-5L has five dimensions:  mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression.  These dimensions are 
measured on a five level scale:  no problems, slight problems, moderate problems, severe 
problems, and extreme problems.  The EQ-5D-5L also contains a visual analog scale 
(VAS) to assess the subject's overall health.
For each of the five dimensions of the EQ-5D-5L, the number and percentage of subjects 
at each level will be summarized at each assessment.  The Visual Analog Scale (VAS) 
will also be summarized (mean, standard deviation, median) at each assessment; in 
addition mean change in VAS values (final assessment versus baseline) will be calculated 
to identify any statistically significant differences versus baseline.


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10.3
Safety Expansion Cohort
10.3.1
Efficacy Analyses
The efficacy analyses for the Safety Expansion Cohort will be performed when the last 
subject in this cohort has discontinued Venetoclax.  The analysis set summarized for the 
Safety Expansion Cohort will be the Safety Expansion Subjects analysis set.  For this 
efficacy assessment, the investigator assessment of response will be used for all analyses.
The following efficacy analyses will be performed and summarized as specified in 
Section 10.2.2:  ORR, CR rate, PR rate, DoR, PFS, EFS, TTP, time to first response, time 
to 50% reduction in ALC, OS, and the percent of subjects who move on to stem cell 
transplant.
10.3.2
Additional Exploratory Efficacy Analyses
Additional efficacy endpoints to be performed on the Safety Expansion Cohort subjects 
are time to next anti-leukemia treatment, MRD response rate, and Health Economic and 
Patient Reported Outcome measures and will be summarized as specified in 
Section 10.2.3.
10.4
Handling of Multiplicity
There will be no multiplicity adjustments performed.  The only testing procedure 
performed will be on the primary endpoint of ORR using a two-sided alpha = 0.05 which 
will include the first 70 subjects enrolled.
10.5
Efficacy Subgroup Analysis
To evaluate the impact of baseline conditions on efficacy, subgroup summaries will be 
performed in the All Treated Subjects in the Main Cohort analysis set, the All Treated 
Subjects in the Main Cohort with 17p Deletion CLL analysis set and All Treated Subjects 
analysis set.
The subgroups defined below will be used for these analyses:  


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1.
Gender (Male, Female)
2.
Age (< 65, or ≥ 65)
3.
Age (< 75, or ≥ 75)
4.
Race (White, Black, Other)
5.
Number of prior therapies (1, 2, 3, 4, ≥ 5)
6.
LDH status (0 - 1 × ULN, > 1 × ULN)
7.
ECOG (0, ≥ 1)
8.
Fludarabine refractory status (Yes, No)
9.
IgVH (mutated, unmutated)
10.
Bulky disease (nodes < 5 cm, nodes ≥ 5 cm)
11.
Bulky disease (nodes < 10 cm, nodes ≥ 10 cm)
12.
ALC (< 25 × 109/L, ≥ 25 × 109/L)
13.
ALC (< 100 × 109/L, ≥ 100 × 109/L)
14.
17p deletion central laboratory testing center
15.
BCRi failure CLL subjects (Yes)
10.6
Efficacy Data Conventions
The following data conventions will be implemented for each of the analysis time points.
●
The window for the 8-week CT confirmation for response will allow a 1-week 
variation post first sign of response (≥ 49 days for a confirmation of response).
●
If the subject does not experience disease progression by the cutoff dates 
specified in Section 4.5, then the data will be censored at the date of last 
available disease assessment prior (clinical or radiographical) to the cutoff 
dates.


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●
A discontinued subject could be a responder if the subject had a CR, CRi, 
confirmed nPR, or confirmed PR prior to discontinuing Venetoclax.  If a 
subject reaches a PR clinical response (per investigator assessment) but was 
not confirmed 8 weeks later then the response will be considered to be SD.  A 
CR clinical response (per investigator assessment) must be confirmed with a 
bone marrow assessment.  If no bone marrow was performed, then the 
response will be considered a PR.
●
Data from the IRC assessment will not be combined with the assessment 
provided by the investigator.  These will be two separate analyses.
●
For a subject to be determined to have an MRD negative status, the level of 
CLL cells in the bone marrow or blood sample must be less than 1 × 10–4 (less 
than one CLL cell per 10,000 leukocytes).  For samples with CLL cells greater 
than or equal to 1 × 10–4, the MRD status will be considered positive.  Only 
subjects with an MRD assessment, as required per protocol, will be used in 
calculation of MRD status.  If a sample from the central laboratory is 
determined to be indeterminate, the local laboratory sample will be used 
instead of the central laboratory, if available.
●
For time to event analyses, months will be computed using 30.4 days per 
month.
11.0
Safety Analysis
Safety assessments will only include subjects who have received at least one dose of 
Venetoclax.
The safety assessment of Venetoclax will be performed at three time points.  The 
first assessment time point for the safety of Venetoclax will be performed for all subjects 
as of 30 April 2015 assessment.  At this time point, all subjects who have been treated in 
the study, either in Main Cohort or Safety Expansion Cohort, will be assessed for safety.  
The analysis sets for this time point will include:  All Treated Subjects analysis set, All 
Treated Subjects in the Main Cohort analysis set, and the Safety Expansion Subjects 
analysis set.


