Conditions: Chronic Lymphocytic Leukemia (CLL) Small Lymphocytic Lymphoma (SLL)
Keywords: Cancer Chronic Lymphocytic Leukemia 17p Deletion Debulking Obinutuzumab Bendamustine Tumor lysis syndrome Venetoclax Small Lymphocytic Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 120
Healthy volunteers: no

Brief summary:
This is a multi-cohort, open-label study in previously untreated participants with chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), excluding those with the 17p deletion, to evaluate a debulking strategy that would enable all participants to receive subsequent venetoclax as outpatients, with lower risk of tumor lysis syndrome.

Detailed description:
Safety and efficacy data through 13 October 2021 are included in the interim analysis, which was conducted after all participants completed the post-treatment Week 65 visit or discontinued from the study.

Arms:
arm 1: Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen.

After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. arm 2: Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m\^2 ) was to be administered to those with nodes or nodal mass \> 10 cm, or with del(11q) and \> 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen.

After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.

Interventions: intervention 1: Obinutuzumab intervention 2: Bendamustine intervention 3: Venetoclax
Intervention descriptions: intervention 1: Administered via intravenous infusion intervention 2: Administered via intravenous infusion intervention 3: The venetoclax dose was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. Venetoclax was continued for a total duration of up to 53 weeks, including the 5-week ramp-up schedule. Participants were instructed to take venetoclax tablets with a meal and water at approximately the same time each day. Venetoclax tablets were to be swallowed whole and not chewed, crushed, or broken prior to swallowing.

Protocol document:
SAP_002.pdf: 
Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
1
1.0
Title Page
Statistical Analysis Plan
Study M16-788
A Phase 3b Study in Previously Untreated Chronic 
Lymphocytic Leukemia (CLL) Subjects, Excluding 
Those with the 17p Deletion, to Evaluate Debulking 
Regimens Prior to Initiating Venetoclax Combination 
Therapy
Date: 26 June 2023
Version 3.0
 
