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Clinical Trial Results:
A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab

Summary
EudraCT number	2013-002110-12
Trial protocol	CZ SE BE GB AT IT FR NL HU DK DE ES PL
Global end of trial date

Results information
Results version number	v2
This version publication date	18 Aug 2023
First version publication date	19 May 2018
Other versions	v1 , v3
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GO28667

ISRCTN number

US NCT number

NCT02005471

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

08 May 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 May 2017

Global end of trial reached?

Main objective of the trial

To evaluate the efficacy of venetoclax and rituximab compared with bendamustine and rituximab in participants with relapsed or refractory chronic lymphocytic leukemia (CLL) as measured by investigator-assessed progression-free survival (PFS)

Protection of trial subjects

This study was conducted in full conformance with the International Council on Harmonization (ICH) E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study complied with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). The study complied with U.S. FDA regulations and applicable local, state, and federal laws. In the EU/EEA the study complied with the EU Clinical Trial Directive (2001/20/EC).

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Mar 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

Taiwan: 3

Country: Number of subjects enrolled

Australia: 73

Country: Number of subjects enrolled

New Zealand: 13

Country: Number of subjects enrolled

Czechia: 44

Country: Number of subjects enrolled

Hungary: 26

Country: Number of subjects enrolled

Poland: 46

Country: Number of subjects enrolled

Russian Federation: 14

Country: Number of subjects enrolled

Canada: 25

Country: Number of subjects enrolled

United States: 9

Country: Number of subjects enrolled

Austria: 10

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Denmark: 7

Country: Number of subjects enrolled

Spain: 14

Country: Number of subjects enrolled

France: 29

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

Italy: 20

Country: Number of subjects enrolled

Netherlands: 16

Country: Number of subjects enrolled

Sweden: 3

Worldwide total number of subjects

389

EEA total number of subjects

237

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

186

From 65 to 84 years

201

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 489 participants were screened, out of which, 389 participants were enrolled into the study.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Bendamustine + Rituximab

Arm description

Participants received bendamustine at a dose of 70 milligrams per meter squared (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Arm type

Active comparator

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab was administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Bendamustine was administered at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles.

Venetoclax + Rituximab

Arm description

Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 milligrams (mg) via tablet orally once daily (QD) for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Arm type

Experimental

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab was administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199, ABT-199

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax was administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during 4-5 weeks ramp-up period. Venetoclax was continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first.

Number of subjects in period 1	Bendamustine + Rituximab	Venetoclax + Rituximab
Started	195	194
Treated	188	194
Completed	0	0
Not completed	195	194
Ongoing in Study	144	171
Physician decision	2	1
Consent withdrawn by subject	18	7
Adverse Event	1	-
Death	26	15
Progressive Disease	3	-
Lost to follow-up	1	-

Baseline characteristics

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Reporting group title

Bendamustine + Rituximab

Reporting group description

Reporting group title

Venetoclax + Rituximab

Reporting group description

Reporting group values	Bendamustine + Rituximab	Venetoclax + Rituximab	Total
Number of subjects	195	194	389
Age Categorical
Units: Subjects
Age Continuous
Analysis was performed on intent-to-treat (ITT) population, which included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
Units: years
arithmetic mean (standard deviation)	64.4 ( 9.6 )	63.9 ( 10.5 )	-
Gender Categorical
Units: Subjects
Female	44	58	102
Male	151	136	287

End points

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Reporting group title

Bendamustine + Rituximab

Reporting group description

Reporting group title

Venetoclax + Rituximab

Reporting group description

Subject analysis set title

Bendamustine + Rituximab 17p Del. Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by Fluorescence in-situ Hybridization (FISH) test were included.

Subject analysis set title

Venetoclax + Rituximab 17p Del. Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included.

Primary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines

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End point title

PFS as Assessed by the Investigator Using Standard iwCLL Guidelines

End point description

PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% confidence interval (CI) was computed using method of Brookmeyer and Crowley.

End point type

Primary

End point timeframe

Baseline up to PD or death from any cause, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[1]	194 ^[2]
Units: months
median (confidence interval 95%)	17.0 (15.5 to 21.6)	99999 (99999 to 99999)

Notes
[1] - Analysis was performed on ITT population.
[2] - ‘99999’ signifies that data could not be estimated due to low number of participants with an event.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.11

upper limit

0.25

Notes
[3] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.12

upper limit

0.26

Notes
[4] - Hazard ratio was estimated by Cox regression model.

Primary: Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death

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End point title

Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death ^[5]

End point description

Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (greater than [>] 1.5 centimeters [cm]); unequivocal progression of non-target lesion; an increase of greater than or equal to (>/=) 50 percent (%) compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000 per microliter (mcL), or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 gram per deciliter (g/dL) or to less than [<] 10 g/dL. Analysis was performed on ITT population.

End point type

Primary

End point timeframe

Baseline up to PD or death from any cause, whichever occurred first (up to approximately 3 years)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned to for this endpoint.

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (not applicable)	58.5	16.5

No statistical analyses for this end point

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines

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End point title

PFS as Assessed by the IRC Using Standard iwCLL Guidelines

End point description

PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the IRC using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

End point type

Secondary

End point timeframe

Baseline up to PD or death from any cause, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[6]	194 ^[7]
Units: months
median (confidence interval 95%)	18.1 (15.8 to 22.3)	99999 (99999 to 99999)

Notes
[6] - Analysis was performed on ITT population.
[7] - ‘99999’ signifies that data could not be estimated due to low number of participants with an event.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.14

upper limit

0.3

Notes
[8] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.13

upper limit

0.28

Notes
[9] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

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End point title

Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

End point description

Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline up to PD or death from any cause, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (not applicable)	54.4	18.0

No statistical analyses for this end point

Secondary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

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End point title

PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

End point description

PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

End point type

Secondary

End point timeframe

Baseline up to PD or death from any cause, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab 17p Del. Population	Venetoclax + Rituximab 17p Del. Population
Number of subjects analysed	46 ^[10]	46 ^[11]
Units: months
median (confidence interval 95%)	15.4 (10.0 to 21.0)	99999 (27.6 to 99999)

Notes
[10] - Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
[11] - ‘99999’ signifies that data could not be estimated due to low number of participants with an event.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

0.29

Notes
[12] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factor: geographic region.

Comparison groups

Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

0.31

Notes
[13] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

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End point title

Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

End point description

Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.

End point type

Secondary

End point timeframe

Baseline up to PD or death from any cause, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab 17p Del. Population	Venetoclax + Rituximab 17p Del. Population
Number of subjects analysed	46	46
Units: percentage of participants
number (not applicable)	58.7	15.2

No statistical analyses for this end point

Secondary: Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

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End point title

Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

End point description

End point type

Secondary

End point timeframe

Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab 17p Del. Population	Venetoclax + Rituximab 17p Del. Population
Number of subjects analysed	46	46
Units: percentage of participants
number (not applicable)	47.8	19.6

No statistical analyses for this end point

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

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End point title

PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

End point description

End point type

Secondary

End point timeframe

Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab 17p Del. Population	Venetoclax + Rituximab 17p Del. Population
Number of subjects analysed	46 ^[14]	46 ^[15]
Units: months
median (confidence interval 95%)	16.1 (13.6 to 22.3)	99999 (27.6 to 99999)

Notes
[14] - Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
[15] - ‘99999’ signifies that data could not be estimated due to low number of participants with an event.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.09

upper limit

0.46

Notes
[16] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factor: geographic region.

Comparison groups

Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.09

upper limit

0.49

Notes
[17] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With Best Overall Response of Complete Response (CR), CR with Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Percentage of Participants With Best Overall Response of Complete Response (CR), CR with Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

End point description

Response was assessed by the investigator according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method.