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The second assessment time point for safety will occur when the last subject enrolled into 
the Safety Expansion Cohort has completed the 5-week step wise dose escalation. For 
this time point the Safety Expansion Subject analysis set will be used.
The final assessment time point for safety will occur when the last subject discontinues 
Venetoclax and has complete the 30-day safety follow-up period.  The analysis sets for 
this final time point will include:  All Treated Subjects analysis set, All Treated Subjects 
in the Main Cohort analysis set, and Safety Expansion Subjects analysis set.
11.1
Analysis of Treatment-Emergent Adverse Events
All summaries/analyses involving AEs will include treatment-emergent adverse events 
(TEAE) only, unless otherwise specified.  TEAE are defined as any event with onset after 
the first dose of Venetoclax and no more than 30 days after the last dose of Venetoclax.  
Events where the onset date is the same as the Venetoclax start date are assumed to be 
treatment-emergent, unless the Venetoclax start time and the AE start time are collected 
and the AE start time is prior to the Venetoclax start time.  If an incomplete onset date 
was collected for an AE, the AE will be assumed to be treatment-emergent unless there is 
evidence that confirms that the AE was not treatment-emergent (e.g., the AE end date was 
prior to the date of the first dose of Venetoclax).
Adverse event data will be summarized and presented using primary MedDRA system 
organ classes (SOCs) and preferred terms (PTs) according to the MedDRA coding 
dictionary version 20.1 or higher.
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be summarized for the following adverse event summaries:
●
Any treatment-emergent adverse event.
●
Any treatment-emergent adverse event with reasonable possibility related to 
Venetoclax by the investigator.
●
Any treatment-emergent NCI toxicity (CTCAE V4.0) grade 3, 4, or 5 adverse 
events.


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●
Any treatment-emergent NCI toxicity (CTCAE V4.0) grade 3 or 4 adverse 
event.
●
Adverse events broken down by NCI toxicity grade (Severity).
●
Any treatment-emergent serious adverse event.
●
Any treatment-emergent adverse event leading to discontinuation of 
Venetoclax.
●
Any treatment-emergent adverse event leading to discontinuation of 
Venetoclax due to progression.
●
Any treatment-emergent adverse event leading to discontinuation of 
Venetoclax not due to progression.
●
Any treatment-emergent adverse event leading to Venetoclax interruption.
●
Any treatment-emergent adverse event leading to Venetoclax reduction.
●
Any treatment-emergent adverse event leading to death.
In addition, adverse events of special interest will be summarized.  The list of adverse 
events of special interest that will be presented is shown in Table 9.
Table 9.
Adverse Events of Special Interest
Adverse Event of Special 
Interest
Search Criteria
Tumor Lysis Syndrome (AE)
SMQ – "Tumor Lysis Syndrome" (Narrow)
Grade ≥ 3 Neutropenia
PT terms – "Neutropenia," "Neutrophil Count Decreased," "Febrile 
Neutropenia," "Agranulocytosis," "Neutropenic Infection," and 
"Neutropenic Sepsis"
Grade ≥ 3 Infection, including 
Opportunistic Infections
SOC of "Infections and Infestations"
Second Primary Malignancy
SMQ – "Malignant Tumours" (Narrow) and "Myelodysplastic 
Syndromes" (Narrow)
Drug-Induced Liver Injury (AE)
PT Term – Drug Induced Liver Injury
Grade ≥ 3 Thrombocytopenia
PT Terms – "Thrombocytopenia" and "Platelet Count Decreased"