NCT03406156


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................4
4.0
Study Background.................................................................4
4.1
Objective................................................................................................ 4
4.2
Study Design.......................................................................................... 5
4.2.1
Study Design and Design Diagram ......................................................... 5
4.2.2
Variables Used for Stratification at Randomization ................................ 7
4.3
Endpoint................................................................................................. 8
4.3.1
Primary Endpoints.................................................................................. 8
4.3.2
Secondary Efficacy Endpoint ................................................................. 8
4.3.3
Safety Endpoint...................................................................................... 9
4.4
Sample Size Justification........................................................................ 9
4.5
Interim Analysis ..................................................................................... 9
4.6
Multiplicity Testing Procedures for Type-I Error Control..................... 10
4.7
Missing Data Imputation ...................................................................... 10
5.0
Analysis Populations and Important Subgroups...............10
5.1
Analysis Population.............................................................................. 10
5.2
Subgroup.............................................................................................. 10
6.0
Efficacy Analyses.................................................................11
6.1
General Considerations......................................................................... 11
6.2
Primary Efficacy Analysis.................................................................... 11
6.3
Secondary Efficacy Analyses ............................................................... 12
6.4
Efficacy Subgroup Analyses................................................................. 14
7.0
Safety Analyses....................................................................15
7.1
General Considerations......................................................................... 15
7.2
Analysis of Adverse Events.................................................................. 15
7.3
Deaths .................................................................................................. 18
7.4
Analysis of Laboratory Data................................................................. 18
7.4.1
Definition of Baseline........................................................................... 18
7.4.2
Analysis of Shift from Baseline in Clinical Laboratory Data................. 19
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
3
7.5
Laboratory Search Strategy for TLS ..................................................... 19
7.6
Analysis of Vital Signs......................................................................... 20
8.0
Summary of Changes ..........................................................21
9.0
Reference .............................................................................21
List of Tables
Table 1.
Selected Adverse Events....................................................................... 18
Table 2.
Howard Criteria for TLS ...................................................................... 20
Table 3.
Criteria for Potentially Clinically Significant Vital Sign Values............ 21
List of Figures
Figure 1.
Study Schematic..................................................................................... 5
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
4
3.0
Introduction
This statistical analysis plan (SAP) describes the full statistical analyses for venetoclax 
(ABT-199) Protocol M16-788 Version 4 or later. It will provide details of statistical 
methods and describe analysis conventions to guide the statistical programming work.
Unless noted otherwise, all analyses will be performed using SAS® version 9.3 or newer 
(SAS Institute Inc, Cary, North Carolina, USA).
SAP will not be updated in case of future administrative or minor amendments to the 
protocol unless the changes have any impact on the analysis of the study data.
4.0
Study Background
4.1
Objective
Primary Objectives:
●
To evaluate the anti-tumor effects of both induction therapies of obinutuzumab
(Group A) or obinutuzumab in combination with bendamustine (Group B) 
prior to initiation of venetoclax and obinutuzumab therapy with the goal of 
initiating venetoclax in all subjects with low-tumor burden as defined by 
peripheral lymphocyte counts of < 25 × 10	/Land all lymph nodes < 5 cm per 
computed tomography (CT) scans.
●
To evaluate the efficacy of this regimen as defined by the complete remission 
(CR) or complete remission with incomplete marrow recovery (CRi) rate 
following the debulking regimens and subsequent venetoclax and 
obinutuzumab therapy per 2008 Modified International Workshop on Chronic 
Lymphocytic Leukemia National Cancer Institute-sponsored Working Group 
[IWCLL NCI-WG] criteria.
Secondary Objectives:
●
To evaluate Overall Response Rate (ORR), Duration of Overall Response 
(DoR), Progression-Free Survival (PFS), Time to Progression (TTP), Overall 
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
5
Survival (OS), and the level of Minimal Residual Disease (MRD) defined as 
the rate of MRD negativity in the peripheral blood.
●
To evaluate safety and tolerability of the debulking regimens, venetoclax 
ramp-up, and the venetoclax and obinutuzumab combination.
4.2
Study Design
This is a multi-cohort, open-label study in previously untreated CLL/SLL, excluding 
those with the 17p deletion, to evaluate a debulking strategy that would enable all subjects 
to receive subsequent venetoclax as outpatients with lower risk of tumor lysis.
4.2.1
Study Design and Design Diagram
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
Debulking
Subjects with median tumor burden (any lymph node 5 to < 10 cm or absolute 
lymphocyte count ≥ 25 × 109 /L) or, with high tumor burden (any lymph node ≥ 10 cm or 
absolute lymphocyte count ≥ 25 × 109 /L and any lymph node ≥ 5 cm)will receive 
induction therapy with either obinutuzumab (Group A) or obinutuzumab in combination 
with bendamustine (Group B) upon initiating the debulking period. Group assignment will 
not change if bendamustine is subsequently added or removed from a subject's debulking 
regimen during the debulking period. Subjects with > 10 cm nodes or nodal mass or the 
presence of del(11q) and > 5 cm nodes should receive obinutuzumab-bendamustine to 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
6
ensure optimal cytoreduction prior to venetoclax initiation. This regimen may also be 
selected for cytoreduction in other subjects at the discretion of the investigator. 
For subjects receiving obinutuzumab-bendamustine during the debulking period, use of 
growth factor support in treating or preventing neutropenia is allowed and encouraged. 
For those patients categorized as having high risk of tumor lysis syndrome (TLS), use of 
prophylactic rasburicase as well as laboratory monitoring on Cycle 1 Day 2 are 
recommended.
Subjects will receive induction therapy with restaging evaluation, including CT scans, at 
2 months. If subjects are not determined to meet low tumor burden criteria, reassessment 
will occur at 4 months, and 6 months, if needed. If tumor burden does not decrease after at 
least two cycles of obinutuzumab, and there are no signs of disease progression, subjects 
in Group A may have bendamustine added, at the start of Cycle 3 or Cycle 5, for the 
remaining cycles of debulking. If a subject's disease progresses, does not respond to, or 
the patient is otherwise intolerant of debulking with bendamustine-obinutuzumab, the 
subject will discontinue the study after discussion with the AbbVie TA MD. Following a 
maximum of six cycles of debulking, if a subject has not met low tumor burden criteria, it 
will be up to PI discretion (after consultation with the AbbVie TA MD) whether to initiate 
venetoclax or discontinue the subject from the study. Any subjects receiving 
obinutuzumab in combination with bendamustine should discontinue bendamustine upon 
achieving low tumor burden status and initiating venetoclax.
Venetoclax Plus Obinutuzumab Regimen
Venetoclax will be initiated when lymphocyte count < 25 × 109 /L and all lymph nodes 
< 5 cm at restaging evaluation with CT scan. If the subject has not achieved low tumor 
burden status (absolute lymphocyte count < 25 × 109 /L and all lymph nodes < 5 cm) after 
six cycles of debulking, the subject may proceed to venetoclax after discussion with the 
study physician.
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
7
For both debulking groups, subjects will receive obinutuzumab in combination with 
venetoclax for 5 months to maximize synergy. Venetoclax therapy will continue for a 
total treatment period of 52 weeks.
Based upon pre-dose laboratory assessments (prior to venetoclax Day 1), venetoclax 
administration will begin with therapy initiated in the home early enough to enable clinic 
monitoring of laboratory values at 6 – 8 hours post dosing to assess for emergence of 
tumor lysis. At the first dose of 20 mg and 50 mg venetoclax, laboratory analytes will be 
assessed pre-dose on Day 0 (prior to venetoclax Day 1), 6 – 8 hours post-dose on Day 1, 
and the following morning prior to dosing to assess emergence of tumor lysis. At all 
subsequent dose levels laboratory analytes will only be assessed prior to the first dose of 
venetoclax at the new dose level. Venetoclax (400 mg) will be continued for a total 
duration of 53 weeks, including a 5-week dose-ramp-up schedule. 
A Disease Assessment for response will be performed at screening, 5 months after the last 
dose of obinutuzumab, and at 3 months from the end of treatment, or any period of the 
study per protocol specified.
In the case of a CR or CRi, a confirmatory bone marrow aspirate will be required. A 
portion of the aspirate will be split from this sample and stored for possible future analysis 
which may include MRD assessment.
Disease response will be assessed by the investigator, based on laboratory results, 
physical examinations, using the 2008 modified IWCLL Guidelines for Tumor Response 
with the addition of CT imaging (or MRI) when available. All measurable disease must be 
documented at Screening by physical examination, laboratory testing, and CT scan (or 
MRI if CT is medically contraindicated).
4.2.2
Variables Used for Stratification at Randomization
This is an open-label study where subjects are enrolled based on tumor burden. No 
randomization or stratification procedures will be performed.
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
8
4.3
Endpoint
4.3.1
Primary Endpoints
●
Rate of Low Tumor Burden: Defined as the proportion of subjects who 
achieved low tumor burden (per the conditions: absolute lymphocyte counts 
< 25 × 10	/L AND all lymph nodes < 5 cm) at the end of the debulking period 
(before the start of venetoclax).
●
Complete Response Rate: Defined as the proportion of subjects who achieved 
a best response of complete remission (CR) or complete remission with 
incomplete marrow recovery (CRi) (per the 2008 Modified IWCLL NCI-WG 
criteria) up through the completion of the 65-week disease response 
assessment after the start of venetoclax.
4.3.2
Secondary Efficacy Endpoint
●
Overall Response Rate (ORR): Defined as the proportion of subjects who 
achieved a best response of complete remission [CR], complete remission with 
incomplete marrow recovery [CRi], nodular partial remission [nPR], and 
partial remission [PR] (per the 2008 Modified IWCLL NCI-WG criteria) up 
through the completion of the 65-week disease response assessment after the 
start of venetoclax.
●
Duration of Response (DoR): Defined as the number of days from the date of 
first response (CR, CRi, nPR, or PR) (per the 2008 Modified IWCLL NCI-WG 
criteria) to the date of disease progression or death. All disease progression 
will be included regardless whether the event occurred while the subject was 
taking any study drug or had previously discontinued any study drug.
●
Progression-Free Survival (PFS): Defined as the number of days from the date 
of first dose of any study drug (either venetoclax, obinutuzumab, or 
bendamustine) to the date of disease progression or death, whichever occurs 
first. All disease progression will be included regardless whether the event 
occurred while the subject was taking study drug or had previously 
discontinued study drug.
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
9
●
Time to Progression (TTP): Defined as the number of days from the date of 
first dose of any study drug (either venetoclax, obinutuzumab, or 
bendamustine) to date of disease progression. All disease progression will be 
included regardless whether the event occurred while the subject was taking 
study drug or had previously discontinued study drug.
●
Overall Survival (OS): Defined as number of days from the date of first dose 
of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the 
date of death.
●
Minimal Residual Disease (MRD) Negativity Rate: Minimal Residual Disease 
negativity will be defined as less than one CLL cell per 10,000 leukocytes (or 
below 10–4). Rate of MRD negativity status will be defined as the proportion 
of subjects who have MRD negativity status.
4.3.3
Safety Endpoint
Safety evaluations include adverse event (AE) monitoring, serious adverse event (SAE) 
monitoring, physical examinations, vital sign measurements, and clinical laboratory 
assessments (hematology, and chemistry), and incidence and reasons for any premature 
discontinuation, dose reductions, or interruptions of study drug as a measure of safety and 
tolerability for the entire study duration.
4.4
Sample Size Justification
Given that this is a hypothesis generating study, no formal statistical comparisons will be 
performed. The planned study will enroll total sample size of 120 subjects.
4.5
Interim Analysis
After 20 subjects have completed the ramp-up regimen with venetoclax, an exploratory 
analysis will be performed to assess the overall safety profile among all subjects who have 
been enrolled and received study drug, with an emphasis on the risk of TLS. As it is 
expected that all 20 subjects will be in the low risk group for tumor lysis, further subgroup 
analyses will be performed to better understand risk stratification in these subjects. These 
results may identify new subsets of risk based on 1) disease related factors such as 
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
10
lymphadenopathy and absolute lymphocyte count and 2) individual subject related factors 
such as renal function, performance status and co-morbidities. In addition, safety and 
efficacy data for the debulking regimens will be reviewed by an internal data monitoring 
committee (DMC) in treating CLL/SLL and the use of venetoclax. Based on that feedback 
the study team may choose to modify the safety monitoring plan and treatment regimens 
by amendment to the protocol.
An additional interim analysis for efficacy and similar safety measures will be performed 
once 50 subjects have completed at least one disease response assessment after the start of 
venetoclax.
4.6
Multiplicity Testing Procedures for Type-I Error Control
This is a hypothesis generating study where subjects are enrolled based on tumor burden 
and not randomization. Therefore multiplicity testing procedures will not be applied for 
the statistical analysis.
4.7
Missing Data Imputation
The missing data imputation will not be performed in statistical analysis.
5.0
Analysis Populations and Important Subgroups
5.1
Analysis Population
For all analyses, study drug is defined as any dose of venetoclax, obinutuzumab, or 
bendamustine. All enrolled subjects who received at least one dose of any study drug (All 
Treated Subjects) will be used for all safety, efficacy, and baseline analyses. Details will 
be explained in a SAP supplement.
5.2
Subgroup
Subgroups will be based on demographic and baseline characteristics (age, gender, race, 
ethnicity, and high risk CLL/SLL factors such as 11q Del, 13q Del, and so forth). Full 
details about subgroups and analysis windows will be provided in the SAP supplement.
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
11
6.0
Efficacy Analyses
6.1
General Considerations
The efficacy analysis will be performed on All Treated Subjects defined in Section 5.1, 
unless otherwise specified. The efficacy analyses will be performed for the debulking 
treatments (obinutuzumab or combination therapy of obinutuzumab + bendamustine), and 
for all treated subjects.
No statistical test will be performed on any efficacy endpoints. Descriptive statistics and 
the 95% confidence interval (CI) will be presented, where applicable. The efficacy 
analysis specified below will be performed either for protocol specified interim analysis, 
or when the last subject has completed the Week 65 disease assessment after the start of 
venetoclax (including early termination from study).
6.2
Primary Efficacy Analysis 
Rate of Low Tumor Burden 
The rate of low tumor burden will be defined as the proportion of subjects who achieved 
the low tumor burden category (absolute lymphocyte counts < 25 × 10	/L AND all 
lymph nodes < 5 cm) at the end of the debulking period (before the start of venetoclax). 
For the rate calculation, the numerator will be the number of subjects who achieved the 
low tumor burden and the denominator will be all treated subjects. In addition, 95% CI for 
the rate based on the binomial distribution (Clopper-Pearson exact method) will be 
constructed. 
Complete Response Rate
Complete response rate will be defined as the proportion of subjects who achieved a best 
response of CR or CRi per the 2008 Modified IWCLL NCI-WG criteria as assessed by 
investigator up through the completion of the 65-week disease response assessment after 
the start of venetoclax. All treated subjects will be used as denominator in the calculation 
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
12
of complete response rate. In addition, the 95% confidence interval for complete response 
rate based on the binomial distribution (Clopper-Pearson exact method) will be provided.
6.3
Secondary Efficacy Analyses
Overall Response Rate (ORR)
ORR will be defined as the proportion of subjects who achieved a best response of CR,
CRi, nPR, or PR based on the 2008 Modified IWCLL NCI-WG criteria as assessed by 
investigator up through the completion of the 65-week disease response assessment after 
the start of venetoclax. PR response will be confirmed by not less than 49 days from the 
first PR was observed. The corresponding exact 95% confidence interval for the 
proportion (Clopper-Pearson exact method) will be constructed. Subjects who do not 
respond will be considered non-responders.
Duration of Response (DoR)
DoR will be defined as the number of days from the day the criteria are met for CR, CRi, 
nPR, or PR (whichever is recorded first per the 2008 Modified IWCLL NCI-WG criteria) 
to the earliest date that progressive disease (PD) is objectively documented (radiographic 
or clinical) or death (i.e., DoR = PD/death/censoring date – earliest CR/CRi/nPR/PR date 
+ 1 day). For subjects who have a PR before CR, CRi, or nPR in subsequent visits, the 
DoR is computed from the earliest PR. If a subject is still responding then the subject's 
data will be censored at the date of the last available disease assessment. Only subjects 
with an objective response will be included in the analysis of DoR. The distribution of the 
duration of overall response will be estimated using Kaplan-Meier methodology. Median 
duration of response will be calculated and the corresponding 95% confidence interval 
will be presented.
Progression-Free Survival (PFS)
PFS will be defined as the number of days from the date of first dose of any study drug to 
the date of earliest disease progression (PD) (radiographic or clinical) or death 
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
13
(i.e., PFS = PD/death/censoring date – first dose date + 1 day). If the subject does not 
experience disease progression or death then the subject's data will be censored at the date 
of the last available disease assessment. If a subject does not have any post baseline tumor 
assessment or clinical assessment for progression, the data will be censored at the date of 
first dose of any study drug plus 1 day. Progression-free survival will be analyzed by 
Kaplan-Meier methodology. Median duration of PFS will be calculated and 95% 
confidence interval for median duration of PFS will be presented.
Time to Progression (TTP)
TTP will be defined as the number of days from the date the subject started any study 
drug to the date of earliest disease progression (radiographic or clinical) 
(i.e., TTP = PD/censoring date – first dose date + 1 day). If the subject does not 
experience disease progression then the subject's data will be censored at the date of the 
last available disease assessment. If a subject does not have any post baseline disease 
assessments, the data will be censored at the first dose date of any study drug plus 1 day. 
The distribution of the time to progression will be estimated using Kaplan-Meier 
methodology. Median time to progression and the corresponding 95% confidence interval 
will be estimated.
Overall Survival (OS)
OS will be defined as the number of days from the first dose date of any study drug to the 
date of the subject's death (i.e., OS = death/censoring date – first dose date + 1 day). All 
events of death will be included, regardless of whether the event occurred while the 
subject was still taking any study drug, or after the subject discontinued any study drug. If 
a subject has not died, then the data will be censored at the date when the subject was last 
known to be alive prior to the cutoff date for any interim analysis. The date of the last 
known to be alive will be determined by selecting the last available date of the following 
study procedures for a subject: study visit/contact date, tumor assessment/disease 
assessment, clinical disease progression, physical examination, vital signs assessment, 
clinical laboratory collection, study drug, adverse event assessment, concomitant 
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
14
medication assessment, drug or study completion, survival visit, and post treatment 
therapy assessment. The distribution of OS will be estimated using Kaplan-Meier 
methodology. Median survival time and the corresponding 95% confidence interval will 
be estimated.
Minimal Residual Disease (MRD) Response Rate
The rate of MRD response will be defined as the proportion of subjects who achieved 
MRD negative status with less than one CLL cell per 10,000 leukocytes (or below 10–4) in 
the peripheral blood after the start of venetoclax. All treated subjects will be included in 
the denominator for the calculation of MRD response rate. Minimal residual disease 
response will be summarized by categories:  MRD negative, MRD positive, or MRD 
unknown/missing. The 95% confidence intervals based on the binomial distribution 
(Clopper-Pearson exact method) will be provided. Additionally, MRD response rate will 
be summarized by overall response category (CR and/or PR).
Additional exploration will be performed for the baseline tumor burden status (high or 
medium) by each debulking treatment to evaluate the rate of low tumor burden at the 
debulking period (before the start of venetoclax). All treated subjects in the denominator 
for the calculation of the low tumor burden rate. The rate will be provided with the 
corresponding 95% confidence interval (Clopper-Pearson exact method).
6.4
Efficacy Subgroup Analyses
To evaluate the impact of initiation of venetoclax on efficacy, the subgroup analyses will 
be performed for complete response rate, and ORR rate for the analysis population 
defined in Section 5.1. Subgroups specified in Section 5.2 will be assessed and visualized 
in a forest plot. Additional subgroups will be deemed as needed and will be mentioned in 
a SAP supplement.
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
15
7.0
Safety Analyses
7.1
General Considerations
Safety assessments will only include subjects who have received at least one dose of any 
study drug. The safety of study drug will be assessed by evaluation of adverse events, 
serious adverse events, deaths, and changes in laboratory determinations, vital sign 
parameters, any study drug and study discontinuation, dose reductions, or interruptions. 
Safety data will also be assessed by the debulking regimen as well as by the post 
debulking regimen. Post debulking period is considered from the first dose date of 
venetoclax. Detail analysis procedures will be provided in SAP supplement.
7.2
Analysis of Adverse Events
All summaries/analyses involving AEs will include treatment-emergent adverse events 
(TEAE) only, unless otherwise specified. Treatment-emergent AEs are defined as any 
event with onset after the first dose of any study drug (venetoclax, obinutuzumab, or 
bendamustine) and no more than 30 days after the last dose of any study drug. Events 
where the onset date is the same as the study drug start date are assumed to be treatment-
emergent. 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 any 
study drug).
For summaries of AEs related (reasonable possibility) to study drug, at each level of 
summation (overall, MedDRA system organ classes [SOCs], and preferred terms [PTs]) 
each subject is counted only once. If a subject has an AE with unknown relationship, then 
the subject will be counted in the relationship category of "unknown," even if the subject 
has another occurrence of the same event with a relationship of "no reasonable 
possibility" present. The only exception is if the subject has another occurrence of the 
same AE with the relationship of "reasonable possibility." In this case, the subject will be 
counted under the reasonable possibility category.
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
16
Adverse event data will be summarized and presented using 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 by debulking and post debulking 
periods (detail explanation in a SAP supplement)
○
Period is define as: debulking regimen period (obinutuzumab or 
combination of obinutuzumab + bendamustine), and post debulking period 
(combination of obinutuzumab + venetoclax, and mono therapy 
venetoclax). Mono therapy venetoclax will be considered 30 days after the 
last dose of obinutuzumab.
●
Any treatment-emergent serious adverse event
●
Any treatment-emergent serious adverse event by debulking and post 
debulking periods
●
Adverse events broken down by NCI toxicity (CTCAE V4.03) grade
●
Any treatment-emergent NCI toxicity (CTCAE V4.03) grade 3, 4, or 5 adverse 
events
●
Any treatment-emergent NCI toxicity (CTCAE V4.03) grade 3 or 4 adverse 
event
●
Any treatment-emergent adverse event leading to death
●
Venetoclax:
a.
Any treatment-emergent adverse event leading to discontinuation of 
venetoclax
b. Any treatment-emergent adverse event leading to venetoclax interruption
c.
Any treatment-emergent adverse event leading to venetoclax reduction
d. Any treatment-emergent adverse event that is rated at least possibly related 
to venetoclax by the investigator (Reasonable Possibility Related)
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
17
●
Obinutuzumab:
a.
Any treatment-emergent adverse event leading to discontinuation of 
obinutuzumab
b. Any treatment-emergent adverse event leading to obinutuzumab 
interruption
c.
Any treatment-emergent adverse event leading to obinutuzumab reduction
d. Any treatment-emergent adverse event that is rated at least possibly related 
to obinutuzumab by the investigator (Reasonable Possibility Related)
●
Bendamustine:
a.
Any treatment-emergent adverse event leading to discontinuation of 
bendamustine
b. Any treatment-emergent adverse event leading to bendamustine 
interruption
c.
Any treatment-emergent adverse event leading to bendamustine reduction
d. Any treatment-emergent adverse event that is rated at least possibly related 
to bendamustine by the investigator (Reasonable Possibility Related)
In addition, the list of selected adverse events that shown in Table 1, based on the PSSAP 
version 4 will be summarized.
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
18
Table 1.
Selected Adverse Events 
Risk
Search Criteria
Tumor Lysis Syndrome -AESI
SMQ 20000219 – "Tumour lysis syndrome" (Narrow-scope)
Neutropenia – expanded search
Neutropenia CMQ 10000101
Neutropenia
PT terms – "Neutropenia," and "Neutrophil count decreased" 
Serious Infection
SAEs in the SOC of "Infections and Infestations"
Second Primary Malignancy 
SMQ 20000194 – "Malignant tumours" (Narrow) and
SMQ 20000217 - "Myelodysplastic syndromes" (Narrow)
Lymphopenia
PT terms – "Lymphopenia" and "Lymphocyte count decreased"
Anemia
PT terms – "Anaemia" and "Haemoglobin decreased"
Thrombocytopenia
PT terms – "Thrombocytopenia" and "Platelet count decreased"
7.3
Deaths
The number of deaths will be summarized (1) for death occurring during the first day of 
any study drug and within 30 days after the last dose of any study drug, (2) for death 
occurring > 30 days after the last dose of any study drug, (3) for all deaths in this study, 
i.e., 1) and 2).
7.4
Analysis of Laboratory Data
7.4.1
Definition of Baseline
The baseline value for laboratory variables will be defined as:
●
For a subject without IV hydration, the baseline value will be defined as the 
last non-missing measurement prior to receiving the first dose of any study 
drug.
●
The baseline lab value for a subject with IV hydration will be defined as the 
last non-missing lab measurement prior to receiving IV hydration before the 
first of dose any study drug.
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
19
7.4.2
Analysis of Shift from Baseline in Clinical Laboratory Data
For shifts relative to National Cancer Institute Common Toxicity Criteria for Adverse 
Events (NCI CTCAE), baseline and post-baseline laboratory observations (maximum and 
final) will be categorized as grade 0, grade 1, grade 2, grade 3, or grade 4 according to 
NCI CTCAE grade version 4.03 (publication date: 14 June 2010).
For laboratory tests for which a normal range limit is one end of the grade 1 range then 
values that are either within the normal range or outside it in direction opposite the test 
will be classified as grade 0 values. For other tests, values outside the grade 1 range in the 
direction opposite that of the test will be classified as grade 0.
The baseline and final grades will be defined respectively as the grade of the last 
measurement collected prior to the first dose of any study drug unless specified 
differently, and as the last post-baseline measurement collected no more than 30 days 
after the last dose of any study drug.
The maximum NCI toxicity grade value is the value with highest NCI toxicity grade 
collected after the first dose of study drug and within 30 days following the last dose of 
study drug. In cases where multiple values are collected on the same day, the maximum 
grade value will be selected as the value for that day.
For each variable, shift tables will be generated that cross tabulate the number of subjects 
with baseline values of grade 0, grade 1, grade 2, grade 3, or grade 4 versus maximum or 
final observations of grade 0, grade 1, grade 2, grade 3, or grade 4. For a laboratory 
parameter for which grading is performed separately for low and high values, a separate 
summary will be presented for each grading scale.
7.5
Laboratory Search Strategy for TLS
To determine if subjects' laboratory values qualify for TLS, the Howard criteria1 will be 
used. The Howard criteria for lab TLS comprise of ≥ 2 of the following electrolyte 
abnormalities within 24 hours of each other and are specified in Table 2.
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
20
Table 2.
Howard Criteria for TLS
Element
Value
Uric Acid
> 475.8 μmol/L or 8 mg/dL
Potassium
> 6.0 mmol/L
Phosphorus
> 1.5 mmol/L or 4.5 mg/dL
Calcium
< 1.75 mmol/L or 7.0 mg/dL
The following summaries of laboratory TLS as assessed by Howard criteria will be 
provided:
●
Number and percentage of subjects meeting the Howard criteria for laboratory 
TLS (at least two values meeting the criteria in Table 2, occurring within 
24 hours of each other).
●
Listing of all the lab test values for each subject meeting the Howard criteria 
for laboratory TLS.
7.6
Analysis of Vital Signs
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 3 below.
 