End point type

Secondary

End point timeframe

Baseline up to last follow-up visit (FUV) (maximum up to data cut-off date, overall approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[18]	194 ^[19]
Units: percentage of participants
number (confidence interval 95%)	67.7 (60.64 to 74.20)	93.3 (88.81 to 96.38)

Notes
[18] - Analysis was performed on ITT population.
[19] - Participants without post-baseline response assessment were considered as non-responders.

Statistical Analysis 2

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

Method

Parameter type

Odds ratio (OR)

Point estimate

7.81

Confidence interval

level

95%

sides

2-sided

lower limit

3.97

upper limit

15.37

Notes
[20] - Odds Ratio (OR) was estimated using logistic regression model. The 95% CI was computed using Wald test.

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rates

Point estimate

25.61

Confidence interval

level

95%

sides

2-sided

lower limit

17.88

upper limit

33.33

Notes
[21] - The 95% CI was computed using Anderson-Hauck method.

Secondary: Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

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End point title

Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

End point description

Response was assessed by the IRC according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method.

End point type

Secondary

End point timeframe

Baseline up to last FUV (maximum up to data cut-off date, overall approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[22]	194 ^[23]
Units: percentage of participants
number (confidence interval 95%)	72.3 (65.46 to 78.46)	92.3 (87.57 to 95.61)

Notes
[22] - Analysis was performed on ITT population.
[23] - Participants without post-baseline response assessment were considered as non-responders.

Statistical Analysis 2

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

Method

Parameter type

Odds ratio (OR)

Point estimate

4.79

Confidence interval

level

95%

sides

2-sided

lower limit

2.56

upper limit

8.99

Notes
[24] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rates

Point estimate

19.96

Confidence interval

level

95%

sides

2-sided

lower limit

12.36

upper limit

27.56

Notes
[25] - The 95% CI was computed using Anderson-Hauck method.

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

End point description

End point type

Secondary

End point timeframe

End of combination treatment response (EoCTR) visit (8 to 12 weeks after Cycle [C] 6 Day [1]); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[26]	194 ^[27]
Units: percentage of participants
number (confidence interval 95%)	62.6 (55.37 to 69.37)	88.1 (82.74 to 92.33)

Notes
[26] - Analysis was performed on ITT population.
[27] - Participants without post-baseline response assessment were considered as non-responders.

Statistical Analysis 2

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

Method

Parameter type

Odds ratio (OR)

Point estimate

4.75

Confidence interval

level

95%

sides

2-sided

lower limit

2.76

upper limit

8.16

Notes
[28] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rates

Point estimate

25.58

Confidence interval

level

95%

sides

2-sided

lower limit

17.13

upper limit

34.03

Notes
[29] - The 95% CI was computed using Anderson-Hauck method.

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

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End point title

Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

End point description

End point type

Secondary

End point timeframe

EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[30]	194 ^[31]
Units: percentage of participants
number (confidence interval 95%)	62.6 (55.37 to 69.37)	87.1 (81.57 to 91.48)

Notes
[30] - Analysis was performed on ITT population.
[31] - Participants without post-baseline response assessment were considered as non-responders.

Statistical Analysis 2

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

Method

Parameter type

Odds ratio (OR)

Point estimate

4.59

Confidence interval

level

95%

sides

2-sided

lower limit

2.68

upper limit

7.85

Notes
[32] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rates

Point estimate

24.55

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

33.1

Notes
[33] - The 95% CI was computed using Anderson-Hauck method.

Secondary: Percentage of Participants Who Died

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End point title

Percentage of Participants Who Died

End point description

Percentage of participants who died from any cause, during the study, was reported. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline up to last FUV (maximum up to Data Cut-off date, overall approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (not applicable)	13.8	7.7

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS was defined as the time from the date of randomization to the date of death from any cause. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. The median OS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. Analysis was performed on ITT population. The data ‘99999 (99999 to 99999)’ in the results signifies that median and corresponding 95% CI could not be estimated due to low number of participants with an event.

End point type

Secondary

End point timeframe

Baseline up to last FUV (maximum up to Data Cut-off date, overall approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

= 0.0186

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.48

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

0.9

Notes
[34] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

= 0.019

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.48

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

0.9

Notes
[35] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With PD/Relapse, Start of a new Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Percentage of Participants With PD/Relapse, Start of a new Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

End point description

Percentage of participants with PD/relapse, death from any cause, or start of a new non-protocol-specified anti-CLL therapy as assessed by the investigator, during the study, was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (maximum up to Data Cut-off date, overall approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (not applicable)	60.5	17.0

No statistical analyses for this end point

Secondary: Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

End point description

EFS was defined as the time from date of randomization until the date of PD/relapse, start of a new non-protocol-specified anti-CLL therapy, or death from any cause, whichever occurred first, as assessed by the investigator. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without any of the specified event at the time of analysis were censored at the date of last adequate response assessment. In case of no post-baseline response assessment, participants were censored at the randomization date. The median EFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

End point type

Secondary

End point timeframe

Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (maximum up to Data Cut-off date, overall approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195 ^[36]	194 ^[37]
Units: months
median (confidence interval 95%)	16.4 (14.6 to 21.2)	99999 (99999 to 99999)

Notes
[36] - Analysis was performed on ITT population.
[37] - ‘99999’ signifies that data could not be estimated due to low number of participants with an event.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.12

upper limit

0.26

Notes
[38] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.11

upper limit

0.25

Notes
[39] - Hazard ratio was estimated by Cox regression model.

Secondary: Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

End point description

Percentage of participants with PD as assessed by the investigator according to the iwCLL guidelines, or death from any cause, during the study, was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Analysis was performed on ITT population participants who had best overall response of CR, CRi, nPR, or PR.

End point type

Secondary

End point timeframe

From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	132	181
Units: percentage of participants
number (not applicable)	53.8	11.0

No statistical analyses for this end point

Secondary: Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

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End point title

Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

End point description

Percentage of participants with start of new non-protocol-specified anti-CLL therapy, as assessed by the investigator, or death from any cause, during the study, was reported. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (not applicable)	42.6	11.9

No statistical analyses for this end point

Secondary: Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

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End point title

Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

End point description

TTNT was defined as the time from randomization until start of new non-protocol-specified anti-CLL treatment or death from any cause. Participants without the event at the time of analysis were censored at the last visit date for this outcome measure analysis. The median TTNT was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. Analysis was performed on ITT population. The data ‘99999 (99999 to 99999)’ in the results signifies that median and corresponding 95% CI could not be estimated due to low number of participants with an event.

End point type

Secondary

End point timeframe

Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: months
median (confidence interval 95%)	26.4 (21.9 to 33.1)	99999 (99999 to 99999)

Statistical Analysis 1

Statistical analysis description

Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.12

upper limit

0.31

Notes
[40] - Hazard ratio was estimated by Cox regression model.

Statistical Analysis 2

Statistical analysis description

Unstratified Analysis

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.12

upper limit

0.31

Notes
[41] - Hazard ratio was estimated by Cox regression model.

Secondary: Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

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End point title

Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

End point description

DOR was defined as the time from first occurrence of a documented response of CR, CRi, nPR, or PR until PD/relapse, as assessed by the investigator according to the iwCLL guidelines, or death from any cause. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without PD or death after response were censored at the last date of adequate response assessment. The median DOR was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. Analysis was performed on ITT population participants who had best overall response of CR, CRi, nPR, or PR.

End point type

Secondary

End point timeframe

From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 3 years)

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	132	181 ^[42]
Units: months
median (confidence interval 95%)	19.4 (16.1 to 22.6)	99999 (99999 to 99999)

Notes
[42] - ‘99999’ signifies that data could not be estimated due to low number of participants with an event.