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11.2
Deaths
The number of deaths will be summarized (1) for death occurring during the first day of 
Venetoclax and within 30 days after the last dose of Venetoclax, (2) for death occurring 
> 30 days after the last dose of Venetoclax, (3) for all deaths in this study, i.e., 1) and 2).
11.3
Analysis of Laboratory and Vital Signs Data
The value for baseline used in laboratory and vital sign analyses is defined in Section 6.0.  
Post baseline visits windows are specified in Table 6 and Table 7.
11.3.1
Analysis of Mean Changes from Baseline in Clinical 
Laboratory Data
Changes from baseline will be analyzed for each scheduled post-baseline visit and for the 
final visit (Table 6 and Table 7) for blood chemistry and hematology parameters, as well 
as urinalysis and vital sign parameters.
Laboratory tests to be summarized are included in Table 10.


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Table 10.
Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
Reticulocyte count
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic 
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol (Screening and Final 
Visit)
Total protein
Glucose
Triglycerides (Screening and 
Final Visit)
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate
Calculated Creatinine Clearance
Specific gravity
pH
Quantitative Immunoglobulins
IgA
IgG
IgM
Lymphocyte Enumeration
T-cells (CD3)
B-cells (CD19)
B-cells (CD5 + CD19)
Natural Killer Cells (CD16 + 
CD56)
Helper T-cells (CD4)
T-Suppressor to T-Cytotoxic 
cells (CD8)
Mean changes from baseline at each scheduled post-baseline visit and Final Visit will be 
summarized with the baseline mean, visit mean, change from baseline mean, standard 
deviation, and median.
11.3.2
Analyses of Shift from Baseline in Clinical Laboratory Data
For shifts relative to NCI CTCAE, baseline and post-baseline laboratory observations will 
be categorized as grade 0, grade 1, grade 2, grade 3, or grade 4 according to NCI CTCAE 
grade version 4.
The baseline and final grades will be defined respectively as the grade of the last 
measurement collected prior to the first dose of Venetoclax unless specified differently in 


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Section 6.0, and as the last post-baseline measurement collected no more than 30 days 
after the last dose of Venetoclax.
The maximum NCI toxicity grade value is the value with highest NCI toxicity grade 
collected after the first dose of Venetoclax and within 30 days following the last dose of 
Venetoclax.  In cases where multiple values are collected on the same day, the maximum 
grade value will be selected as the value for that day.
For each variable, shift tables will be generated that cross tabulate the number of subjects 
with baseline values of grade 0, grade 1, grade 2, grade 3, or grade 4 versus final 
observations of grade 0, grade 1, grade 2, grade 3, or grade 4.
Additionally, for each variable, the number and percentage of subjects that have a baseline 
observation that is categorized as a grade 0, grade 1, or grade 2 and that also have a 
grade 3 or 4 final observation will be presented.  A similar set of summaries will be 
produced for the maximum post-baseline laboratory observations.
Detailed listings of data for subjects experiencing NCI CTCAE grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of Venetoclax, will be included in 
these listings.
11.3.3
Assessment of Potentially Clinically Significant Laboratory 
Values
For selected laboratory variables, a listing of all observations collected will be generated 
for subjects that had at least one post-baseline observation meeting pre-defined criteria for 
potentially clinically significant values.  The number and percentage of subjects who have 
at least one post-baseline observation meeting the pre-defined criteria for potentially 
clinically significant values will be provided for each variable.