Venetoclax (ABT-199)
M16-788 – Statistical Analysis Plan
Version 3.0 – 26 June 2023
21
Table 3.
Criteria for Potentially Clinically Significant Vital Sign
Values
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
8.0
Summary of Changes
●
Updated the efficacy analysis 
●
Included exploratory analysis 
●
Updated the censoring rules for time to the events analysis
●
Updated the definition of baseline lab data
●
Updated the safety data analysis 
9.0
Reference
1.
Howard SC, Jones DP, Pui CH, et al. The tumor lysis syndrome. N Engl J Med. 
2011;364(19):1844-54.
 

Prot_000.pdf: 


p. 2 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
9
2.1
BACKGROUND AND RATIONALE
9
2.2
BENEFITS AND RISKS TO PATIENTS
10
3
STUDY OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES
10
3.2
PRIMARY ENDPOINTS
11
3.3
SECONDARY ENDPOINTS
11
3.4
SAFETY EVALUATIONS AND POTENTIAL ENDPOINTS
11
3.5
BIOMARKER RESEARCH
13
4
INVESTIGATIONAL PLAN
13
4.1
OVERALL STUDY DESIGN AND PLAN
13
4.2
DISCUSSION OF STUDY DESIGN
17
5
STUDY ACTIVITIES
18
5.1
ELIGIBILITY CRITERIA
18
5.2
CONTRACEPTION RECOMMENDATIONS
21
5.3
PROHIBITED MEDICATIONS AND THERAPY
22
5.4
PRIOR AND CONCOMITANT THERAPY
24
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY AND/OR STUDY TREATMENT
24
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY AND/OR STUDY TREATMENT
25
5.7
STUDY DRUG
25
5.8
DRUG ASSIGNMENT
26
5.9
PROTOCOL DEVIATIONS
27
6
SAFETY CONSIDERATIONS
27
6.1
COMPLAINTS AND ADVERSE EVENTS
27
6.2
TOXICITY MANAGEMENT
30
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
31
 


p. 3 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.1
STATISTICAL AND ANALYTICAL PLANS
31
7.2
DETERMINATION OF SAMPLE SIZE
31
7.3
DEFINITION FOR ANALYSIS POPULATIONS
31
7.4
STATISTICAL ANALYSES FOR EFFICACY
31
7.5
STATISTICAL ANALYSES FOR SAFETY
31
7.6
STUDY INTERIM ANALYSIS
31
7.7
DATA MONITORING COMMITTEE
32
8
ETHICS
32
8.1
INSTITUTIONAL REVIEW BOARD (IRB)
32
8.2
ETHICAL CONDUCT OF THE STUDY
32
8.3
SUBJECT CONFIDENTIALITY
32
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
33
10 DATA QUALITY ASSURANCE
33
11 COMPLETION OF THE STUDY
33
12 REFERENCES
33
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
13
FIGURE 2.
DEBULKING PERIOD SCHEMATIC
14
FIGURE 3.
VENETOCLAX OUTPATIENT DOSING SCHEMA (20 MG AND 50 MG INITIAL DOSES)
15
FIGURE 4.
VENETOCLAX OUTPATIENT DOSING SCHEMA (100 MG, 200 MG, AND 400 MG INITIAL DOSES)
16
FIGURE 5.
VENETOCLAX PLUS OBINUTUZUMAB PERIOD SCHEMATIC
17
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
35
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
38
 


p. 4 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
39
APPENDIX D.
ACTIVITY SCHEDULE
40
APPENDIX E.
DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS SYNDROME
45
APPENDIX F.
2008 MODIFIED IWCLL NCI-WG CRITERIA FOR TUMOR RESPONSE
46
APPENDIX G.
INTERNATIONAL WORKSHOP ON CLL RECOMMENDATIONS REGARDING INDICATIONS FOR 
TREATMENT IN CLL
48
APPENDIX H.
SAMPLE LIST OF EXCLUDED AND CAUTIONARY MEDICATIONS
50
APPENDIX I.
PROTOCOL SUMMARY OF CHANGES
52
 




p. 6 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Secondary Endpoints:

Overall Response Rate (ORR):  Defined as the proportion of 
subjects with an overall response (complete remission, 
complete remission with incomplete marrow recovery, 
nodular partial remission [nPR] or partial remission [PR]) (per 
the 2008 Modified IWCLL NCI-WG criteria).