No statistical analyses for this end point

Secondary: Percentage of Participants With Minimal Residual Disease (MRD) Negativity at the EoCTR Visit

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End point title

Percentage of Participants With Minimal Residual Disease (MRD) Negativity at the EoCTR Visit

End point description

MRD-negativity was defined as the presence of <1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed by the allele specific oligonucleotide polymerase chain reaction (ASO-PCR) and/or flow cytometry technique. Percentage of participants with MRD-negativity at the EoCTR visit was reported. The 95% CI was computed using Pearson-Clopper method. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	195	194
Units: percentage of participants
number (confidence interval 95%)	13.3 (8.90 to 18.92)	62.4 (55.15 to 69.21)

Statistical Analysis 2

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[43]

Method

Parameter type

Odds ratio (OR)

Point estimate

10.77

Confidence interval

level

95%

sides

2-sided

lower limit

6.5

upper limit

17.85

Notes
[43] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.

Statistical Analysis 1

Comparison groups

Bendamustine + Rituximab v Venetoclax + Rituximab

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

P-value

< 0.0001

Method

Chi-squared

Parameter type

Difference in MRD Negativity Rates

Point estimate

49.04

Confidence interval

level

95%

sides

2-sided

lower limit

40.44

upper limit

57.64

Notes
[44] - The 95% CI was computed using Anderson-Hauck method.

Secondary: Plasma Venetoclax Concentrations

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End point title

Plasma Venetoclax Concentrations ^[45]

End point description

Analysis was performed on Pharmacokinetic (PK)-Evaluable population, which included all participants in the ‘Venetoclax + Rituximab’ arm and who received at least one dose of venetoclax with at least one post-dose PK concentration result available. Here, 'Number of Subject Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.

End point type

Secondary

End point timeframe

Pre-dose (0 hour, anytime before venetoclax administeration) and 4 hours post-dose on D1 of Cycles 1 and 4; Cycle length = 28 days

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Plasma venetoclax concentrations was only analyzed for VR arm of the study

End point values	Venetoclax + Rituximab
Number of subjects analysed	184
Units: micrograms per milliliter (mcg/mL)
arithmetic mean (standard deviation)
C1D1, Pre-dose (n=151)	0.626 ( 0.540 )
C1D1, 4 hours Post-Dose (n=159)	1.34 ( 0.881 )
C4D1, Pre-dose (n=112)	0.681 ( 0.745 )
C4D1, 4 hours Post-Dose (n=121)	1.34 ( 0.905 )

No statistical analyses for this end point

Secondary: Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

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End point title

Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

End point description

MDASI is a 25-item validated questionnaire consisting of 2 parts. Part 1: 19-items divided into 2 scales, Core Symptom Severity (average of Questions 1 to 13) and Module Symptom Severity (average of Questions 14 to 19). Part 2: 6-items to assess Interference (symptom distress) (average of Questions 20 to 25). Each item was rated from 0 to 10, with lower scores indicating better outcome. Total score for Core Symptom Severity, Module Symptom Severity, and Interference are reported which range from 0 to 10, with lower scores indicating better health-related quality of life (HRQoL). Analysis was performed on patient reported outcome (PRO)-evaluable population, which included all participants with baseline and at least one post-baseline PRO assessment. ‘99999’ = either data were not available because no participant was evaluable or standard deviation (SD) was not available because only 1 participant was evaluable at indicated time point.

End point type

Secondary

End point timeframe

Baseline, Days 1, 8, and 15 of Cycles 1, 2, and 3; Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	117 ^[46]	42 ^[47]
Units: units on a scale
arithmetic mean (standard deviation)
Baseline; Core symptom severity (n=116,42)	1.76 ( 1.55 )	1.55 ( 1.31 )
Change at C1D1; Core symptom severity (n=116,36)	0.0 ( 0.0 )	-0.08 ( 0.98 )
Change at C1D8; Core symptom severity (n=107,36)	0.26 ( 1.34 )	-0.30 ( 0.84 )
Change at C1D15; Core symptom severity (n=104,33)	0.00 ( 1.31 )	-0.27 ( 0.93 )
Change at C2D1; Core symptom severity (n=101,35)	-0.23 ( 1.30 )	-0.33 ( 0.91 )
Change at C2D8; Core symptom severity (n=91,36)	0.17 ( 1.59 )	-0.45 ( 0.91 )
Change at C2D15; Core symptom severity (n=90,37)	-0.13 ( 1.53 )	-0.53 ( 0.90 )
Change at C3D1; Core symptom severity (n=89,36)	-0.26 ( 1.60 )	-0.40 ( 1.13 )
Change at C3D8; Core symptom severity (n=72,30)	-0.13 ( 1.63 )	-0.66 ( 1.20 )
Change at C3D15; Core symptom severity (n=73,32)	-0.42 ( 1.52 )	-0.53 ( 1.05 )
Baseline; Module symptom severity (n=116,42)	1.60 ( 1.46 )	1.57 ( 1.11 )
Change at C1D1; Module symptom severity (n=116,36)	0.00 ( 0.00 )	-0.19 ( 0.96 )
Change at C1D8;Module symptom severity(n=107,36)	-0.22 ( 1.40 )	-0.53 ( 0.96 )
Change atC1D15;Module symptom severity(n=104,33)	-0.43 ( 1.51 )	-0.73 ( 1.13 )
Change at C2D1; Module symptom severity (n=101,34)	-0.49 ( 1.46 )	-0.65 ( 0.92 )
Change at C2D8; Module symptom severity (n=91,35)	-0.46 ( 1.63 )	-0.77 ( 0.87 )
Change at C2D15; Module symptom severity (n=90,36)	-0.69 ( 1.47 )	-0.94 ( 0.93 )
Change at C3D1; Module symptom severity (n=86,35)	-0.65 ( 1.48 )	-0.81 ( 0.97 )
Change at C3D8; Module symptom severity (n=72,30)	-0.51 ( 1.58 )	-0.83 ( 0.97 )
Change at C3D15; Module symptom severity (n=73,32)	-0.83 ( 1.51 )	-0.92 ( 0.97 )
Baseline; Interference (n=116,41)	1.81 ( 2.05 )	1.90 ( 2.25 )
Change at C1D1; Interference (n=116,35)	0.00 ( 0.00 )	-0.13 ( 1.49 )
Change at C1D8; Interference (n=107,33)	0.45 ( 1.78 )	-0.29 ( 2.14 )
Change at C1D15; Interference (n=104,32)	0.36 ( 1.85 )	0.01 ( 2.04 )
Change at C2D1; Interference (n=101,33)	0.01 ( 1.73 )	-0.34 ( 1.78 )
Change at C2D8; Interference (n=91,34)	0.58 ( 2.20 )	-0.58 ( 1.81 )
Change at C2D15; Interference (n=89,35)	0.06 ( 1.84 )	-0.64 ( 1.59 )
Change at C3D1; Interference (n=86,34)	-0.02 ( 2.02 )	-0.73 ( 2.06 )
Change at C3D8; Interference (n=72,29)	0.15 ( 1.91 )	-0.82 ( 2.09 )
Change at C3D15; Interference (n=72,30)	-0.07 ( 2.01 )	-0.55 ( 2.18 )

Notes
[46] - 'Number of Subject Analysed' = participants evaluable for this outcome measure
[47] - 'n' = participants evaluable at specified time point, for each arm respectively

No statistical analyses for this end point

Secondary: Change From Baseline in Lymphocyte Subset Counts at Specified Time Points

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End point title

Change From Baseline in Lymphocyte Subset Counts at Specified Time Points

End point description

End point type

Secondary

End point timeframe

Baseline, C4D14-28, Study Treatment Completion/Early Withdrawal (STC/EW, up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and at FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	0 ^[48]	0 ^[49]
Units: lymphocyte counts

Notes
[48] - Anticipated Posting Date: Sep 2019
[49] - Anticipated Posting Date: Sep 2019

No statistical analyses for this end point

Secondary: Change from Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

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End point title

Change from Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

End point description

EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into five functional scales (Physical, Role, Cognitive, Emotional, and Social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), a global health status/global QoL scale, and single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea). Most questions used 4-point scale (1='Not at all' to 4='Very much'), while 2 questions used 7-point scale (1='very poor' to 7='Excellent'). Functional scales score and global health status/global QoL scale score are reported. Scores were averaged, transformed to 0-100 scale; where higher score for functional scales=poor level of functioning; higher score for global health status/global QoL=better HRQoL. Analysis was performed on PRO-evaluable population. ‘99999’=either data were not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time point.

