A Study in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Subjects, Excluding Those With the 17p Deletion, to Evaluate Debulking Regimens Prior to Initiating Venetoclax Combination Therapy

• ClinicalTrials.gov Identifier: NCT03406156
• Recruitment Status: Active, not recruiting
• First Posted: January 23, 2018
• Results First Posted: November 3, 2022
• Last Update Posted: November 3, 2022
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL)
• Interventions: Drug: Obinutuzumab; Drug: Bendamustine; Drug: Venetoclax
• Enrollment: 120

Participant Flow

Recruitment Details
Pre-assignment Details	All Treated Participants: all enrolled participants who received at least one dose of any study drug

Arm/Group Title	Obinutuzumab	Obinutuzumab/Bendamustine
Arm/Group Description	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.
Period Title: Overall Study
Started	84	36
Completed	77	30
Not Completed	7	6
Reason Not Completed
Death	6	2
Withdrawal by Subject	0	2
COVID-19 infection	1	0
Non-compliance with study procedures	0	1
Other, not specified	0	1

Baseline Characteristics

Arm/Group Title		Obinutuzumab	Obinutuzumab/Bendamustine	Total
Arm/Group Description		Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Total of all reporting groups
Overall Number of Baseline Participants		84	36	120
Baseline Analysis Population Description		All Treated Participants: all enrolled participants who received at least one dose of any study drug
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	84 participants	36 participants	120 participants
		64.5 (10.06)	60.7 (9.07)	63.4 (9.90)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	36 participants	120 participants
	Female	29	9	38
	Male	55	27	82
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	84 participants	36 participants	120 participants
White		76	34	110
Black or African American		5	2	7
Asian		0	0	0
American Indian/Alaska Native		0	0	0
Native Hawaiian or Other Pacific Islander		0	0	0
Other		0	0	0
Missing		3	0	3

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Achieving Low Tumor Burden Status With Induction of Obinutuzumab or Obinutuzumab Plus Bendamustine (Debulking Period)
Description	Low tumor burden is defined as absolute lymphocyte count (ALC) < 25 × 10^9 /L and all lymph nodes < 5 cm per computed tomography (CT) scans.
Time Frame	From Baseline to the end of Cycles 2, 4, and 6, up to approximately 24 weeks after initial dose of study drug

Outcome Measure Data

Analysis Population Description

Participants who completed debulking and were subsequently treated with venetoclax with available data

Arm/Group Title		Obinutuzumab	Obinutuzumab/Bendamustine
Arm/Group Description:		Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.
Overall Number of Participants Analyzed		82	35
Measure Type: Number; Unit of Measure: percentage of participants
From Baseline to the End of Cycle 2	Number Analyzed	59 participants	31 participants
		81.4	83.9
From Baseline to the End of Cycle 4	Number Analyzed	60 participants	31 participants
		88.3	87.1
From Baseline to the End of Cycle 6	Number Analyzed	60 participants	31 participants
		95.0	90.3

2. Primary Outcome

Title	Complete Response Rate
Description	Complete response rate is defined as the percentage of participants achieving complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: Peripheral blood lymphocytes <4000/μL; Absence of lymphadenopathy by physical examination and computed tomography scan; No hepatomegaly or splenomegaly by physical examination; Absence of disease or constitutional symptoms (unexplained fevers >38°C, drenching night sweats, ≥10% weight loss in last 6 months); Blood counts above the following: Neutrophils >1500/μL Platelets >100,000/μL Hemoglobin >11.0 g/dL; Bone marrow at least normocellular for age, <30% lymphocytes CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity.
Time Frame	From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days

Outcome Measure Data

Analysis Population Description

All treated participants who received at least 1 dose of any study drug

Arm/Group Title	Obinutuzumab	Obinutuzumab/Bendamustine
Arm/Group Description:	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.
Overall Number of Participants Analyzed	84	36
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	51.2; (40.0 to 62.3)	16.7; (6.4 to 32.8)

3. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	ORR is defined as the percentage of participants who achieved a best response of complete remission (CR), complete remission with incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR) based on the 2008 Modified IWCLL NCI-WG criteria at any time during the study as assessed by investigator up through the completion of the 65-week disease response assessment after the start of venetoclax. Participants who did not respond were considered non-responders.
Time Frame	From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days