Duration of Response (DoR):  Defined as the number of days 
from the date of first response (CR, CRi, nPR, or PR) (per the 
2008 Modified IWCLL NCI-WG criteria) to the date of disease 
progression or death, whichever occurs first.  All disease 
progression will be included regardless whether the event 
occurred during or after the subject was taking any study drug 
(either venetoclax, obinutuzumab, or bendamustine).

Progression-Free Survival (PFS):  Defined as the number of 
days from the date of first dose of any study drug (either 
venetoclax, obinutuzumab, or bendamustine) to the date of 
disease progression or death, whichever occurs first.  All 
disease progression will be included regardless whether the 
event occurred during or after the subject was taking any 
study drug.

Time to Progression (TTP):  Defined as the number of days 
from the date of first dose of any study drug (either 
venetoclax, obinutuzumab, or bendamustine) to date of 
disease progression.  All disease progression will be included 
regardless of whether the event occurred during or after the 
subject was taking any study drug.

Overall Survival (OS):  Defined as number of days from the 
date of first dose of any study drug (either venetoclax, 
obinutuzumab, or bendamustine) to the date of death.

Undetectable Minimal Residual Disease (UMRD) Rate:  The 
level of MRD will be assessed in the peripheral blood of all 
subjects at 5 months after last dose of obinutuzumab, and at 
the end of treatment (including early study termination) to 
determine the rate of UMRD.  Undetectable Minimal Residual 
Disease will be defined as less than one CLL cell per 
10,000 leukocytes (< 10–4).  Rate of UMRD status will be 
defined as the proportion of subjects who have UMRD.
Safety Evaluations and Potential Endpoints:

Adverse Event (AE) monitoring

Serious Adverse Event (SAE) monitoring

Vital sign measurements

Physical examinations

Laboratory assessments

Incidence and reasons for any premature discontinuation, 
dose reductions, or interruptions of obinutuzumab, 
bendamustine, and/or venetoclax
 






p. 9 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Chronic lymphocytic leukemia (CLL) is the most common of the chronic leukemias, comprising 30% of all 
adult leukemias.1  The World Health Organization classification of hematopoietic neoplasias describes 
CLL as leukemic, lymphocytic lymphoma, being only distinguishable from small lymphocytic lymphoma 
(SLL) by its leukemic appearance.2  Patients' median age at first diagnosis is 71 years.3  Chronic 
lymphocytic leukemia is a clonal disease of unknown etiology, characterized by the accumulation of 
mature B cells in blood, lymph nodes, spleen, liver, and bone marrow.  Morphologically, CLL cells are 
relatively mature looking but immunologically incompetent.  About 95% of CLL is of B-cell origin (B-CLL) 
with a characteristic phenotype (CD19+, CD5+, CD23+ and FMC7–; weak expression of surface 
immunoglobulin (sIg) and membrane CD79b).  The most common chromosomal abnormalities of 
leukemia cells in CLL are deletion 13q14 (incidence 51%), deletion 11q22-q23 (17 – 20%), trisomy 12 
(15%), and deletion 17p13 (5%) and 6q21 (6%).4  Response rates to initial chemoimmunotherapy 
treatment tend to be high, but residual disease often remains and patients tend to relapse or progress, 
eventually becoming resistant to chemotherapy, (i.e., fludarabine, alkylator).
Bendamustine is an alkylating agent, which also has properties of a purine and amino acid antagonist.  
Bendamustine is mainly metabolized in the liver via cytochrome P450; renal elimination accounts for 
about 20% of its excretion.  Bendamustine was developed in the 1960s and is approved by the Food and 
Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of CLL.5,6
Obinutuzumab is a humanized and glycoengineered type II anti-CD20 monoclonal antibody that 
recognizes the CD20 antigen present on normal and malignant B cells.  It was developed for the 
treatment of hematological malignancies by F. Hoffmann-La Roche LTD and was approved by the FDA in 
November 20137 and by the EMA in July 20148 for the use in combination with chlorambucil in patients 
with previously untreated CLL.  The combination of bendamustine and obinutuzumab has recently 
shown high overall response rates in frontline CLL patients, with an overall response rate (ORR) of 90%.9
The B-cell lymphoma-2 (Bcl-2) family proteins are important regulators of the intrinsic apoptosis 
pathway.  Bcl-2 overexpression is a major contributor to the pathogenesis of some types of lymphoid 
malignancies, including in chronic leukemias.  Chronic lymphocytic leukemia is a genetic disease where 
the microRNAs miR15a and miR16-1 that negatively regulate the transcription of Bcl-2 are deleted or 
downregulated, resulting in uncontrolled expression of Bcl-2.10-13  The Bcl2-antagonist venetoclax has 
very promising efficacy and a favorable toxicity profile in del(17p) CLL and is currently being studied in 
frontline CLL patients in combination with obinutuzumab.14  Preliminary data in the first 12 treated 
patients reported 100% ORR and 90% peripheral blood Undetectable Minimal Residual Disease (UMRD).  
However, due to the fast and overwhelming activity of venetoclax, tumor lysis syndrome (TLS) has 
occurred in patients with high tumor burden.  TLS can be managed and prevented with certain measures 
of precaution, especially during dose-escalation.
As most patients with frontline CLL/SLL are likely to present with medium to high tumor cell burden, the 
ability to start patients with newly diagnosed CLL/SLL on venetoclax is complicated by the risk of TLS.  As 
 


p. 10 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
such, this trial explores the role of obinutuzumab, or obinutuzumab in combination with bendamustine, 
in safely debulking patients prior to the initiation of venetoclax therapy.
Clinical Hypothesis
Obinutuzumab or obinutuzumab and bendamustine may safely be used to achieve low tumor burden 
status prior to initiation of venetoclax in subjects with previously untreated CLL/SLL.
2.2 Benefits and Risks to Patients
Clinical data show efficacy of venetoclax therapy in the treatment of CLL/SLL.  Clinical safety data 
indicate that the adverse effects of venetoclax, when administered with appropriate measures, are 
manageable and as expected from a treatment targeting hematologic cells.  Due to the medium to high 
tumor burden of subjects with newly diagnosed CLL/SLL, treatment with venetoclax is associated with a 
higher risk of TLS.  Successful debulking before treatment initiation with venetoclax may significantly 
reduce the risk of TLS.
For further details, please see findings from completed studies, including safety data in the current 
venetoclax Investigator's Brochure.14
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
Primary
1.
To evaluate the anti-tumor effects of both induction therapies of obinutuzumab (Group A), or 
obinutuzumab in combination with bendamustine (Group B), prior to initiation of venetoclax 
and obinutuzumab therapy, with the goal of initiating venetoclax in all subjects with low-tumor 
burden as defined by peripheral lymphocyte counts of < 25 × 109/L and all lymph nodes < 5 cm 
per computed tomography (CT) scans.
2.
To evaluate the efficacy of this regimen as defined by the rate of complete remission (CR) and 
complete remission with incomplete marrow recovery (CRi) following the debulking regimens 
and subsequent venetoclax and obinutuzumab therapy per 2008 Modified International 
Workshop on Chronic Lymphocytic Leukemia National Cancer Institute-sponsored Working 
Group [IWCLL NCI-WG] criteria.15
Secondary
3.
To evaluate Overall Response Rate (ORR), Duration of Overall Response (DoR), Progression-Free 
Survival (PFS), Time to Progression (TTP), Overall Survival (OS), and the level of Minimal Residual 
Disease (MRD) defined as rate of subjects who achieve Undetectable Minimal Residual Disease 
(UMRD; < 10–4) in the peripheral blood.
4.
To evaluate safety and tolerability of the debulking regimens, venetoclax ramp-up, and the 
venetoclax and obinutuzumab combination.
 


p. 11 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.2 Primary Endpoints
The primary endpoints are:

Percent of subjects achieving low tumor burden status after 2, 4 and 6 cycles of therapy with 
obinutuzumab or obinutuzumab and bendamustine.

The rate of complete remission (CR) and complete remission with incomplete marrow recovery 
(CRi):  Defined as the proportion of subjects who achieved CR or CRi (per the 2008 Modified 
IWCLL NCI-WG criteria).15
3.3 Secondary Endpoints
Key Secondary Endpoints

Overall Response Rate (ORR):  Defined as the proportion of subjects with an overall response 
(complete remission, complete remission with incomplete marrow recovery, nodular partial 
remission [nPR] or partial remission [PR]) (per the 2008 Modified IWCLL NCI-WG criteria).

Duration of Response (DoR):  Defined as the number of days from the date of first response (CR, 
CRi, nPR, or PR) (per the 2008 Modified IWCLL NCI-WG criteria) to the date of disease 
progression or death, whichever occurs first.  All disease progression will be included regardless 
whether the event occurred during or after the subject was taking any study drug (either 
venetoclax, obinutuzumab, or bendamustine).

Progression-Free Survival (PFS):  Defined as the number of days from the date of first dose of 
any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of disease 
progression or death, whichever occurs first.  All disease progression will be included regardless 
whether the event occurred during or after the subject was taking any study drug.

Time to Progression (TTP):  Defined as the number of days from the date of first dose of any 
study drug (either venetoclax, obinutuzumab, or bendamustine) to date of disease progression.  
All disease progression will be included regardless of whether the event occurred during or after 
the subject was taking any study drug.

Overall Survival (OS):  Defined as number of days from the date of first dose of any study drug 
(either venetoclax, obinutuzumab, or bendamustine) to the date of death.

Undetectable Minimal Residual Disease (UMRD) Rate:  The level of MRD will be assessed in the 
peripheral blood of all subjects at 5 months after last dose of obinutuzumab, and at the end of 
treatment (including early study termination) to determine the rate of UMRD.  Undetectable 
Minimal Residual Disease will be defined as less than one CLL cell per 10,000 leukocytes (< 10–4).  
Rate of UMRD status will be defined as the proportion of subjects who have UMRD.
3.4 Safety Evaluations and Potential Endpoints
The following safety evaluations will be performed during the study:  Serious Adverse Event (SAE) and 
Adverse Event (AE) monitoring, vital signs, physical examinations, and laboratory assessments.  Certain 
 


p. 12 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
types of events require immediate reporting to the Sponsor, as outlined in Section 6.1.  Safety will be 
monitored on an ongoing basis and summarized periodically in aggregate safety reports and end of 
study.  All AEs will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) version 4.03.16
The safety evaluations for this study are as follows:

All SAEs during and after treatment with obinutuzumab, bendamustine, and/or venetoclax up to 
2 years or until another anti-cancer therapy has been started.