End point type

Secondary

End point timeframe

Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	177 ^[50]	69 ^[51]
Units: units on a scale
arithmetic mean (standard deviation)
Baseline; Physical functioning (n=177,69)	82.59 ( 17.46 )	83.77 ( 15.27 )
Change at C1D1; Physical functioning (n=177,67)	0.0 ( 0.0 )	1.39 ( 12.90 )
Change at C2D1; Physical functioning (n=172,67)	0.31 ( 15.81 )	2.99 ( 12.83 )
Change at C3D1; Physical functioning (n=160,64)	0.22 ( 16.43 )	1.46 ( 14.76 )
Change at C4D1; Physical functioning (n=154,65)	2.11 ( 14.95 )	5.54 ( 14.17 )
Change at C5D1; Physical functioning (n=149,65)	2.44 ( 18.19 )	4.62 ( 15.27 )
Change at C6D1; Physical functioning (n=143,65)	2.25 ( 16.82 )	4.51 ( 16.59 )
Change at STC/EW; Physical functioning (n=162,64)	1.68 ( 18.76 )	4.53 ( 16.04 )
Change at EoCTR; Physical functioning (n=142,63)	2.92 ( 18.03 )	4.34 ( 16.12 )
Change at FUV1; Physical functioning (n=124,63)	2.27 ( 18.86 )	3.81 ( 16.27 )
Change at FUV2; Physical functioning (n=114,63)	2.40 ( 19.21 )	2.75 ( 17.17 )
Change at FUV3; Physical functioning (n=95,62)	2.54 ( 17.83 )	3.44 ( 17.31 )
Change at FUV4; Physical functioning (n=77,47)	4.74 ( 20.14 )	0.85 ( 21.06 )
Change at FUV5; Physical functioning (n=57,19)	1.90 ( 17.68 )	-1.75 ( 19.35 )
Change at FUV6; Physical functioning (n=33,5)	-1.41 ( 15.34 )	1.33 ( 5.58 )
Change at FUV7; Physical functioning (n=13,1)	-3.08 ( 11.74 )	0.00 ( 99999 )
Change at FUV8; Physical functioning (n=5,1)	-9.33 ( 23.38 )	0.00 ( 99999 )
Change at FUV9; Physical functioning (n=2,0)	-10.00 ( 33.0 )	99999 ( 99999 )
Baseline; Role functioning (n=177,69)	78.25 ( 25.67 )	83.82 ( 21.00 )
Change at C1D1; Role functioning (n=177,67)	0.0 ( 0.0 )	-1.74 ( 23.23 )
Change at C2D1; Role functioning (n=172,67)	-1.26 ( 27.45 )	2.49 ( 23.07 )
Change at C3D1; Role functioning (n=160,64)	-0.10 ( 29.64 )	1.82 ( 26.08 )
Change at C4D1; Role functioning (n=154,65)	0.87 ( 29.01 )	5.13 ( 22.03 )
Change at C5D1; Role functioning (n=149,65)	0.45 ( 30.75 )	4.36 ( 23.44 )
Change at C6D1; Role functioning (n=143,65)	0.70 ( 29.92 )	1.79 ( 25.71 )
Change at STC/EW; Role functioning (n=162,64)	-0.41 ( 32.91 )	2.60 ( 25.58 )
Change at EoCTR; Role functioning (n=143,63)	3.26 ( 29.95 )	2.12 ( 26.69 )
Change at FUV1; Role functioning (n=125,63)	2.93 ( 32.31 )	2.65 ( 27.47 )
Change at FUV2; Role functioning (n=114,63)	3.07 ( 32.63 )	-1.85 ( 31.84 )
Change at FUV3; Role functioning (n=95,62)	5.26 ( 31.16 )	1.88 ( 28.17 )
Change at FUV4; Role functioning (n=77,47)	5.41 ( 33.16 )	-0.35 ( 30.39 )
Change at FUV5; Role functioning (n=57,19)	2.34 ( 29.79 )	1.75 ( 34.20 )
Change at FUV6; Role functioning (n=33,5)	-4.04 ( 27.01 )	-13.33 ( 32.06 )
Change at FUV7; Role functioning (n=13,1)	2.56 ( 29.54 )	-16.67 ( 99999 )
Change at FUV8; Role functioning (n=5,1)	0.00 ( 23.57 )	16.67 ( 99999 )
Change at FUV9; Role functioning (n=2,0)	-16.67 ( 23.57 )	99999 ( 99999 )
Baseline; Emotional functioning (n=176,69)	78.98 ( 22.47 )	82.13 ( 15.80 )
Change at C1D1; Emotional functioning (n=176,67)	0.0 ( 0.0 )	4.35 ( 15.17 )
Change at C2D1; Emotional functioning (n=171,67)	2.24 ( 20.07 )	5.60 ( 14.68 )
Change at C3D1; Emotional functioning (n=158,64)	2.99 ( 20.06 )	5.34 ( 19.09 )
Change at C4D1; Emotional functioning (n=151,65)	2.61 ( 18.35 )	4.19 ( 15.45 )
Change at C5D1; Emotional functioning (n=146,65)	1.14 ( 18.79 )	3.97 ( 17.37 )
Change at C6D1; Emotional functioning (n=143,65)	2.06 ( 18.74 )	3.08 ( 17.96 )
Change at STC/EW; Emotional functioning (n=160,64)	2.43 ( 20.61 )	5.34 ( 18.69 )
Change at EoCTR; Emotional functioning (n=142,62)	2.58 ( 19.45 )	3.49 ( 17.83 )
Change at FUV1; Emotional functioning (n=124,63)	3.49 ( 20.91 )	4.37 ( 18.50 )
Change at FUV2; Emotional functioning (n=114,63)	4.39 ( 20.33 )	0.66 ( 21.02 )
Change at FUV3; Emotional functioning (n=92,62)	0.63 ( 19.97 )	2.82 ( 17.66 )
Change at FUV4; Emotional functioning (n=76,47)	4.82 ( 19.73 )	1.95 ( 18.41 )
Change at FUV5; Emotional functioning (n=56,19)	3.13 ( 17.95 )	2.63 ( 20.61 )
Change at FUV6; Emotional functioning (n=33,5)	2.27 ( 21.78 )	5.00 ( 17.28 )
Change at FUV7; Emotional functioning (n=13,1)	5.77 ( 17.48 )	-8.33 ( 99999 )
Change at FUV8; Emotional functioning (n=5,1)	3.33 ( 28.01 )	0.00 ( 99999 )
Change at FUV9; Emotional functioning (n=2,0)	-16.67 ( 11.79 )	99999 ( 99999 )