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Criteria for potentially clinically significant laboratory values are defined as laboratory 
grade values ≥ 3 per the NCI CTCAE version 4.  The NCI CTCAE grade 3 criteria are 
given in Table 11 and Table 12 below.
Table 11.
Criteria for Potentially Clinically Significant Laboratory Values –
Chemistry Variables
Chemistry Variables
Units
Definition of Potentially Clinically 
Significant Current (Version 4) Grade 3
Very Low
Very High
Total bilirubin
mcmol/L
> 3.0 × ULN
Albumin
g/L
< 20
Aspartate amino transaminase (AST/SGOT)
U/L
> 5.0 × ULN
Alanine amino transferase (ALT/SGPT)
U/L
> 5.0 × ULN
Alkaline phosphatase
U/L
> 5.0 × ULN
Creatinine
mcmol/L
> 3.0 × ULN
Sodium
mmol/L
< 130
> 155
Potassium
mmol/L
< 3.0
> 6.0
Total calcium
mmol/L
< 1.75
> 3.1
Glucose
mmol/L
< 2.2
> 13.9
Inorganic Phosphate
mmol/L
< 0.6
Bicarbonate
mmol/L
< 11
Cholesterol
mmol/L
> 10.34
Triglycerides
mmol/L
> 5.0 × ULN
Magnesium
mmol/L
< 0.4
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Table 12.
Criteria for Potentially Clinically Significant Laboratory Values –
Hematology Variables
Hematology Variables
Units
Definition of Potentially Clinically Significant 
Current (Version 4) Grade 3
Very Low
Hemoglobin
g/L
< 80
White blood cell count
109/L
< 2
Neutrophils
109/L
< 1
Lymphocytes
109/L
< 0.5
Platelets
109/L
< 50
A listing of subjects who meet Hy's law to assess drug-induced liver injury (DILI) will be 
provided.  The listing will contain subjects with ALT or AST > 3 × ULN who also show 
elevation of total bilirubin > 2 × ULN on laboratory samples taken within 72 hours of 
each other.
Laboratory Search Strategy for TLS
To determine if a subjects laboratory values qualify for TLS, the Howard criteria2 will 
assessed.  The Howard criteria for TLS comprises of ≥ 2 of the following electrolyte 
abnormalities within 24 hours of each other and are specified in Table 13.
Table 13.
Howard Criteria for TLS
Element
Value
Uric Acid
> 476 μmol/L or 8 mg/dL
Potassium
> 6.0 mmol/L or 6 mEq/L
Inorganic Phosphorus
> 1.5 mmol/L
Calcium
< 1.75 mmol/L
The following summaries of Howard criteria will be provided:
●
Number and percentage of subjects meeting Howard criteria in Table 12 (at 
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●
Listing of all the Howard criteria lab test values for each subject meeting 
Howard criteria.
●
Number of subjects meeting single Howard criteria in Table 13 (at least 
one value meeting the criteria).
●
Listing of all the Howard criteria lab test values for each subject who meets 
single Howard criteria Table 13.
11.3.4
Assessment of Mean Changes from Baseline in Vital Signs 
Variables
Analyses of mean change from baseline in continuous vital signs variables which are 
measured longitudinally will be performed (systolic blood pressure, diastolic blood 
pressure, heart rate, and temperature).  Similar analyses may be performed for the mean 
change from baseline to the minimum, maximum, and final observations.
For each change from baseline analysis, the following summary statistics will be 
presented:  sample size, baseline mean, visit mean, and the mean, standard deviation, and 
median of the changes from baseline.  The baseline and visit means will be calculated for 
each visit for subjects who have both a baseline and visit value.
11.3.5
Assessment of Potentially Clinically Significant Vital Signs 
Values
For selected vital signs variables, a listing of all observations collected will be generated 
for subjects that had at least one post-baseline observation meeting pre-defined criteria for 
potentially clinically significant values.  The number and percentage of subjects who have 
at least one post-baseline observation meeting the pre-defined criteria for potentially
clinically significant values will be provided for each variable.
Pre-defined criteria for potentially clinically significant vital signs values are given in 
Table 14 below based on CTCAE criteria:


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Table 14.
Criteria for Potentially Clinically Significant Laboratory Values –
Vital Signs Variables
Vital Signs Variables
Criterion
Definition of Potentially Clinically Significant
Systolic blood pressure
High
Value ≥ 160 mmHg
Diastolic blood pressure
High
Value ≥ 100 mmHg
Heart rate
Low
Value < 50 bpm
High
Value ≥ 120 bpm
Temperature
Low
Value < 36°C
High
Value ≥ 38.5°C
11.4
ECG/2D Echocardiogram
For ECG testing, subjects were only required to have a screening and a final visit 
assessment.  If an ECG was clinically indicated, additional measurement could have been 
performed.  Only ECG results that were abnormal were collected in the database.
For 2D echocardiogram testing, subjects had a screening assessment if clinically 
indicated.  If an echocardiogram was clinically indicated, additional measurement could 
have been performed.
Data from ECG or 2D Echocardiogram that were collected will be provided in data 
listings.
No analyses are planned given the limited collection of data.
12.0
Pharmacokinetic Analyses
12.1
Tabulations and Summary Statistics
Plasma concentrations of Venetoclax and possible metabolites(s) will be listed for each 
subject by scheduled visit.  Summary statistics will also be computed for each dose level 
by scheduled visit.  Samples with significant sampling time deviations will be excluded 
from summary statistics calculations.  Binning will also be performed for trough samples 
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sample collection date and time and their last dose date and time of Venetoclax.  
Summary statistics will also be computed for each bin.
12.2
Attainment of Steady State 
Exploratory analyses of trough (pre-dose) concentrations for Weeks 8 (first visit), 
12 (second visit), 16 (third visit) and 24 (fourth visit) will be done to characterize the 
achievement of steady state pharmacokinetics.  The model will include Visit as a fixed 
effect and will account for both intra- and inter-subject variability.  Trough concentrations 
from subjects receiving 400 mg Venetoclax for which samples were taken between 22 and 
26 hours after their last dose at each above visit will be included in the analysis.
Within the framework of the model, trend analyses will be performed on the contrasts in 
the visit effects to determine the earliest visit after which there is no statistically 
significant change.  The trend analyses will begin with a test of hypothesis on the 
orthogonal linear contrast for all the specified visits.  If the test result is not statistically 
significant for this linear contrast, the trend analysis will be stopped to suggest that steady 
state was reached on the first visit identified in the linear contrast.  If the test result is 
statistically significant, the next trend analysis will be performed on the orthogonal linear 
contrast re-established for the visits from the second visit through the last visit.  This 
process will be repeated with a elimination of the visits one by one from the beginning 
until the trend test is not statistically significant, or until only two visits (the second to the 
last and the last visits) remain for the trend analysis.
13.0
Summary of Changes
13.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
●
Updated the data cutoff date for the 36-week disease assessment for the 
107 subjects in the main cohort to 30 April 2015.  Bone marrow assessments 
required by the NCI-WG criteria to confirm the complete remission responses 
were to be completed by 30 April 2015.


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●
Updated the Adverse of special interest to be more relevant for clinical 
significance determination.
●
Clarification of the laboratory values to be summarized.
●
Updated the pharmacokinetics analyses section.
●
Corrected typographical errors and minor language or word revisions 
throughout the document.
●
The Appendix B - AE Search Criteria for AE of Special Interest is removed.
●
The SAP was updated to include analyses for the 3rd Interim CSR
14.0
References
1.
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.
2.
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  
2011;364(19):1844-54.


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Appendix A.
List of Abbreviations 
AE
Adverse Event
ALT
Alanine aminotransferase
ALC
Absolute Lymphocyte Count
AST
Aspartate aminotransferase
aPTT
Activated Partial Thromboplastin Time
Bcl
B-Cell Lymphoma
BM
Bone Marrow
BR
Bendamusitne plus Rituximab
BUN
Blood Urea Nitrogen
CLL
Chronic Lymphocytic Leukemia
cm
Centimeter
CR
Complete Remission
CRi
Complete Remission with Incomplete Marrow Recovery
CrCL
Creatinine Clearance
CSR
Clinical Study Report
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DILI
Drug-Induced Liver Injury
DoR
Duration of Overall Response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EFS
Event-free Survival
FCR
Fludarabine, cyclophosphamide, and rituximab
G-CSF
Granulocyte-colony stimulating factor
IDMC
Independent Data Monitoring Committee
IRC
Independent Review Committee
IWCLL
International Workshop for Chronic Lymphocytic Leukemia
IxRS
Interactive Response System
LDH
Lactate Dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
mm
Millimeter
MPV
Mean Platelet Volume


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MRD
Minimal Residual Disease
MUGA
Multi Gated Acquisition Scan
NCI
National Cancer Institute
NCI-WG
National Cancer Institute-Working Group
nPR
Nodular Partial Remission
NPT
Non-protocol Anti-leukemia Therapy
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-free Survival
PR
Partial Remission
PT
Prothrombin Time
QA
Quality Assurance
QC
Quality Control
QD
Once Daily
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
SGOT
Serum Glutamic-oxaloacetic Transaminase
SGPT
Serum Glutamic-pyruvic Transaminase
SLL
Small Lymphocytic Lymphoma
SMQ
Standard MedDRA Query
SPD
Sum of the products of the greatest diameters
TEAE
Treatment-emergent Adverse Event
TLS
Tumor Lysis Syndrome
TTNT
Time to next anti-CLL treatment
TTP
Time to Tumor Progression
ULN
Upper Limit of Normal
VAS
Visual Analog Scale
WBC
White Blood Cell