Incidence, nature and severity of all AEs during and after treatment with obinutuzumab, 
bendamustine, and/or venetoclax up to 2 years or until another anti-cancer therapy has been 
started.

Incidence and nature of all Grade 3 – 4 AEs during and after treatment with obinutuzumab, 
bendamustine, and/or venetoclax up to 2 years or until another anti-cancer therapy has been 
started.

Grade 5 AEs or AEs leading to death while receiving obinutuzumab, bendamustine, and/or 
venetoclax and up to 30 days after receiving last dose of study drug.

Incidence and reasons for any premature discontinuation, dose reductions, or interruptions of 
obinutuzumab, bendamustine, and/or venetoclax.
For venetoclax:

Single laboratory abnormalities that meet the following criteria:  calcium < 1.75 mmol/L 
(< 7 mg/dL), phosphorus > 1.5 mmol/L (> 4.5 mg/dL), potassium > 6 mmol/L (> 6 mEq/L), and 
uric acid > 476 µmol/L (> 8 mg/dL) will be collected through up to 53 weeks of treatment.

Incidence and prevalence of cytopenias from initiation of venetoclax through up to 53 weeks of 
treatment will be collected.
For obinutuzumab:

Grade 1 or 2 AEs (related and unrelated) up to 28 days after the last dose of obinutuzumab or 
until another anti-cancer therapy has been started.

Grade 3 or 4 AEs other than infections (related and unrelated) for up to 6 months after the last 
dose of obinutuzumab or until another anti-cancer therapy has been started.

Grade 3 to 4 infections (related and unrelated) for up to 2 years after the last dose of 
obinutuzumab or until another anti-cancer therapy has been started.

Unrelated SAEs for up to 12 months after the last dose of obinutuzumab or until another anti-
cancer therapy has been started.

Study drug-related SAEs will be collected from the last study drug administration up to 2 years 
or until another anti-cancer therapy has been started.
 


p. 13 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

All events of second malignancies will be collected from the last study drug administration 
indefinitely (or until another anti-cancer therapy has been started) even after study closure, but 
not after study termination.
3.5 Biomarker Research
Peripheral blood will be collected at specified time points (Appendix D) throughout the study to evaluate 
known and/or novel disease-related or drug-related biomarkers.  Types of biomarkers may include 
nucleic acids, proteins, lipids, and/or metabolites.  The planned analyses include identification and 
tracking of CLL cells for determination of minimal or measurable residual disease in the peripheral 
blood.  Additional analyses (e.g., UMRD [< 10–4] in bone marrow and/or other known or novel 
biomarkers) may be conducted but may not be included in the clinical study report.  Furthermore, 
biomarker analyses which are exploratory in nature may be performed in non-Good Laboratory 
Practice/Good Clinical Practice (GLP/GCP) laboratories.  Further details regarding the biomarker 
research rationale and collection time points are located in the Operations Manual, Section 3.17 and 
Table 2.  The samples may be retained for no longer than 20 years after study completion or per local 
requirements.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a multi-cohort, open-label study in previously untreated CLL/SLL patients, excluding those with 
the 17p deletion, to evaluate a debulking strategy that would enable all patients to receive subsequent 
venetoclax as outpatients, with lower risk of tumor lysis.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual.
Figure 1.
Study Schematic
Abbreviations:  1L = first line; ALC = absolute lymphocyte count; CLL = chronic lymphocytic leukemia; CT = computed 
tomography
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
   
  
  
 
 
 
 








p. 17 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Figure 5.
Venetoclax Plus Obinutuzumab Period Schematic
Abbreviations:  CR = complete remission; CRi = complete remission with incomplete marrow recovery; CT = computed 
tomography; D = day; MRD = minimal residual disease
Previously untreated subjects with CLL/SLL excluding those with the 17p deletion will be enrolled in this 
study.  See Section 5 for information regarding eligibility criteria.
At the time the 20th subject completes the venetoclax ramp-up, an internal safety committee will review 
data from all subjects who have been enrolled and received study drug in order to determine the 
relative safety of the debulking and ramp-up regimen, as well as to assess feasibility of modification to 
monitoring.  An interim safety and efficacy analysis will be conducted after 50 subjects have completed 
the Week 38 disease assessment.  This analysis will include review by an advisory steering committee as 
well as the Data Monitoring Committee (DMC).
4.2 Discussion of Study Design
Choice of Control Group
This is a single-arm study without control group.
Appropriateness of Efficacy and Safety Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with CLL/SLL.  All 
clinical and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
Previously untreated subjects with CLL/SLL excluding those with the 17p deletion are expected to 
respond well to the debulking regimen followed by venetoclax treatment.  Subjects with 17p deletion 
were excluded due to their expected poor response to the proposed debulking regimen.
Selection of Doses in the Study
After a weekly ramp-up schedule over 5 weeks, venetoclax will be administered at a daily dose of 
400 mg.  Bendamustine will be administered intravenously at a dose of 90 mg/m2 during debulking on 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


p. 18 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Days 1 and 2 of Cycles 1 and 2 (Days 2 and 3 at the investigator's discretion during Cycle 1), for 
subsequent cycles (up to Cycle 6) as needed based on debulking achieved.  During debulking, 
obinutuzumab will be administered intravenously at a dose of 100 mg on Day 1 of Cycle 1, 900 mg on 
Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1.  In subsequent debulking cycles, 
obinutuzumab will be administered intravenously at a dose of 1000 mg on Day 1 of each cycle.
During the venetoclax/obinutuzumab regimen, obinutuzumab will be administered intravenously at a 
dose of 1000 mg on Day 1 of Cycles 1 through 5.  The dose selection in this study is based on prior 
clinical experience with the study drugs.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects, or their legally authorized representative, 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.
Demographic and Laboratory Assessments
2. Adult male or female, at least 18 years old.
3. Laboratory values meeting the following criteria within the screening period prior to the 
first dose of obinutuzumab or obinutuzumab plus bendamustine:

Creatinine clearance (CrCl) ≥ 30 mL/min unless bendamustine will be used, in which case 
CrCl must be ≥ 40 mL/min

Adequate marrow function independent of growth factor or transfusion support within 
2 weeks of Screening as follows, unless cytopenia is due to marrow involvement of CLL/SLL:

Absolute neutrophil count (ANC) ≥ 1.0 × 109/L

Platelet counts ≥ 25 × 109/L without any of the following:

Transfusion support within 14 days of screening

Evidence of mucosal bleeding

Known history of major bleeding episode within 3 months of screening

Total hemoglobin ≥ 8 g/dL (without transfusion support, unless anemia is due to marrow 
involvement of CLL/SLL)

Adequate liver function as indicated by a total bilirubin, aspartate aminotransferase (AST), 
and alanine aminotransferase (ALT) ≤ 3 times the institutional upper limit of normal (ULN), 
 


p. 19 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
unless bendamustine will be used, in which case bilirubin ≤ 1.5 × ULN, and AST and ALT 
≤2.5 × ULN, unless directly attributable to the subject's CLL/SLL.

No positive test results for, or suspicion of, active infection, including hepatitis B virus (HBV) 
infection (defined as positive hepatitis B surface antibody [HBsAg] serology), based on site 
standard practices prior to anti-CD20 antibody infusion and obinutuzumab prescribing
information.7  Testing should be conducted prior to initiation of obinutuzumab per site 
standard of care and obinutuzumab prescribing information.

For subjects who show evidence of hepatitis B infection (HBsAg positive [regardless of 
antibody status] or HBsAg negative but anti-HBc positive), consult physicians with 
expertise in managing hepatitis B regarding monitoring and consideration for HBV 
antiviral therapy.  Subjects may be included if HBV deoxyribonucleic acid (DNA) is 
undetectable, provided that they are willing to undergo monthly DNA testing, during 
and for several months following treatment with obinutuzumab.  Subjects who have 
protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but 
cured hepatitis B are eligible.

No positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing), 
based on site standard practices prior to anti-CD20 antibody infusion and obinutuzumab 
prescribing information.7  Testing should be conducted prior to initiation of obinutuzumab 
per site standard of care and obinutuzumab prescribing information.

Subjects who are positive for HCV antibody are eligible only if polymerase chain reaction 
(PCR) is negative for HCV ribonucleic acid (RNA).

No known infection with human immunodeficiency virus (HIV) or Human T-Cell Leukemia 
Virus 1 (HTLV-1).
4. No serious medical condition or abnormality in a clinical laboratory test that, in the 
investigator's judgment, precludes the subject's safe participation in, and completion of, the 
study.
5. Are willing and able to comply with procedures required in this protocol.
Disease Activity
6. Diagnosis of previously untreated CLL/SLL according to IWCLL criteria.15  Subjects must not 
have received systemic therapy for CLL/SLL prior to the time of study enrollment.
7. Subject meets the following disease activity criteria:

Eastern Cooperative Oncology Group (ECOG) performance score of 0 – 1.

CLL/SLL requires treatment according to the IWCLL criteria (Appendix G).

Medium tumor burden (any lymph node [LN] 5 to < 10 cm OR absolute lymphocyte count 
[ALC] ≥ 25 × 109/L) OR High tumor burden (any LN ≥ 10 cm OR ALC ≥ 25 × 109/L AND LN 
≥5 cm).
8. No presence of 17p deletion at Screening (or within 2 years if an historical test result is used).
9. No Richter's syndrome (transformation of CLL/SLL to aggressive non-Hodgkin's lymphoma or 
Hodgkin's lymphoma).
 


p. 20 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
10. No prolymphocytic leukemia.
11. No known central nervous system involvement.
12. No uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia within 
2 weeks of study entry.
Subject History
13. No history of confirmed progressive multifocal leukoencephalopathy (PML).
14. No history of prior malignancy, except for conditions as listed below if subjects have 
recovered from the acute side effects incurred as a result of previous therapy:

Malignancies surgically treated, or treated with radiation, with curative intent and with no 
known active disease present for ≥3 years before randomization.

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease.

Adequately treated cervical carcinoma in situ without evidence of disease.

Surgically/adequately treated low grade, early stage, localized prostate cancer without 
evidence of disease.
15. No history of an allergic reaction or significant sensitivity to constituents of the study drug 
(and its excipients) and/or other products in the same class.
16. No history of severe allergic reaction or anaphylactic reactions to humanized or murine 
monoclonal antibodies or known sensitivity or allergy to murine products.
17. No history of clinically significant (per Investigator's judgment) drug or alcohol abuse within 
the last 6 months.
18. No conditions that could interfere with drug absorption including but not limited to short 
bowel syndrome.
19. No history of clinically significant medical conditions or any other reason that in the opinion 
of the Investigator would interfere with the subject's participation in this study or would make 
the subject an unsuitable candidate to receive study drug.
20. No history of clinically relevant or significant electrocardiogram (ECG) abnormalities, 
including ECG with QT interval corrected for heart rate (QTc) using Fridericia's formula (QTcF) 
> 450 msec (males) or > 470 msec (females).
Contraception
21. A negative serum pregnancy test for all female subjects (except post-menopausal) at the 
Screening Visit and a negative urine pregnancy test for all female subjects (except post-
menopausal) at baseline prior to the first dose of study drug.
 