Baseline; Cognitive functioning (n=176,69)	86.55 ( 16.78 )	89.86 ( 14.91 )
Change at C1D1; Cognitive functioning (n=176,67)	0.0 ( 0.0 )	-1.24 ( 14.01 )
Change at C2D1; Cognitive functioning (n=171,67)	-0.19 ( 15.34 )	0.25 ( 14.06 )
Change at C3D1; Cognitive functioning (n=158,64)	-0.32 ( 16.34 )	-1.56 ( 17.50 )
Change at C4D1; Cognitive functioning (n=152,65)	-1.54 ( 17.41 )	-0.26 ( 17.05 )
Change at C5D1; Cognitive functioning (n=146,65)	-1.94 ( 18.10 )	-0.26 ( 14.28 )
Change at C6D1; Cognitive functioning (n=143,65)	-2.68 ( 16.97 )	-0.77 ( 15.98 )
Change at STC/EW; Cognitive functioning (n=160,64)	-2.19 ( 17.65 )	1.04 ( 18.28 )
Change at EoCTR; Cognitive functioning (n=142,62)	-2.23 ( 18.11 )	-0.27 ( 16.94 )
Change at FUV1; Cognitive functioning (n=124,63)	-2.02 ( 17.21 )	-0.26 ( 15.98 )
Change at FUV2; Cognitive functioning (n=114,63)	1.32 ( 16.16 )	-2.38 ( 18.17 )
Change at FUV3; Cognitive functioning (n=92,62)	-1.63 ( 14.84 )	-2.96 ( 18.24 )
Change at FUV4; Cognitive functioning (n=76,47)	0.44 ( 17.63 )	-1.77 ( 19.11 )
Change at FUV5; Cognitive functioning (n=56,19)	-1.49 ( 15.66 )	-6.14 ( 21.67 )
Change at FUV6; Cognitive functioning (n=33,5)	-0.51 ( 14.72 )	0.00 ( 0.00 )
Change at FUV7; Cognitive functioning (n=13,1)	-1.28 ( 14.37 )	0.00 ( 99999 )
Change at FUV8; Cognitive functioning (n=5,1)	0.00 ( 23.57 )	0.00 ( 99999 )
Change at FUV9; Cognitive functioning (n=2,0)	16.67 ( 23.57 )	99999 ( 99999 )
Baseline; Social functioning (n=176,69)	82.48 ( 22.06 )	85.51 ( 21.18 )
Change at C1D1; Social functioning (n=176,67)	0.0 ( 0.0 )	-1.74 ( 19.92 )
Change at C2D1; Social functioning (n=171,67)	-2.44 ( 21.44 )	0.25 ( 18.46 )
Change at C3D1; Social functioning (n=158,64)	-2.32 ( 22.61 )	3.65 ( 25.45 )
Change at C4D1; Social functioning (n=151,65)	-0.55 ( 22.15 )	4.62 ( 20.09 )
Change at C5D1; Social functioning (n=146,65)	-5.48 ( 26.49 )	2.56 ( 20.46 )
Change at C6D1; Social functioning (n=143,65)	-5.13 ( 24.80 )	3.85 ( 24.61 )
Change at STC/EW; Social functioning (n=160,64)	-4.06 ( 27.71 )	1.04 ( 19.22 )
Change at EoCTR; Social functioning (n=142,62)	-0.47 ( 24.95 )	1.88 ( 20.49 )
Change at FUV1; Social functioning (n=124,63)	-1.08 ( 26.09 )	1.59 ( 24.27 )
Change at FUV2; Social functioning (n=114,63)	0.58 ( 24.68 )	1.32 ( 27.97 )
Change at FUV3; Social functioning (n=92,62)	-0.91 ( 24.00 )	1.88 ( 25.98 )
Change at FUV4; Social functioning (n=76,47)	1.97 ( 27.35 )	1.06 ( 32.12 )
Change at FUV5; Social functioning (n=56,19)	1.79 ( 26.72 )	0.00 ( 33.79 )
Change at FUV6; Social functioning (n=33,5)	1.52 ( 29.27 )	10.00 ( 14.91 )
Change at FUV7; Social functioning (n=13,1)	-2.56 ( 23.42 )	33.33 ( 99999 )
Change at FUV8; Social functioning (n=5,1)	-10.00 ( 22.36 )	33.33 ( 99999 )
Change at FUV9; Social functioning (n=2,0)	-25.00 ( 35.36 )	99999 ( 99999 )
Baseline; Global health status/QoL (n=176,69)	63.02 ( 21.45 )	67.39 ( 22.17 )
Change at C1D1;Global health status/QoL(n=176,67)	0.0 ( 0.0 )	6.34 ( 18.41 )
Change at C2D1;Global health status/QoL (n=171,67)	2.73 ( 21.69 )	5.35 ( 20.14 )
Change at C3D1;Global health status/QoL (n=157,64)	2.34 ( 24.66 )	2.21 ( 23.58 )
Change at C4D1;Global health status/QoL (n=152,65)	3.84 ( 22.26 )	7.05 ( 21.05 )
Change at C5D1;Global health status/QoL (n=146,65)	7.36 ( 24.20 )	7.18 ( 21.94 )
Change at C6D1;Global health status/QoL (n=143,65)	4.25 ( 25.00 )	5.90 ( 25.16 )
Change at STC/EW;Global health status/QoL;n=160,64	4.32 ( 26.20 )	6.51 ( 23.22 )
Change at EoCTR;Global health status/QoL(n=142,62)	6.10 ( 23.65 )	7.66 ( 24.11 )
Change at FUV1;Global health status/QoL (n=124,63)	5.91 ( 24.57 )	7.01 ( 25.01 )
Change at FUV2;Global health status/QoL (n=114,63)	6.94 ( 24.81 )	4.50 ( 26.51 )
Change at FUV3; Global health status/QoL (n=92,62)	4.80 ( 25.30 )	6.32 ( 27.36 )
Change at FUV4; Global health status/QoL (n=76,47)	7.35 ( 26.77 )	6.38 ( 27.60 )
Change at FUV5; Global health status/QoL (n=56,19)	4.46 ( 23.89 )	4.39 ( 18.08 )
Change at FUV6; Global health status/QoL (n=33,5)	1.01 ( 24.00 )	5.00 ( 7.45 )
Change at FUV7; Global health status/QoL (n=13,1)	8.33 ( 25.69 )	16.67 ( 99999 )
Change at FUV8; Global health status/QoL (n=5,1)	6.67 ( 16.03 )	8.33 ( 99999 )
Change at FUV9; Global health status/QoL (n=2,0)	0.00 ( 0.00 )	99999 ( 99999 )