Outcome Measure Data

Analysis Population Description

All treated participants who received at least 1 dose of any study drug

Arm/Group Title	Obinutuzumab	Obinutuzumab/Bendamustine
Arm/Group Description:	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.
Overall Number of Participants Analyzed	84	36
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	94.0; (86.7 to 98.0)	88.9; (73.9 to 96.9)

4. Secondary Outcome

Title	Duration of Response (DoR)
Description	DoR is defined as the number of days from the date of first response (CR, CRi, nPR, or PR per the 2008 Modified IWCLL NCI-WG criteria) to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless whether the event occurred during or after the participant was taking any study drug (either venetoclax, obinutuzumab, or bendamustine). Duration of response was analyzed by Kaplan-Meier (K-M) methodology.
Time Frame	From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days

Outcome Measure Data

Analysis Population Description

All treated participants who received at least 1 dose of any study drug and who had a record of first response (CR, CRi, PR, or nPR)

Arm/Group Title	Obinutuzumab	Obinutuzumab/Bendamustine
Arm/Group Description:	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.
Overall Number of Participants Analyzed	79	32
Median (95% Confidence Interval); Unit of Measure: months
	21.7 [1]; (11.8 to NA)	NA [1]; (NA to NA)

[1]

Not calculable/estimable due to low number of participants with events

5. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS is defined as the number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless whether the event occurred during or after the participant was taking any study drug. Progression-free survival was analyzed by Kaplan-Meier methodology.
Time Frame	From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days

Outcome Measure Data

Analysis Population Description

All treated participants who received at least 1 dose of any study drug

Arm/Group Title	Obinutuzumab	Obinutuzumab/Bendamustine
Arm/Group Description:	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.
Overall Number of Participants Analyzed	84	36
Median (95% Confidence Interval); Unit of Measure: months
	23.3 [1]; (NA to NA)	NA [1]; (17.5 to NA)

[1]

Not calculable/estimable due to low number of participants with events

6. Secondary Outcome

Title	Time to Progression (TTP)
Description	TTP is defined as the number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to date of disease progression. All disease progression was to be included regardless of whether the event occurred during or after the participant was taking any study drug.The distribution of the time to progression was estimated using Kaplan-Meier methodology.
Time Frame	From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days

Outcome Measure Data

Analysis Population Description

All treated participants who received at least 1 dose of any study drug

Arm/Group Title	Obinutuzumab	Obinutuzumab/Bendamustine
Arm/Group Description:	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.
Overall Number of Participants Analyzed	84	36
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Not calculable/estimable due to zero participants with events

7. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of death. If a participant had not died, their data was censored at the date when they were last known to be alive prior to the cutoff date.The distribution of OS was estimated using Kaplan-Meier methodology.
Time Frame	From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days

Outcome Measure Data

Analysis Population Description

All treated participants who received at least 1 dose of any study drug

Arm/Group Title	Obinutuzumab	Obinutuzumab/Bendamustine
Arm/Group Description:	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.
Overall Number of Participants Analyzed	84	36
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Not calculable/estimable due to low number of participants with events

8. Secondary Outcome

Title	Undetectable Minimal Residual Disease (UMRD) Rate
Description	The level of MRD was assessed in the peripheral blood of all participants at 5 months after last dose of obinutuzumab, and at 3 months after last dose of venetoclax/end of treatment (including early study termination) to determine the rate of UMRD. Undetectable Minimal Residual Disease is defined as less than one CLL cell per 10,000 leukocytes (< 10^-4 ).
Time Frame	From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021)

Outcome Measure Data

Analysis Population Description

All treated participants who received at least 1 dose of any study drug

Arm/Group Title		Obinutuzumab	Obinutuzumab/Bendamustine
Arm/Group Description:		Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.	Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.
Overall Number of Participants Analyzed		84	36
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
At Week 38	Number Analyzed	76 participants	28 participants
		100; (95.3 to 100)	100; (87.7 to 100)
At Week 65	Number Analyzed	67 participants	21 participants
		95.5; (87.5 to 99.1)	100; (83.9 to 100)