  
 
 
 
 
 
 
 
 
 
 
 
 


p. 21 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
22. If female, subject must be either postmenopausal, OR permanently surgically sterile OR for 
women of childbearing potential practicing at least 1 protocol-specified highly effective method 
of birth control, that is effective from Study Day 1 through at least 30 days after the last dose of 
venetoclax or 18 months after the last dose of obinutuzumab or 3 months after the last dose of 
bendamustine, whichever is longer.
23. If male, and subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from Study Day 1 through at least 18 months after the last dose of obinutuzumab or 
3 months after the last dose of bendamustine, whichever is longer, to practice the protocol-
specified contraception.
24. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study or for at least 30 days after the last dose of venetoclax or 18 months after the last dose of 
obinutuzumab or 3 months after the last dose of bendamustine, whichever is longer.
25. Male who is not considering fathering a child or donating sperm during the study or for at 
least 18 months after the last dose of obinutuzumab or 3 months after the last dose of 
bendamustine, whichever is longer.
Concomitant Medications
26. Subject must not have been treated with any investigational drug within 30 days or 
5 half-lives of the drug (whichever is longer) prior to the first dose of study drug or is currently 
enrolled in another clinical study.
27. Subject must not have received any live vaccine within 4 weeks prior to the first dose of 
study drug, or expected need of live vaccination during study participation including at least 
4 weeks after the last dose of study drug.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:

Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.

Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle-stimulating hormone (FSH) level > 40 IU/L.

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).
 


p. 22 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy throughout the study including at 
least 30 days after the last dose of venetoclax or 18 months after the last dose of 
obinutuzumab or 3 months after the last dose of bendamustine, whichever is longer.

Females must commit to one of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal) associated with inhibition of ovulation initiated at least 
1 month prior to study Cycle 1 Day 1.  Also, barrier method must be used during this 
study from initial study drug administration to 30 days after the last dose of venetoclax 
as drug-drug interaction with venetoclax upon the hormonal contraception is unknown.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month prior to study Cycle 1 Day 1.  Also, 
barrier method must be used during this study from initial study drug administration to 
30 days after the last dose of venetoclax as drug-drug interaction with venetoclax upon 
the hormonal contraception is unknown.

Bilateral tubal occlusion/ligation at least 1 month before study Cycle 1 Day 1.

Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a hysterosalpingogram 
confirms success of the procedure at least 1 month before study Cycle 1 Day 1.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Vasectomized sexual partner(s) (the vasectomized partner(s) provided the vasectomized 
partner has received medical assessment of the surgical success and is the sole sexual 
partner of the trial participant).

True abstinence:  Refraining from heterosexual intercourse when this is in line with the 
preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, 
ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable).
Contraception Requirements for Males
Male subjects who are sexually active with a female partner of childbearing potential must agree to use 
condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 through at 
least 18 months after the last dose of obinutuzumab or 3 months after the last dose of bendamustine, 
whichever is longer, and his female partner(s) must use at least one of the contraceptive measures (as 
defined above for female study subjects of childbearing potential).
5.3 Prohibited Medications and Therapy
During treatment with venetoclax:

Steroid therapy for anti-neoplastic intent will not be allowed either during, or within 7 days prior 
to, the first dose of venetoclax with the exception of inhaled steroids for the treatment of 
 


p. 23 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
asthma or Chronic Obstructive Pulmonary Disease (COPD), topical steroids, replacement 
corticosteroid therapy for an inherited or acquired deficiency.

Anticancer therapies including chemotherapy, radiotherapy, or other investigational therapy, 
including targeted small molecule agents are excluded 5 half-lives prior to first dose and 
throughout venetoclax administration.

Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent are excluded 30 days 
prior to first dose and throughout venetoclax administration.
Excluded during initiation and dose-titration (ramp-up) of venetoclax and cautionary at 400 mg steady 
daily dose (See Appendix H):

Exclude strong cytochrome P450 3A (CYP3A) inhibitors (Appendix H) during initiation and the 
dose-titration (ramp-up) phase.  If subject requires use of these medications after the dose 
titration phase at steady daily doses, use with caution and reduce the venetoclax dose by at 
least 75% during co-administration.  Resume the venetoclax dose that was used prior to 
initiating the CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor.

Do not consume grapefruit, grapefruit products, Seville oranges (often used in marmalades), or 
star fruit.

Avoid concomitant use of venetoclax with moderate CYP3A inhibitors.  Consider alternative 
treatments.  If a moderate CYP3A inhibitor must be used, reduce the venetoclax dose by at least 
50%.  Monitor these subjects more closely for signs of toxicities.  Resume the venetoclax dose 
that was used prior to initiating the CYP3A inhibitor 2 to 3 days after discontinuation of the 
inhibitor.

Avoid concomitant use of venetoclax with strong or moderate CYP3A inducers.  Consider 
alternative treatments with less CYP3A induction.

Avoid concomitant use of venetoclax with P-glycoprotein (P-gp) inhibitors.  If a moderate P-gp 
inhibitor must be used, reduce the venetoclax dose by at least 50%.  Monitor these subjects 
more closely for signs of toxicities.
For subjects being treated with bendamustine (See Appendix H):

Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma 
concentrations of bendamustine and decrease plasma concentrations of active metabolites.  
Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma 
concentrations of bendamustine and increase plasma concentrations of its active metabolites.  
Caution should be used, or alternative treatments considered if concomitant treatment with 
CYP1A2 inhibitors or inducers is needed.

Due to the risk of toxic skin reactions (e.g., Stevens-Johnson syndrome/toxic epidermal 
necrolysis), concomitant administration of bendamustine and allopurinol should be avoided.  If 
allopurinol is indispensable, it should be stopped > 24 hours before and reinitiated ≥ 24 hours 
after administration of bendamustine.
 


p. 24 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over the counter or prescription medicines, vitamins and/or herbal 
supplements) that the subject is receiving at the time of enrollment or receives during the study must be 
recorded through the post-treatment visit for venetoclax (Week 157).
Please refer to Appendix H.  Any questions regarding concomitant or prior therapy should be raised to 
the AbbVie emergency contact (see title page).  Information regarding potential drug interactions with 
obinutuzumab, bendamustine, or venetoclax can be located in the respective Investigator's Brochures.
Subjects must be able to safely discontinue any prohibited medications 5 half-lives or 4 weeks prior to 
initial study drug administration, whichever is shorter.  Subjects must be consented for the study prior 
to discontinuing any prohibited medications for the purpose of meeting study eligibility.
5.5 Withdrawal of Subjects and Discontinuation of Study and/or Study 
Treatment
A subject may voluntarily withdraw or be withdrawn from the study and/or study drug treatment at any 
time for reasons including, but not limited to, the following:

Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the Investigator or the AbbVie TA MD.

The Investigator believes it is in the best interest of the subject.

The subject requests withdrawal from the study.

The subjects' response to therapy is unsatisfactory, as evidenced by progression of disease while 
on study drug.

The subject requires other cancer treatment (e.g., radiotherapy, alternate anti-neoplastic 
agent).

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

The subject becomes pregnant while on study drug.

Subject is significantly non-compliant with study procedures which would put the subject at risk 
for continued participation in the trial.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the final status of the subject.  At a minimum, 2 telephone calls must be made and 
1 certified letter must be sent and documented in the subject's source documentation.
 


p. 25 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The Investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the Investigator.
In the event AbbVie is notified in writing that a subject withdraws consent to participate in the clinical 
study and no longer consents to the biomarker research, no new biomarker data will be collected for the 
withdrawn subject or added to the existing data or database(s).  Data generated from biomarker 
research collected before subject withdrawal of consent is received will remain part of the study results.
5.6 Follow-Up for Subject Withdrawal from Study and/or Study 
Treatment
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed up, unless subjects have decided to discontinue 
the study participation entirely (e.g., withdrawal of informed consent).  Subjects should be advised on 
the continued scientific importance of their data even if they discontinue treatment with study drug 
early.
If a subject prematurely discontinues study participation (e.g., withdrawal of informed consent) and/or 
study treatment, the procedures outlined for the early termination visit should be completed as soon as 
possible, preferably within 2 weeks of early termination, but before initiation of another treatment 
algorithm, if applicable.  In addition, if subject is willing, a 30-day follow-up phone call after the last dose 
of study drug may be completed to ensure all treatment-emergent AEs/SAEs have been resolved.  If the 
subject refuses, this should be noted in the subject's source documentation.
Subjects prematurely discontinuing study treatment will be followed for disease progression and 
survival.  Post-treatment follow-up calls will be performed every 3 months until discontinuation from 
the study.  Survival information (e.g., the date and cause of death, post-treatment cancer therapies, 
date of progression) will be collected.  This period will continue for 2 years following discontinuation of 
venetoclax.
All attempts must be made to determine the date of the last study drug dose and the primary reason for
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate electronic Case Report Form (eCRF) page.  However, these procedures should not interfere 
with the initiation of any new treatments or therapeutic modalities that the Investigator feels are 
necessary to treat the subject's condition.  Following discontinuation of study drug, the subject will be 
treated in accordance with the Investigator's best clinical judgment, irrespective of whether or not the 
subject decides to continue participation in the study.
5.7 Study Drug
Venetoclax will be initiated when lymphocyte count is < 25 × 109/L and all lymph nodes are < 5 cm at 
restaging evaluation with CT scan.  If the subject has not achieved low tumor burden status after 
6 cycles of debulking, the subject may proceed to venetoclax per the discretion of the treating physician 
after discussion with the study physician.  The venetoclax dose will be administered according to a 
weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.  Subjects will be 
 


p. 26 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
instructed to take venetoclax tablets with a meal and water at approximately the same time each day.  
Venetoclax tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.  
If a subject misses a dose of venetoclax within 8 hours of the time it is usually taken, the subject should 
take the missed dose as soon as possible and resume the normal daily dosing schedule.  If a subject 
misses a dose by more than 8 hours, the subject should not take the missed dose and should resume the 
usual dosing schedule the next day.
If a subject vomits following dosing, no additional dose should be taken that day.  The next prescribed 
dose should be taken at the usual time.
Subjects will be instructed to return all drug containers (even if empty) to the study site personnel at 
each study visit.  The study site personnel will document compliance.
Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 
of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 – 6 (1000 mg on Day 1) only as needed for subjects to 
achieve low tumor burden) will be administered via intravenous infusion during the debulking regimen.  
After debulking, obinutuzumab (1000 mg) will be administered via intravenous infusion on Day 1 of 
one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the 
regimen.
Bendamustine (90 mg/m2) will be administered in subjects with nodes or nodal mass > 10 cm, or with 
del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion 
over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of 
each 28-day cycle for up to 6 cycles during the debulking regimen.
Bendamustine and obinutuzumab will be packaged in vials and venetoclax will be packaged in blister 
cards and bottles with quantities sufficient to accommodate study design.  Each kit will be labeled per 
local requirements and this label must remain affixed to the kit.  Upon receipt, study drug should be 
stored as specified on the label and kept in a secure location.  Each kit will contain a unique kit number.  
This kit number is assigned to a subject via interactive response technology (IRT) and encodes the 
appropriate study drug to be dispensed at the subject's corresponding study visit.  All blank spaces on 
the label will be completed by the site staff prior to dispensing to subjects.  Study drug will only be used 
for the conduct of this study.
Instructions for drug preparation will be provided by AbbVie.
AbbVie will not supply drugs other than obinutuzumab, bendamustine and venetoclax.
5.8 Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the Screening visit.  For
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.
Subjects with 1) > 10 cm lymph nodes or nodal mass or 2) with del(11q) and > 5 cm nodes, or 3) for 
whom aggressive debulking would be beneficial in the opinion of the investigator, should be assigned to 
the obinutuzumab plus bendamustine debulking regimen to ensure adequate cytoreduction.  All other 
subjects should be assigned to the obinutuzumab debulking regimen.  For all subjects, but particularly 
 


p. 27 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
for those receiving obinutuzumab plus bendamustine during the debulking period, use of growth factor 
support in treating or preventing neutropenia is allowed and encouraged.
5.9 Protocol Deviations
The Investigator is responsible for complying with all protocol requirements, written instructions and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified), the Investigator is responsible for notifying Independent Ethics Committee 
(IEC)/Independent Review Board (IRB), regulatory authorities (as applicable) and AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
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.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
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 (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An adverse event is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not the event is considered causally related to the 
use of the product.
 