Notes
[50] - 'Number of Subject Analysed' = participants evaluable for this outcome measure
[51] - 'n' = participants evaluable at specified time point, for each arm respectively

No statistical analyses for this end point

Secondary: Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

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End point title

Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

End point description

The EORTC QLQ-CLL16 module is designed for participants with Stage 0 to Stage 4 CLL. It is composed of 16 questions and there are four multi-item scales on Fatigue (2 items), Treatment-related side effects (TRSE, 4 items), Disease-related symptoms (DRS, 4 items), and Infection (4 items); and two single-item scales on social activities and future health worries. Multi-item scales score are reported and the total score for each multi-item scale was transformed to result in a total score range of 0 to 100, where higher score = poor HRQoL. Analysis was performed on PRO-evaluable population. 'Number of Subject Analysed' = participants evaluable for this outcome measure; 'n' = participants evaluable at specified time point; ‘99999’ = either mean was not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time points.

End point type

Secondary

End point timeframe

Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	175	69
Units: units on a scale
arithmetic mean (standard deviation)
Baseline; TRSE (n=175,69)	14.29 ( 13.95 )	9.42 ( 8.80 )
Change at C1D1; TRSE (n=175,67)	0.0 ( 0.0 )	0.12 ( 10.10 )
Change at C2D1; TRSE (n=170,67)	1.62 ( 13.82 )	0.62 ( 12.76 )
Change at C3D1; TRSE (n=159,63)	-0.26 ( 13.76 )	1.98 ( 14.72 )
Change at C4D1; TRSE (n=152,64)	-0.49 ( 13.97 )	0.52 ( 11.87 )
Change at C5D1; TRSE (n=147,65)	-0.51 ( 14.57 )	0.64 ( 10.02 )
Change at C6D1; TRSE (n=144,65)	0.46 ( 15.51 )	-0.13 ( 10.04 )
Change at STC/EW; TRSE (n=161,64)	0.81 ( 18.11 )	0.13 ( 10.76 )
Change at EoCTR; TRSE (n=142,63)	-0.88 ( 16.06 )	0.26 ( 12.61 )
Change at FUV1; TRSE (n=123,63)	-1.20 ( 14.87 )	1.19 ( 12.24 )
Change at FUV2; TRSE (n=113,63)	-1.70 ( 15.28 )	2.65 ( 14.03 )
Change at FUV3; TRSE (n=95,62)	-2.08 ( 12.64 )	-0.13 ( 13.70 )
Change at FUV4; TRSE (n=76,47)	-1.97 ( 12.76 )	2.84 ( 15.18 )
Change at FUV5; TRSE (n=56,19)	-2.68 ( 11.02 )	1.32 ( 10.49 )
Change at FUV6; TRSE (n=33,5)	-1.01 ( 12.10 )	-1.67 ( 3.73 )
Change at FUV7; TRSE (n=13,1)	2.56 ( 22.67 )	-8.33 ( 99999 )
Change at FUV8; TRSE (n=5,1)	1.67 ( 13.69 )	0.00 ( 99999 )
Change at FUV9; TRSE (n=2,0)	8.33 ( 11.79 )	99999 ( 99999 )
Baseline; DRS (n=175,69)	19.57 ( 16.81 )	16.95 ( 17.37 )
Change at C1D1; DRS (n=175,67)	0.0 ( 0.0 )	-2.74 ( 16.18 )
Change at C2D1; DRS (n=170,67)	-3.33 ( 16.05 )	-4.77 ( 16.84 )
Change at C3D1; DRS (n=159,63)	-4.77 ( 16.49 )	-3.35 ( 17.48 )
Change at C4D1; DRS (n=152,64)	-6.03 ( 16.51 )	-5.12 ( 17.72 )
Change at C5D1; DRS (n=147,65)	-5.90 ( 16.73 )	-4.79 ( 17.50 )
Change at C6D1; DRS (n=144,65)	-6.40 ( 17.26 )	-5.30 ( 16.72 )
Change at STC/EW; DRS (n=161,64)	-5.80 ( 18.52 )	-6.51 ( 18.45 )
Change at EoCTR; DRS (n=142,63)	-6.57 ( 17.21 )	-5.86 ( 20.38 )
Change at FUV1; DRS (n=123,63)	-6.55 ( 15.73 )	-5.82 ( 19.20 )
Change at FUV2; DRS (n=113,63)	-8.63 ( 14.39 )	-3.57 ( 18.31 )
Change at FUV3; DRS (n=95,62)	-7.37 ( 14.88 )	-3.76 ( 19.25 )
Change at FUV4; DRS (n=76,47)	-8.55 ( 18.56 )	-2.66 ( 20.49 )
Change at FUV5; DRS (n=56,19)	-8.33 ( 16.13 )	-2.19 ( 19.41 )
Change at FUV6; DRS (n=33,5)	-6.31 ( 16.01 )	-3.33 ( 13.94 )
Change at FUV7; DRS (n=13,1)	-15.38 ( 20.08 )	-8.33 ( 99999 )
Change at FUV8; DRS (n=5,1)	-10.00 ( 16.03 )	-8.33 ( 99999 )
Change at FUV9; DRS (n=2,0)	-4.17 ( 5.89 )	99999 ( 99999 )
Baseline; Fatigue (n=175,69)	28.76 ( 24.66 )	21.74 ( 20.67 )
Change at C1D1; Fatigue (n=175,67)	0.0 ( 0.0 )	-2.24 ( 20.29 )
Change at C2D1; Fatigue (n=170,67)	-2.55 ( 22.86 )	-5.47 ( 21.40 )
Change at C3D1; Fatigue (n=159,63)	-2.83 ( 25.17 )	-3.17 ( 23.73 )
Change at C4D1; Fatigue (n=152,64)	-3.18 ( 23.23 )	-4.17 ( 22.02 )
Change at C5D1; Fatigue (n=147,65)	-2.38 ( 27.52 )	-4.36 ( 20.89 )
Change at C6D1; Fatigue (n=144,65)	-2.66 ( 26.35 )	-2.31 ( 21.42 )
Change at STC/EW; Fatigue (n=161,64)	-3.11 ( 28.64 )	-4.69 ( 21.30 )
Change at EoCTR; Fatigue (n=142,63)	-6.69 ( 26.78 )	-3.97 ( 24.27 )
Change at FUV1; Fatigue (n=123,63)	-6.37 ( 26.61 )	-4.23 ( 22.99 )
Change at FUV2; Fatigue (n=113,63)	-6.64 ( 24.55 )	-1.85 ( 24.70 )
Change at FUV3; Fatigue (n=95,62)	-5.79 ( 23.29 )	-2.42 ( 23.73 )
Change at FUV4; Fatigue (n=76,47)	-9.65 ( 26.84 )	-0.35 ( 25.18 )
Change at FUV5; Fatigue (n=56,19)	-6.55 ( 25.56 )	3.51 ( 23.95 )
Change at FUV6; Fatigue (n=33,5)	-5.05 ( 24.82 )	3.33 ( 24.72 )
Change at FUV7; Fatigue (n=13,1)	-10.26 ( 30.08 )	-33.33 ( 99999 )
Change at FUV8; Fatigue (n=5,1)	-6.67 ( 19.00 )	0.00 ( 99999 )
Change at FUV9; Fatigue (n=2,0)	-8.33 ( 11.79 )	99999 ( 99999 )
Baseline; Infection (n=175,69)	15.92 ( 17.63 )	14.01 ( 18.99 )
Change at C1D1; Infection (n=175,67)	0.0 ( 0.0 )	-2.24 ( 20.03 )
Change at C2D1; Infection (n=170,67)	-0.02 ( 19.98 )	-3.61 ( 21.72 )
Change at C3D1; Infection (n=159,63)	-1.66 ( 19.21 )	-1.32 ( 20.48 )
Change at C4D1; Infection (n=152,64)	-1.44 ( 22.07 )	-3.13 ( 21.28 )
Change at C5D1; Infection (n=147,65)	-1.91 ( 24.00 )	-2.56 ( 23.47 )
Change at C6D1; Infection (n=143,65)	-1.09 ( 20.66 )	-2.95 ( 20.54 )
Change at STC/EW; Infection (n=161,64)	-0.12 ( 23.28 )	-1.69 ( 23.34 )
Change at EoCTR; Infection (n=142,63)	-0.55 ( 21.73 )	-3.44 ( 25.78 )
Change at FUV1; Infection (n=121,63)	1.08 ( 18.77 )	-2.65 ( 26.51 )
Change at FUV2; Infection (n=113,63)	0.05 ( 23.29 )	-0.53 ( 25.74 )
Change at FUV3; Infection (n=95,62)	-1.90 ( 16.97 )	-0.54 ( 26.48 )
Change at FUV4; Infection (n=76,47)	-4.24 ( 16.71 )	0.53 ( 25.56 )
Change at FUV5; Infection (n=56,19)	-4.51 ( 22.66 )	7.46 ( 27.20 )
Change at FUV6; Infection (n=33,5)	-1.60 ( 18.90 )	8.33 ( 15.59 )
Change at FUV7; Infection (n=13,1)	-0.43 ( 21.84 )	-16.67 ( 99999 )
Change at FUV8; Infection (n=5,1)	8.89 ( 23.36 )	-25.00 ( 99999 )
Change at FUV9; Infection (n=2,0)	-2.78 ( 3.93 )	99999 ( 99999 )