Adverse Events

Time Frame	All-cause mortality is reported from enrollment to the data cutoff date of 13 October 2021; median time on follow up was up to 863 days. TEAEs and SAEs were collected from first dose of study drug until 30 days after last dose of study drug; mean duration on study drug was 210 days, 56 days, and 371 days for obinutuzumab, bendamustine, and venetoclax, respectively.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Obinutuzumab_Debulk		Obinutuzumab_Bendamustine_Debulk		Obinutuzumab_Venetoclax_Postdebulk		Venetoclax_MONO_Postdebulk
Arm/Group Description	Participants who received obinutuzumab during the debulking regimen period		Participants who received obinutuzumab and bendamustine during the debulking regimen period		Participants who received obinutuzumab and venetoclax during the post debulking period		Participants who received venetoclax monotherapy during the post debulking period; safety data were collected starting 30 days after the last dose of obinutuzumab
All-Cause Mortality
	Obinutuzumab_Debulk		Obinutuzumab_Bendamustine_Debulk		Obinutuzumab_Venetoclax_Postdebulk		Venetoclax_MONO_Postdebulk
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/84 (0.00%)		0/36 (0.00%)		1/117 (0.85%)		7/114 (6.14%)
Serious Adverse Events
	Obinutuzumab_Debulk		Obinutuzumab_Bendamustine_Debulk		Obinutuzumab_Venetoclax_Postdebulk		Venetoclax_MONO_Postdebulk
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/84 (8.33%)		3/36 (8.33%)		14/117 (11.97%)		13/114 (11.40%)
Blood and lymphatic system disorders
FEBRILE NEUTROPENIA † 1	1/84 (1.19%)	1	0/36 (0.00%)	0	0/117 (0.00%)	0	0/114 (0.00%)	0
NEUTROPENIA † 1	0/84 (0.00%)	0	1/36 (2.78%)	1	0/117 (0.00%)	0	0/114 (0.00%)	0
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION † 1	1/84 (1.19%)	1	0/36 (0.00%)	0	1/117 (0.85%)	1	0/114 (0.00%)	0
ATRIAL FIBRILLATION † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
VENTRICULAR TACHYCARDIA † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
Gastrointestinal disorders
PANCREATITIS ACUTE † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
General disorders
CHEST PAIN † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	1/117 (0.85%)	1	0/114 (0.00%)	0
PYREXIA † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
Hepatobiliary disorders
CHOLECYSTITIS † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
Infections and infestations
BRONCHITIS † 1	1/84 (1.19%)	1	0/36 (0.00%)	0	0/117 (0.00%)	0	0/114 (0.00%)	0
COVID-19 † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	1/117 (0.85%)	2	2/114 (1.75%)	2
COVID-19 PNEUMONIA † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	4/117 (3.42%)	5	0/114 (0.00%)	0
ENDOMETRITIS † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
MENINGITIS ASEPTIC † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