p. 28 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study.  All adverse events will be followed to a satisfactory conclusion; 
improvements in grade should not be captured as a separate event.
An elective surgery/procedure scheduled to occur during a study will not be considered an adverse 
event if the surgery/procedure is being performed for a pre-existing condition and/or 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.
If an adverse event, whether associated with study drug or not, meets any of the following criteria, it is 
to be reported to AbbVie clinical pharmacovigilance as a serious adverse event within 24 hours of the 
site being made aware of the serious adverse event (refer to Section 4.5 of the Operations Manual for 
reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
 


p. 29 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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.
All adverse events reported from the time of study drug administration until 30 days after 
discontinuation of study drug administration will be collected, whether solicited or spontaneously 
reported by the subject.  In addition, protocol-related serious adverse events and nonserious adverse 
events will be collected from the time the subject signs the study-specific informed consent.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local guidelines.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Events of Special Interest 
The following adverse events of special interest (AESI) will be monitored during the study:

Tumor lysis syndrome;

Second primary malignancies;

Serious infections.
These AESIs are to be entered into the electronic data capture (EDC) system immediately (i.e., no more 
than 24 hours after the site becoming aware of the event), also if they do not meet seriousness criteria.  
Adverse events of lab or clinical TLS need to be reported as adverse events of special interest.
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each adverse event according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.  If a reported AE increases in 
severity, the initial AE should be given an outcome date and a new AE must be reported on a different 
onset date than the end date of the previous AE to reflect the change in severity.  The dates on the AEs 
cannot overlap.  For all reported SAEs that increase in severity, the supplemental eCRFs also need to be 
updated to reflect any changes due to the increase in severity.
 


p. 30 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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.
Pregnancy
While not an adverse event, pregnancy in a study subject must be reported to AbbVie within 24 hours of 
the site becoming aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (see Section 5.5).  If a pregnancy occurs in a study subject or in the partner of a study 
subject, information regarding the pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written informed consent 
from the partner must be obtained prior to collection of any such information.  A separate consent will 
be provided by AbbVie for this purpose.  Pregnancies in study subject's partners will be collected from 
the date of the first dose through 90 days after the last dose of venetoclax or 18 months after the last 
dose of obinutuzumab, whichever is longer.
The medical outcome for either mother or infant, meeting any serious criteria including an elective or 
spontaneous abortion, stillbirth, or congenital anomaly is considered a serious adverse event and must 
be reported to AbbVie within 24 hours of the site becoming aware of the event.
6.2 Toxicity Management
The management of specific AEs and laboratory parameters is described in the Operations Manual.  This 
includes AEs of TLS, febrile infections, and any grade 3/4 AEs non-hematologic AEs, and Grade 3 
neutropenia with infection or fever, or Grade 4 hematologic toxicities (except lymphopenia).  For 
allowed study drug interruption, the following rules apply:
1.
Allow study drug interruption up to 14 consecutive days for AEs and emergency surgery.  
Elective surgery will not be allowed during the debulking period, or within 4 weeks of 
completion of the venetoclax ramp up period.  If study drug administration is interrupted for 
more than 3 days (i.e., AE), the site will contact the AbbVie study team or AbbVie Therapeutic 
Area Medical Director (TA MD) to adjust the subject's visit schedule, procedures and/or dosing 
on a case by case basis.  For subjects who have had a dosing interruption greater than 1 week 
during the first 5 weeks of dose titration or greater than 2 weeks when at the daily dose of 
400 mg, TLS risk should be reassessed to determine if restarting at a reduced dose is necessary 
(e.g., all or some levels of the dose titration).
2.
If the subject must undergo emergency surgery, the study drug should be interrupted at the 
time of the surgery and the AbbVie study team must be notified, but does not need to be 
consulted.  After emergency surgery, consult with AbbVie study team before reintroduction of 
 


p. 31 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
study drug, once the physician has examined the surgical site and determined that it has healed 
and there is no sign of infection.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  All statistical analyses will be performed using SAS version 9.4 or newer 
(SAS Institute Inc., Cary, North Carolina, USA).
7.2 Determination of Sample Size
Given that this is a hypothesis generating study, no formal statistical comparisons will be performed.  
The planned study will enroll total sample size of 120 subjects.
7.3 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all enrolled subjects who received at least 1 dose of any study drug.  
The FAS will be used for all safety, efficacy and baseline analyses.
7.4 Statistical Analyses for Efficacy
Analysis of the primary endpoint will be conducted on the FAS.  Only descriptive statistical analyses will 
be performed on both induction therapies of obinutuzumab (Group A) or obinutuzumab plus 
bendamustine (Group B) at 2, 4, and 6 cycles of therapy.
Point estimates and 95% confidence interval of complete remission rate (defined as % of CR + CRi) will 
be calculated based on the 2008 Modified IWCLL NCI-WG criteria.  Details of the analysis methods for all 
efficacy endpoints will be provided in the SAP.
7.5 Statistical Analyses for Safety
Details pertaining to the safety analyses can be found in the SAP.
7.6 Study Interim Analysis
After 20 subjects have completed the ramp-up regimen with venetoclax, an exploratory analysis will be 
performed to assess the overall safety profile among all subjects who have been enrolled and received 
study drug, with an emphasis on the risk of TLS.  As it is expected that all 20 subjects will be in the low-
risk group for tumor lysis, further subgroup analyses will be performed to better understand risk 
stratification in these subjects.  These results may identify new subsets of risk based on 1) disease-
related factors such as lymphadenopathy and absolute lymphocyte count and 2) individual subject-
 


p. 32 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
related factors such as renal function, performance status and co-morbidities.  In addition, safety and 
efficacy data for the debulking regimens will be reviewed by an advisory committee of experts in 
treating CLL/SLL and the use of venetoclax.  Based on that feedback the study team may choose to 
modify the safety monitoring plan and treatment regimens by amendment to the protocol.
An additional interim analysis for efficacy and similar safety measures will be performed once 
50 subjects have completed the Week 38 disease assessment.  This data will also be reviewed by the 
steering committee and, in the case of the safety data, by the DMC.
7.7 Data Monitoring Committee
A DMC comprised of persons independent of the study team and with relevant expertise in their field 
will review data from all subjects who have been enrolled and received study drug at the time the 
first 20 subjects complete the venetoclax ramp-up, in order to determine relative safety of the debulking 
and ramp up regimen, as well as to assess feasibility of modification to monitoring.  The primary 
responsibility of the DMC will be to protect the safety of the subjects participating in this study.
A separate DMC charter will be prepared outside of the protocol and will describe the roles and 
responsibilities of the DMC members, frequency of data reviews, relevant safety data to be assessed 
and expectations for blinded communications.
8 ETHICS
8.1 Institutional Review Board (IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the informed consent 
form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study.  In addition, all 
changes to the consent form(s) will be IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (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 Investigator are specified in Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
 


p. 33 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented and reported in compliance with the protocol, ICH GCP and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
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.
Subjects will be followed for disease progression and survival.  Post-treatment follow-up calls will be 
performed every 3 months until discontinuation from the study.  Survival information (e.g., the date and 
cause of death, post-treatment cancer therapies, date of progression) will be collected.  This period will 
continue for 2 years following discontinuation of venetoclax.
12
REFERENCES
1.
Jaglowski S, Jones JA.  Choosing first-line therapy for chronic lymphocytic leukemia.  Expert Rev 
Anticancer Ther.  2011;11(9):1379-90.
2.
Müller-Hermelink HK, Montserrat E, Catovsky D, et al.  Chronic lymphocytic leukemia/small 
lymphocytic lymphoma.  In:  Jaffe ES, Harris NL, Stein H, Vardiman JW, eds.  World Health 
Organization Classification of Tumours:  Pathology and Genetics of Tumours of Haematopoietic
and Lymphoid Tissues.  Lyon, France:  IARC Press; 2001:127-30.
3.
Roswell-Turner RB, Barr PM.  Treatment of chronic lymphocytic leukemia in older adults.  J 
Geriatr Oncol.  2017; 8(5):315-9.
4.
Boelens J, Lust S, Vanhoecke BA, et al.  Chronic Lymphocytic Leukaemia.  Anticancer Res.  
2009;29(2):605-16.
5.
Bendeka® (bendamustine hydrochloride) injection, for intravenous use [prescribing 
information].  North Wales, PA; Teva, Current edition.
 


p. 34 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6.
European Medicines Agency:  
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Levact/hum
an_referral_000199.jsp&mid=WC0b01ac0580024e9a; last accessed 23 August 2017.
7.
GAZYVA® (obinutuzumab) [prescribing information].  South San Francisco, CA; Genentech, Inc., 
Current edition.
8.
European Medicines Agency:  
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002799/h
uman_med_001780.jsp&mid=WC0b01ac058001d124; last accessed 23 August 2017.
9.
Brown JR, O'Brien S, Kingsley CD, et al.  Obinutuzumab plus fludarabine/cyclophosphamide or 
bendamustine in the initial therapy of CLL patients:  the phase 1b GALTON trial.  Blood.  
2015;125(18):2779-85. 
10. Willis S, Day CL, Hinds MG, et al.  The Bcl-2-regulated apoptotic pathway.  J Cell Sci.  
2003;116 (Pt 20):4053-6.
11. Cory S, Adams JM.  The Bcl2 family:  regulators of the cellular life-or-death switch.  Nature 
Reviews.  Cancer.  2002;2(9):647-56.
12. Borner C.  The Bcl-2 protein family:  sensors and checkpoints for life-or-death decisions.  
Molecular Immunology.  2003;39(11):615-47.
13. Cory S, Huang DCS, Adams JM.  The Bcl-2 family:  roles in cell survival and oncogenesis.  
Oncogene.  2003;22(53):8590-607.
14. AbbVie.  Venetoclax Investigator's Brochure.  Current edition.
15. 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.
16. National Cancer Institute.  Common Terminology Criteria for Adverse Events (CTCAE), v4.03.  
Accessed on:  08 October 2017.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
17. Fischer K, Al-Sawaf O, Fink AM, et al.  Safety and efficacy of venetoclax and obinutuzumab in 
patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting medical 
conditions:  final results of the run-in phase of the randomized CLL14 Trial (BO25323).  Blood.  
2016;128:2054.
18. Levin A, Kellum JA, Mehta RL, et al.  Acute kidney injury:  toward an integrated understanding 
through development of a research agenda.  Clin J Am Soc Nephrol.  2008;3(3):862-3.
19. Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  2011;364(19):1844-54.
20. Hallek M, Cheson BD, Catovsky D, et al.  iwCLL guidelines for diagnosis, indications for 
treatment, response assessment and supportive management of CLL.  Blood.  
2018;131(25):2745-60.
 