No statistical analyses for this end point

Post-hoc: Euro QoL 5 Dimension (EQ-5D) Questionnaire Score

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End point title

Euro QoL 5 Dimension (EQ-5D) Questionnaire Score

End point description

End point type

Post-hoc

End point timeframe

Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

End point values	Bendamustine + Rituximab	Venetoclax + Rituximab
Number of subjects analysed	0 ^[52]	0 ^[53]
Units: units on a scale
arithmetic mean (standard deviation)	( )	( )

Notes
[52] - Anticipated Posting Date: Sep 2019
[53] - Anticipated Posting Date: Sep 2019

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to Follow-up (maximum up to Data Cut-off date, overall approximately 3 years)

Adverse event reporting additional description

Analysis was performed on safety evaluable (SE) population, which included all randomized participants who received at least one dose of study treatment (venetoclax, rituximab, or bendamustine), with participants grouped according to the actual treatment received.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Venetoclax + Rituximab

Reporting group description

Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally once daily (QD) for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Reporting group title

Bendamustine + Rituximab

Reporting group description

Participants received bendamustine at a dose of 70 milligrams per meter square (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

Serious adverse events	Venetoclax + Rituximab	Bendamustine + Rituximab
Total subjects affected by serious adverse events
subjects affected / exposed	90 / 194 (46.39%)	81 / 188 (43.09%)
number of deaths (all causes)	15	27
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphoma
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Acute myeloid leukaemia
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Adenocarcinoma gastric
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal cancer
subjects affected / exposed	2 / 194 (1.03%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 194 (0.00%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Malignant melanoma
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastatic malignant melanoma
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	2 / 194 (1.03%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatic adenoma
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin cancer
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	3 / 194 (1.55%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	2 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Medullary thyroid cancer
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 194 (0.52%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 194 (0.00%)	5 / 188 (2.66%)
occurrences causally related to treatment / all	0 / 0	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Unevaluable event
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Sudden cardiac death
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pyrexia
subjects affected / exposed	5 / 194 (2.58%)	13 / 188 (6.91%)
occurrences causally related to treatment / all	2 / 5	11 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperpyrexia
subjects affected / exposed	1 / 194 (0.52%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bronchiectasis
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 194 (0.52%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Investigations
Body temperature increased
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Humerus fracture
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	1 / 194 (0.52%)	6 / 188 (3.19%)
occurrences causally related to treatment / all	1 / 1	8 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Ventricular tachycardia
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	2 / 194 (1.03%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Lacunar infarction
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Syncope
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 194 (1.55%)	5 / 188 (2.66%)
occurrences causally related to treatment / all	3 / 4	4 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	3 / 194 (1.55%)	3 / 188 (1.60%)
occurrences causally related to treatment / all	4 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	2 / 194 (1.03%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	1 / 2	1 / 2
deaths causally related to treatment / all	1 / 1	0 / 0
Autoimmune haemolytic anaemia
subjects affected / exposed	3 / 194 (1.55%)	3 / 188 (1.60%)
occurrences causally related to treatment / all	3 / 3	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	7 / 194 (3.61%)	16 / 188 (8.51%)
occurrences causally related to treatment / all	7 / 7	14 / 16
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Deafness
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Eye haemorrhage
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Crohn's disease
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 194 (0.52%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal obstruction
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 194 (1.03%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal impairment
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	1 / 194 (0.52%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 194 (0.00%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	2 / 194 (1.03%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess neck
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Campylobacter gastroenteritis
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemophilus infection
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes simplex otitis externa
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	3 / 194 (1.55%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	2 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Listeria sepsis
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Localised infection
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rhinovirus infection
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Moraxella infection
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal tuberculosis
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 194 (0.00%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumococcal bacteraemia
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	16 / 194 (8.25%)	15 / 188 (7.98%)
occurrences causally related to treatment / all	6 / 20	5 / 17
deaths causally related to treatment / all	0 / 3	0 / 0
Pneumonia influenzal
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia legionella
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia streptococcal
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	2 / 194 (1.03%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection fungal
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	3 / 194 (1.55%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Scedosporium infection
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Septic shock
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	2 / 194 (1.03%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	3 / 194 (1.55%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	2 / 3	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 194 (0.52%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection pseudomonal
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella zoster virus infection
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 194 (0.52%)	4 / 188 (2.13%)
occurrences causally related to treatment / all	1 / 1	2 / 4
deaths causally related to treatment / all	1 / 1	1 / 2
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 194 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	1 / 194 (0.52%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	2 / 194 (1.03%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperphosphataemia
subjects affected / exposed	2 / 194 (1.03%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	4 / 194 (2.06%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	4 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 194 (1.03%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Venetoclax + Rituximab	Bendamustine + Rituximab
Total subjects affected by non serious adverse events
subjects affected / exposed	190 / 194 (97.94%)	176 / 188 (93.62%)
Vascular disorders
Hypertension
subjects affected / exposed	12 / 194 (6.19%)	7 / 188 (3.72%)
occurrences all number	13	7
General disorders and administration site conditions
Chills
subjects affected / exposed	8 / 194 (4.12%)	16 / 188 (8.51%)
occurrences all number	10	20
Fatigue
subjects affected / exposed	34 / 194 (17.53%)	39 / 188 (20.74%)
occurrences all number	40	44
Oedema peripheral
subjects affected / exposed	11 / 194 (5.67%)	7 / 188 (3.72%)
occurrences all number	15	11
Pyrexia
subjects affected / exposed	27 / 194 (13.92%)	33 / 188 (17.55%)
occurrences all number	39	44
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	35 / 194 (18.04%)	31 / 188 (16.49%)
occurrences all number	49	37
Oropharyngeal pain
subjects affected / exposed	10 / 194 (5.15%)	7 / 188 (3.72%)
occurrences all number	12	7
Productive cough
subjects affected / exposed	12 / 194 (6.19%)	4 / 188 (2.13%)
occurrences all number	14	5
Dyspnoea
subjects affected / exposed	11 / 194 (5.67%)	14 / 188 (7.45%)
occurrences all number	14	17
Psychiatric disorders
Insomnia
subjects affected / exposed	21 / 194 (10.82%)	12 / 188 (6.38%)
occurrences all number	22	13
Investigations
Alanine aminotransferase increased
subjects affected / exposed	9 / 194 (4.64%)	10 / 188 (5.32%)
occurrences all number	15	11
Neutrophil count decreased
subjects affected / exposed	11 / 194 (5.67%)	13 / 188 (6.91%)
occurrences all number	26	27
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	15 / 194 (7.73%)	40 / 188 (21.28%)
occurrences all number	19	54
Nervous system disorders
Dizziness
subjects affected / exposed	12 / 194 (6.19%)	10 / 188 (5.32%)
occurrences all number	14	13
Headache
subjects affected / exposed	21 / 194 (10.82%)	19 / 188 (10.11%)
occurrences all number	21	21
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	28 / 194 (14.43%)	40 / 188 (21.28%)
occurrences all number	48	68
Thrombocytopenia
subjects affected / exposed	24 / 194 (12.37%)	42 / 188 (22.34%)
occurrences all number	31	56
Neutropenia
subjects affected / exposed	118 / 194 (60.82%)	82 / 188 (43.62%)
occurrences all number	288	181
Gastrointestinal disorders
Nausea
subjects affected / exposed	41 / 194 (21.13%)	64 / 188 (34.04%)
occurrences all number	57	82
Vomiting
subjects affected / exposed	15 / 194 (7.73%)	22 / 188 (11.70%)
occurrences all number	18	29
Diarrhoea
subjects affected / exposed	76 / 194 (39.18%)	31 / 188 (16.49%)
occurrences all number	115	43
Constipation
subjects affected / exposed	27 / 194 (13.92%)	39 / 188 (20.74%)
occurrences all number	30	47
Abdominal pain
subjects affected / exposed	13 / 194 (6.70%)	6 / 188 (3.19%)
occurrences all number	14	7
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	10 / 194 (5.15%)	8 / 188 (4.26%)
occurrences all number	10	8
Rash
subjects affected / exposed	14 / 194 (7.22%)	24 / 188 (12.77%)
occurrences all number	17	30
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	12 / 194 (6.19%)	10 / 188 (5.32%)
occurrences all number	17	13
Muscle spasms
subjects affected / exposed	4 / 194 (2.06%)	11 / 188 (5.85%)
occurrences all number	4	11
Back pain
subjects affected / exposed	15 / 194 (7.73%)	11 / 188 (5.85%)
occurrences all number	15	11
Infections and infestations
Bronchitis
subjects affected / exposed	20 / 194 (10.31%)	13 / 188 (6.91%)
occurrences all number	31	15
Conjunctivitis
subjects affected / exposed	10 / 194 (5.15%)	5 / 188 (2.66%)
occurrences all number	11	5
Lower respiratory tract infection
subjects affected / exposed	11 / 194 (5.67%)	4 / 188 (2.13%)
occurrences all number	15	4
Nasopharyngitis
subjects affected / exposed	22 / 194 (11.34%)	10 / 188 (5.32%)
occurrences all number	27	14
Oral herpes
subjects affected / exposed	8 / 194 (4.12%)	12 / 188 (6.38%)
occurrences all number	11	12
Pharyngitis
subjects affected / exposed	13 / 194 (6.70%)	1 / 188 (0.53%)
occurrences all number	16	1
Pneumonia
subjects affected / exposed	5 / 194 (2.58%)	11 / 188 (5.85%)
occurrences all number	6	13
Sinusitis
subjects affected / exposed	17 / 194 (8.76%)	5 / 188 (2.66%)
occurrences all number	22	5
Urinary tract infection
subjects affected / exposed	11 / 194 (5.67%)	7 / 188 (3.72%)
occurrences all number	21	9
Upper respiratory tract infection
subjects affected / exposed	41 / 194 (21.13%)	28 / 188 (14.89%)
occurrences all number	71	39
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	8 / 194 (4.12%)	17 / 188 (9.04%)
occurrences all number	11	18
Hyperkalaemia
subjects affected / exposed	11 / 194 (5.67%)	0 / 188 (0.00%)
occurrences all number	16	0
Hypokalaemia
subjects affected / exposed	12 / 194 (6.19%)	7 / 188 (3.72%)
occurrences all number	14	7