PNEUMONIA † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	3/117 (2.56%)	3	1/114 (0.88%)	1
SKIN INFECTION † 1	1/84 (1.19%)	1	0/36 (0.00%)	0	0/117 (0.00%)	0	0/114 (0.00%)	0
UPPER RESPIRATORY TRACT INFECTION † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	1/117 (0.85%)	1	0/114 (0.00%)	0
UROSEPSIS † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
Injury, poisoning and procedural complications
DRUG DISPENSED TO WRONG PATIENT † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	1/117 (0.85%)	1	0/114 (0.00%)	0
FALL † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
Investigations
PLATELET COUNT DECREASED † 1	1/84 (1.19%)	1	0/36 (0.00%)	0	0/117 (0.00%)	0	0/114 (0.00%)	0
Metabolism and nutrition disorders
TUMOUR LYSIS SYNDROME † 1	2/84 (2.38%)	2	1/36 (2.78%)	1	1/117 (0.85%)	1	0/114 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
PROSTATE CANCER RECURRENT † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	1/117 (0.85%)	1	0/114 (0.00%)	0
SQUAMOUS CELL CARCINOMA † 1	0/84 (0.00%)	0	1/36 (2.78%)	1	1/117 (0.85%)	1	0/114 (0.00%)	0
Nervous system disorders
CAROTID ARTERY STENOSIS † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	1/117 (0.85%)	1	0/114 (0.00%)	0
CEREBROVASCULAR ACCIDENT † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
Respiratory, thoracic and mediastinal disorders
HYPOXIA † 1	1/84 (1.19%)	1	0/36 (0.00%)	0	0/117 (0.00%)	0	0/114 (0.00%)	0
Skin and subcutaneous tissue disorders
DERMAL CYST † 1	0/84 (0.00%)	0	0/36 (0.00%)	0	0/117 (0.00%)	0	1/114 (0.88%)	1
1 Term from vocabulary, MedDRA 24.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Obinutuzumab_Debulk		Obinutuzumab_Bendamustine_Debulk		Obinutuzumab_Venetoclax_Postdebulk		Venetoclax_MONO_Postdebulk
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	82/84 (97.62%)		36/36 (100.00%)		107/117 (91.45%)		89/114 (78.07%)
Blood and lymphatic system disorders
ANAEMIA † 1	8/84 (9.52%)	9	7/36 (19.44%)	9	2/117 (1.71%)	3	1/114 (0.88%)	2
LEUKOPENIA † 1	3/84 (3.57%)	6	3/36 (8.33%)	9	3/117 (2.56%)	4	1/114 (0.88%)	1
NEUTROPENIA † 1	14/84 (16.67%)	31	13/36 (36.11%)	27	35/117 (29.91%)	70	16/114 (14.04%)	36
THROMBOCYTOPENIA † 1	13/84 (15.48%)	18	7/36 (19.44%)	10	11/117 (9.40%)	12	2/114 (1.75%)	3
Cardiac disorders
PALPITATIONS † 1	1/84 (1.19%)	1	3/36 (8.33%)	3	2/117 (1.71%)	2	1/114 (0.88%)	1
Gastrointestinal disorders
CONSTIPATION † 1	11/84 (13.10%)	11	11/36 (30.56%)	12	9/117 (7.69%)	10	2/114 (1.75%)	2
DIARRHOEA † 1	17/84 (20.24%)	24	11/36 (30.56%)	13	36/117 (30.77%)	48	22/114 (19.30%)	30
DYSPEPSIA † 1	6/84 (7.14%)	7	4/36 (11.11%)	4	5/117 (4.27%)	6	1/114 (0.88%)	1
HAEMORRHOIDAL HAEMORRHAGE † 1	0/84 (0.00%)	0	2/36 (5.56%)	2	0/117 (0.00%)	0	0/114 (0.00%)	0
NAUSEA † 1	35/84 (41.67%)	45	21/36 (58.33%)	27	35/117 (29.91%)	36	8/114 (7.02%)	8
VOMITING † 1	5/84 (5.95%)	7	5/36 (13.89%)	6	6/117 (5.13%)	9	5/114 (4.39%)	6
General disorders
CHEST DISCOMFORT † 1	1/84 (1.19%)	1	2/36 (5.56%)	2	0/117 (0.00%)	0	1/114 (0.88%)	1
CHILLS † 1	4/84 (4.76%)	4	4/36 (11.11%)	4	1/117 (0.85%)	1	6/114 (5.26%)	6
FATIGUE † 1	37/84 (44.05%)	45	13/36 (36.11%)	15	17/117 (14.53%)	17	14/114 (12.28%)	18
INFLUENZA LIKE ILLNESS † 1	7/84 (8.33%)	9	0/36 (0.00%)	0	1/117 (0.85%)	1	1/114 (0.88%)	2
OEDEMA PERIPHERAL † 1	4/84 (4.76%)	5	3/36 (8.33%)	3	5/117 (4.27%)	5	3/114 (2.63%)	3
PAIN † 1	4/84 (4.76%)	4	2/36 (5.56%)	2	3/117 (2.56%)	3	2/114 (1.75%)	2
PYREXIA † 1	10/84 (11.90%)	12	11/36 (30.56%)	14	5/117 (4.27%)	6	4/114 (3.51%)	4
Infections and infestations
BRONCHITIS † 1	0/84 (0.00%)	0	2/36 (5.56%)	3	3/117 (2.56%)	3	0/114 (0.00%)	0
NASOPHARYNGITIS † 1	1/84 (1.19%)	1	1/36 (2.78%)	1	6/117 (5.13%)	7	2/114 (1.75%)	2
SINUSITIS † 1	3/84 (3.57%)	4	3/36 (8.33%)	4	5/117 (4.27%)	6	4/114 (3.51%)	4
UPPER RESPIRATORY TRACT INFECTION † 1	4/84 (4.76%)	5	5/36 (13.89%)	6	14/117 (11.97%)	14	5/114 (4.39%)	6
URINARY TRACT INFECTION † 1	2/84 (2.38%)	2	0/36 (0.00%)	0	6/117 (5.13%)	7	1/114 (0.88%)	1
Injury, poisoning and procedural complications
INFUSION RELATED REACTION † 1	63/84 (75.00%)	72	25/36 (69.44%)	30	3/117 (2.56%)	3	0/114 (0.00%)	0
Investigations
ASPARTATE AMINOTRANSFERASE INCREASED † 1	7/84 (8.33%)	8	4/36 (11.11%)	4	1/117 (0.85%)	1	3/114 (2.63%)	3
BLOOD CREATININE INCREASED † 1	1/84 (1.19%)	2	4/36 (11.11%)	4	4/117 (3.42%)	4	0/114 (0.00%)	0
BLOOD LACTATE DEHYDROGENASE INCREASED † 1	0/84 (0.00%)	0	2/36 (5.56%)	2	0/117 (0.00%)	0	0/114 (0.00%)	0
LYMPHOCYTE COUNT DECREASED † 1	1/84 (1.19%)	2	2/36 (5.56%)	2	3/117 (2.56%)	4	1/114 (0.88%)	1
NEUTROPHIL COUNT DECREASED † 1	17/84 (20.24%)	30	5/36 (13.89%)	7	22/117 (18.80%)	42	17/114 (14.91%)	25
PLATELET COUNT DECREASED † 1	14/84 (16.67%)	25	5/36 (13.89%)	7	9/117 (7.69%)	13	4/114 (3.51%)	7
WEIGHT DECREASED † 1	1/84 (1.19%)	1	3/36 (8.33%)	3	1/117 (0.85%)	1	0/114 (0.00%)	0
WHITE BLOOD CELL COUNT DECREASED † 1	4/84 (4.76%)	8	4/36 (11.11%)	9	7/117 (5.98%)	13	5/114 (4.39%)	6
Metabolism and nutrition disorders
DECREASED APPETITE † 1	5/84 (5.95%)	5	3/36 (8.33%)	3	1/117 (0.85%)	1	1/114 (0.88%)	1
DEHYDRATION † 1	9/84 (10.71%)	15	4/36 (11.11%)	4	3/117 (2.56%)	9	1/114 (0.88%)	1
HYPERGLYCAEMIA † 1	3/84 (3.57%)	3	2/36 (5.56%)	3	1/117 (0.85%)	2	0/114 (0.00%)	0
HYPERPHOSPHATAEMIA † 1	3/84 (3.57%)	3	3/36 (8.33%)	4	2/117 (1.71%)	2	0/114 (0.00%)	0
HYPERURICAEMIA † 1	4/84 (4.76%)	5	8/36 (22.22%)	8	1/117 (0.85%)	1	2/114 (1.75%)	5
HYPOKALAEMIA † 1	3/84 (3.57%)	3	1/36 (2.78%)	1	6/117 (5.13%)	10	1/114 (0.88%)	1
TUMOUR LYSIS SYNDROME † 1	3/84 (3.57%)	3	6/36 (16.67%)	6	0/117 (0.00%)	0	0/114 (0.00%)	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA † 1	12/84 (14.29%)	13	8/36 (22.22%)	8	15/117 (12.82%)	16	5/114 (4.39%)	5
BACK PAIN † 1	5/84 (5.95%)	5	2/36 (5.56%)	2	8/117 (6.84%)	9	5/114 (4.39%)	5
BONE PAIN † 1	2/84 (2.38%)	2	2/36 (5.56%)	2	5/117 (4.27%)	5	1/114 (0.88%)	1
MUSCLE SPASMS † 1	3/84 (3.57%)	3	3/36 (8.33%)	3	5/117 (4.27%)	5	4/114 (3.51%)	4
MYALGIA † 1	5/84 (5.95%)	6	4/36 (11.11%)	4	4/117 (3.42%)	4	2/114 (1.75%)	2
NECK PAIN † 1	6/84 (7.14%)	7	2/36 (5.56%)	2	3/117 (2.56%)	3	1/114 (0.88%)	1
PAIN IN EXTREMITY † 1	2/84 (2.38%)	2	5/36 (13.89%)	6	7/117 (5.98%)	7	1/114 (0.88%)	2
Nervous system disorders
DIZZINESS † 1	16/84 (19.05%)	18	2/36 (5.56%)	2	5/117 (4.27%)	6	6/114 (5.26%)	6
DYSGEUSIA † 1	3/84 (3.57%)	3	2/36 (5.56%)	2	3/117 (2.56%)	3	0/114 (0.00%)	0
HEADACHE † 1	22/84 (26.19%)	25	10/36 (27.78%)	10	10/117 (8.55%)	10	9/114 (7.89%)	10
PARAESTHESIA † 1	0/84 (0.00%)	0	3/36 (8.33%)	3	0/117 (0.00%)	0	0/114 (0.00%)	0
PERIPHERAL SENSORY NEUROPATHY † 1	0/84 (0.00%)	0	2/36 (5.56%)	2	2/117 (1.71%)	2	1/114 (0.88%)	1
Psychiatric disorders
INSOMNIA † 1	16/84 (19.05%)	19	3/36 (8.33%)	4	5/117 (4.27%)	5	1/114 (0.88%)	1
Respiratory, thoracic and mediastinal disorders
COUGH † 1	15/84 (17.86%)	17	4/36 (11.11%)	4	11/117 (9.40%)	14	10/114 (8.77%)	13
DYSPNOEA † 1	8/84 (9.52%)	9	1/36 (2.78%)	1	4/117 (3.42%)	4	3/114 (2.63%)	3
EMPHYSEMA † 1	0/84 (0.00%)	0	2/36 (5.56%)	2	0/117 (0.00%)	0	0/114 (0.00%)	0
EPISTAXIS † 1	5/84 (5.95%)	5	3/36 (8.33%)	3	1/117 (0.85%)	1	3/114 (2.63%)	5
HICCUPS † 1	6/84 (7.14%)	6	4/36 (11.11%)	4	0/117 (0.00%)	0	0/114 (0.00%)	0
NASAL CONGESTION † 1	7/84 (8.33%)	7	1/36 (2.78%)	1	8/117 (6.84%)	9	4/114 (3.51%)	4
OROPHARYNGEAL PAIN † 1	6/84 (7.14%)	6	2/36 (5.56%)	2	6/117 (5.13%)	6	5/114 (4.39%)	5
RHINITIS ALLERGIC † 1	0/84 (0.00%)	0	2/36 (5.56%)	2	3/117 (2.56%)	3	1/114 (0.88%)	1
SINUS CONGESTION † 1	0/84 (0.00%)	0	1/36 (2.78%)	1	6/117 (5.13%)	6	3/114 (2.63%)	3
Skin and subcutaneous tissue disorders
ALOPECIA † 1	2/84 (2.38%)	2	0/36 (0.00%)	0	7/117 (5.98%)	7	0/114 (0.00%)	0
HYPERHIDROSIS † 1	0/84 (0.00%)	0	2/36 (5.56%)	2	0/117 (0.00%)	0	2/114 (1.75%)	2
PRURITUS † 1	5/84 (5.95%)	5	5/36 (13.89%)	6	7/117 (5.98%)	7	3/114 (2.63%)	3
RASH † 1	2/84 (2.38%)	2	8/36 (22.22%)	9	3/117 (2.56%)	3	1/114 (0.88%)	1
RASH MACULO-PAPULAR † 1	5/84 (5.95%)	5	3/36 (8.33%)	4	5/117 (4.27%)	6	4/114 (3.51%)	4
Vascular disorders
HYPOTENSION † 1	5/84 (5.95%)	5	1/36 (2.78%)	1	0/117 (0.00%)	0	0/114 (0.00%)	0
PHLEBITIS † 1	1/84 (1.19%)	1	2/36 (5.56%)	3	1/117 (0.85%)	1	1/114 (0.88%)	1
1 Term from vocabulary, MedDRA 24.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.

Results Point of Contact

• Name/Title: Global Medical Services
• Organization: AbbVie
• Phone: 800-633-9110
• EMail: abbvieclinicaltrials@abbvie.com

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT03406156
• Other Study ID Numbers: M16-788
• First Submitted: January 16, 2018
• First Posted: January 23, 2018
• Results First Submitted: October 7, 2022
• Results First Posted: November 3, 2022
• Last Update Posted: November 3, 2022