p. 35 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALC
Absolute Lymphocyte Count
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ANC
Absolute Neutrophil Count
Bcl-2
B-cell lymphoma-2
CLL
Chronic Lymphocytic Leukemia
COPD
Chronic Obstructive Pulmonary Disease
CR
Complete Remission
CrCl
Creatinine Clearance
CRi
Complete Remission with Incomplete Marrow Recovery
CT
Computed Tomography
CYP3A
Cytochrome P450 3A 
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DoR
Duration of Overall Response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
EMA
European Medicines Agency
FAS
Full Analysis Set
FDA
Food and Drug Administration
FISH
Fluorescence in-situ hybridization
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAb
Hepatitis B surface Antibody
HBsAg
Hepatitis B surface Antigen
 


p. 36 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HTLV-1
Human T-Cell Leukemia Virus 1
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgHV
Immunoglobulin variable region heavy chain 
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IWCLL
International Workshop for Chronic Lymphocytic Leukemia
LDH
Lactate dehydrogenase
LN
Lymph Node
MRD
Minimal Residual Disease
MRI
Magnetic Resonance Imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NCI-WG
National Cancer Institute – Working Group 
nPR
Nodular Partial Remission
ORR
Overall Response Rate
OS
Overall Survival
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PFS
Progression-Free Survival
P-gp
P-glycoprotein
PI
Principal Investigator
PML
Progressive Multifocal Leukoencephalopathy
PR
Partial Remission
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia's formula
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
 


p. 37 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
SD
Stable Disease
sIg
Surface Immunoglobulin
SLL
Small Lymphocytic Lymphoma
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
Therapeutic Area Medical Director
TLS
Tumor Lysis Syndrome
TTP
Time To Progression
ULN
Upper Limit of Normal
UMRD
Undetectable MRD
 


p. 38 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-788:  Debulking Regimens Prior to Initiating Venetoclax Combination Therapy in Frontline 
CLL Excluding 17p Deletion
Protocol Date:  19 December 2019
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
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., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
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 protocol and all of its amendments.
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. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


p. 39 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Study Project Manager
Clinical Program Development
Assistant Medical Director
Global Medical Affairs
Hematology Lead
Medical Affairs
Director Statistics
Statistics
Principal Medical Writer
Medical Writing
 








p. 43 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
*
The Week 1 Day 1 visit may be performed within +3 days/– 0 days; thereafter Day 1 of each subsequent Cycle may be performed within +/– 3 days of the expected visit date 
provided that the planned 28-day interval between cycles is maintained.
**
The Week 3 Day 1, Week 4 Day 1, and Week 5 Day 1 (+/– 3 days) visits are optional if the investigator wants to recheck lab values.
 




p. 45 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX E. DEFINITIONS OF LABORATORY AND CLINICAL 
TUMOR LYSIS SYNDROME
Metabolic Abnormality
Criteria for Classification of Laboratory 
Tumor Lysis Syndrome
Criteria for Classification of Clinical 
Tumor Lysis Syndrome
Hyperuricemia
Uric acid > 8.0 mg/dL (475.8 µmol/liter) in 
adults or above the upper limit of the 
normal range for age in children
Hyperphosphatemia
Phosphorus > 4.5 mg/dL (1.5 mmol/liter) in 
adults or > 6.5 mg/dL (2.1 mmol/liter) in 
children
Hyperkalemia
Potassium > 6.0 mmol/liter
Cardiac dysrhythmia or sudden 
death probably or definitely caused 
by hyperkalemia
Hypocalcemia
Corrected calcium < 7.0 mg/dL 
(1.75 mmol/liter) or ionized calcium < 1.12 
(0.3 mmol/liter)†
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesias, muscle 
twitching, carpopedal spasm, 
Trousseau's sign, Chvostek's sign, 
laryngospasm, or bronchospasm), 
hypotension, or heart failure 
probably or definitely caused by 
hypocalcemia
Acute kidney injury‡
Not applicable
Increase in the serum creatinine 
level of 0.3 mg/dL (26.5 µmol/liter) 
(or a single value > 1.5 times the 
upper limit of the age-appropriate 
normal range if no baseline 
creatinine measurement is available) 
or the presence of oliguria, defined 
as an average urine output 
< 0.5 mL/kg/hr for 6 hrs
†
The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × 
(4-albumin in grams per deciliter).
‡
Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 µmol per liter) or a 
period of oliguria lasting 6 hours or more.  By definition, if acute kidney injury is present, the subject has clinical tumor lysis 
syndrome.  Data about acute kidney injury from Levin et al.18
Note:
In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be present during the same 24 hour
period within 3 days before the start of therapy or up to 7 afterward.  Clinical tumor lysis syndrome requires the 
presence of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or 
death.
Source:  Howard et al., 201119
 


p. 46 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX F. 2008 MODIFIED IWCLL NCI-WG CRITERIA FOR 
TUMOR RESPONSE
Parameter
Complete 
Remission (CR) All 
Criteria Must Be 
Meta,b
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 Metc
Stable Disease 
(SD) All Criteria 
Must Be Met
Group A
Lymphadenopathy
None > 1.5 cm
Decrease ≥ 50%d 
from baseline
Increase ≥ 50%e
from baseline or any 
new LN > 1.5 cm
Change of –49% 
to +49%f
from baseline
Blood 
Lymphocytes
< 4000/µL
Decrease ≥ 50% 
from baseline
Increase ≥ 50% over 
baseline (≥ 5000/µL)
Change of –49% 
to +49% 
from baseline
Hepatomegalyg
None
Decrease ≥ 50% 
from baseline
Increase ≥ 50%h
from baseline
Change of –49% 
to +49% 
from baseline
Splenomegalyg
None
Decrease ≥ 50% 
from baseline
Increase ≥ 50%h
from baseline
Change of –49% 
to +49% 
from baseline
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 CLL
Change of –49% 
to +49% 
from baseline
Hemoglobin
> 11.0 g/dLi
> 11.0 g/dL or 
increase ≥ 50% 
over baselinei
Decrease of > 2 g/dL 
from baseline 
secondary to CLL
Increase to 
≤11.0 g/dL over 
baseline, or 
decrease 
< 2 g/dL
Neutrophils
> 1500/µLi
> 1500/µL or 
increase ≥ 50% 
over baselinei
Decrease ≥ 50% 
from baseline 
secondary to CLL
N/A
 


p. 47 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Parameter
Complete 
Remission (CR) All 
Criteria Must Be 
Meta,b
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 Metc
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 
(regardless of size) or 
transformation to a 
more aggressive 
histology, e.g., Richter 
Syndromee
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, nPR, 
PR, or PD
Abbreviations:  CLL = chronic lymphocytic leukemia; CR = complete remission; CRi = complete remission with incomplete 
marrow recovery; CT = computed tomography; LN = lymph nodes; N/A = Not applicable; nPR = nodular partial remission; 
PD = progressive disease; PR = partial remission; SD = stable disease; SPD = sum of the products of diameters
a.
CR also requires the lack of disease-related constitutional symptoms.
b.
Complete Remission plus the presence of persistent lymphoid nodules on bone marrow biopsy is nodular partial remission 
(nPR).
c.
Transformation to a more aggressive histology (e.g., Richter Syndrome) would also qualify as a PD.
d.
Sum of the products of multiple LNs (as evaluated by CT scans).  Note in eCRF if by physical examination only.
e.
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.
f.
Sum products of up to 6 LNs or LN masses (target lesions), with no increase in an LN or new enlarged LN.  Increase of 
< 25% in small LNs (< 2 cm) not significant.  Decreases should be measured compared to baseline (pre-treatment) values.
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.
 




p. 49 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6.
Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine).
7.
Disease-related symptoms as defined by any of the following:
a) Unintentional weight loss ≥ 10% within the previous 6 months.
b) Significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform usual 
activities).
c) Fevers ≥ 100.5° F or 38.0° C for 2 or more weeks without evidence of infection.
d) Night sweats for 1 month without evidence of infection.
Source:  Hallek et al., 201820
 






p. 52 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX I.
PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
07 December 2017
Version 2.0
13 July 2018
Version 3.0
25 October 2018
Version 4.0
18 July 2019
The purpose of this Version is to correct minor inconsistencies within the protocol in addition to the 
following:
Section 3.1, Objectives, and Section 3.3:  Secondary Endpoints:  Changed the term "MRD negativity" to 
"Undetectable MRD (< 10–4)" or "UMRD;" updated text throughout to indicate this change in 
terminology.
Rationale:  To update the terminology used to define minimal residual disease status of < 10–4
Section 4.1:  Overall Study Design and Plan:  Clarified in Figure 1 and in text that venetoclax therapy 
would continue for a total treatment period of up to 53 weeks; clarified that in addition to bone marrow 
aspirate, biopsy is required to confirm CR or CRi; updated Figure 5 to correct inconsistencies; clarified 
that interim analysis will occur after 50 subjects have completed the Week 38 disease assessment; 
Rationale:  Clarifications.
Section 5.5:  Withdrawal of Subjects and Discontinuation of Study and/or Study Treatment:  Clarified 
that subjects may be withdrawn from the study and/or study drug treatment; specified two additional 
reasons for withdrawal from the study and/or study drug treatment, including that subject's response to 
therapy is unsatisfactory, as evidenced by progression of disease while on study drug, or requiring other 
cancer treatment.
Rationale:  Clarifications and to ensure consistency with other AbbVie protocols in this therapeutic area.
Section 5.6:  Follow-Up for Subject Withdrawal from Study and/or Study Treatment:  Clarified that 
subjects who discontinue study participation and/or study treatment should have an early termination 
visit before initiation of another treatment, if applicable; clarified post-treatment follow-up for subjects 
who prematurely discontinue study treatment.
Rationale:  Clarifications.
Section 7.6, Study Interim Analysis:  Clarified that interim analysis will occur after 50 subjects have 
completed the Week 38 disease assessment.
Rationale:  Clarification.
 


p. 53 of 53
STUDY M16-788  |  Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Appendix D, Activity Schedule:  Specified that MRD assessment will use peripheral blood; removed term 
"Treatment Completion Visit" from Week 65 Day 1 visit; clarified that Week 38 and Week 65 bone 
marrow aspirate and biopsy will be collected only if needed to confirm CR or CRi.
Rationale:  Clarifications.