More information

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Were there any global substantial amendments to the protocol? Yes

26 Nov 2013

An exclusion of participants who had received potent cytochrome (CYP3A4) inhibitors was clarified to make consistent with the rest of the protocol; An exclusion criterion was added for participants with recent major surgery in line with the prescribing information for bendamustine; The pregnancy testing procedure was modified such that testing was required at each cycle of combination therapy and every 3 months thereafter until the end of treatment in order to obtain a more timely diagnosis of pregnancy.

10 Jun 2014

Modifications to the tumor lysis syndrome prophylaxis measures for participants with CLL were implemented following analysis of participants enrolled in different venetoclax trials: All participants randomized to the ‘Venetoclax + Rituximab’ arm were to initiate dosing with 20 mg venetoclax daily for at least 7 days; Outpatient dosing and monitoring for the first venetoclax dose at all dose levels (20 mg, 50 mg, 100 mg, 200 mg, 400 mg) was introduced for low- and medium-risk participants, if there was no indication to hospitalize; Outpatient IV hydration prior to the first venetoclax dose was introduced for medium-risk participants at 20 and 50 mg; Inpatient dosing and monitoring was introduced for high-risk participants prior to the first venetoclax dose only at the 20 mg and 50 mg dose levels; Outpatient dosing and IV hydration prior to the first venetoclax dose was introduced for high-risk participants at dose levels of 100 mg and above, if there was no indication to hospitalize; Reduced frequency of laboratory assessments after dosing; Prophylaxis with rasburicase had to be administered prior to the first dose of venetoclax only for high-risk participants with high uric acid levels and per regional standards/guidelines; Dose Modification for venetoclax + rituximab in case of non-hematologic toxicity was clarified globally.

16 Oct 2014

The recruitment of participants with occult or prior hepatitis B virus (HBV) infection if HBV deoxy-ribonucleic acid (DNA) was undetectable was allowed; In order to collect appropriate MRD information, bone marrow aspiration was added. This was previously only mandated in participants with CR. To synchronize with other venetoclax development studies MRD in peripheral blood was to be monitored for up to 1 year after completion of venetoclax single-agent therapy.

22 Dec 2015

The interim analysis was changed to be information-fraction-based as opposed to time-based (that is, percentage of total PFS) events; A secondary objective of best overall response rate as assessed by the investigator was added; Details regarding multiplicity adjustment and order for testing the key secondary endpoints were added; The secondary outcome measure of MRD response rate was clarified that this assessment was based on the EoCTR visit. MRD response rate at other disease response assessment timepoints were designated as exploratory outcome measures; Additional details were provided on the use of strong, moderate and weak CYP3A4 inhibitors and inducers as well as cautionary medications; Timings for the baseline QoL questionnaires for the ‘Venetoclax + Rituximab’ arm were incorporated; PK outcome measures were further defined to include concentrations of venetoclax.

21 Nov 2016

Allowed for a change in the clinical prioritization of the secondary efficacy endpoints to mirror the evolving relapsed/refractory CLL therapeutic and scientific landscape.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines

Primary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines

Primary: Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death

Primary: Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines

Secondary: Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

Secondary: Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

Secondary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Secondary: Percentage of Participants With Best Overall Response of Complete Response (CR), CR with Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With Best Overall Response of Complete Response (CR), CR with Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

Secondary: Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

Secondary: Percentage of Participants Who Died

Secondary: Percentage of Participants Who Died

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Percentage of Participants With PD/Relapse, Start of a new Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With PD/Relapse, Start of a new Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

Secondary: Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

Secondary: Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

Secondary: Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

Secondary: Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

Secondary: Percentage of Participants With Minimal Residual Disease (MRD) Negativity at the EoCTR Visit

Secondary: Percentage of Participants With Minimal Residual Disease (MRD) Negativity at the EoCTR Visit

Secondary: Plasma Venetoclax Concentrations

Secondary: Plasma Venetoclax Concentrations

Secondary: Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

Secondary: Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

Secondary: Change From Baseline in Lymphocyte Subset Counts at Specified Time Points

Secondary: Change From Baseline in Lymphocyte Subset Counts at Specified Time Points

Secondary: Change from Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

Secondary: Change from Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

Secondary: Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

Secondary: Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

Post-hoc: Euro QoL 5 Dimension (EQ-5D) Questionnaire Score

Post-hoc: Euro QoL 5 Dimension (EQ-5D) Questionnaire Score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab