Trial Outcomes & Findings for A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) (NCT NCT03462719)

Last Updated: 2025-11-13

Results Overview

PFS: time between date of randomization and date of disease progression, as assessed by IRC, or date of death due to any cause, whichever occurs first, regardless of use of subsequent anti-cancer therapy prior to PD or death using iWCLL2008 criteria : New enlarged lymph nodes \>15 mm, new hepatomegaly or splenomegaly, or other organ infiltrates, bone lesion, ascites or pleural effusion due to CLL; \>=50% increase in longest diameter (LDi) from nadir in existing lymph node (LDi \>15 mm) or \>=50% increase from nadir in sum of diameters of multiple nodes (and at least 1 node with LDi \>15 mm); \>=50% increase from nadir in enlargement of liver/spleen; \>=50% increase from baseline in lymphocyte count (ALC; to \>=5\*10\^9/L); or \>=50% increase from nadir in ALC in \>=2 serial assessments if ALC is \>=30000\*10\^9/L and lymphocyte doubling time is rapid unless considered treatment-related lymphocytosis; new cytopenia attributable to CLL; transformation to more aggressive histology.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

211 participants

Primary outcome timeframe

Up to 2 years 10 months

Results posted on

2025-11-13

Participant Flow

Participant milestones

Participant milestones
Measure	Treatment Arm A (Ibrutinib + Venetoclax) Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Overall Study STARTED	106	105
Overall Study COMPLETED	15	30
Overall Study NOT COMPLETED	91	75

Reasons for withdrawal

Reasons for withdrawal
Measure	Treatment Arm A (Ibrutinib + Venetoclax) Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Overall Study Withdrawal by Subject	4	3
Overall Study Ongoing	87	72

Baseline Characteristics

A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Total n=211 Participants Total of all reporting groups
Region of Enrollment BELGIUM	7 Participants n=10 Participants	2 Participants n=10 Participants	9 Participants n=20 Participants
Region of Enrollment CANADA	7 Participants n=10 Participants	10 Participants n=10 Participants	17 Participants n=20 Participants
Age, Continuous	71 years STANDARD_DEVIATION 8.02 • n=10 Participants	72 years STANDARD_DEVIATION 6.16 • n=10 Participants	71.5 years STANDARD_DEVIATION 7.01 • n=20 Participants
Sex: Female, Male Female	47 Participants n=10 Participants	42 Participants n=10 Participants	89 Participants n=20 Participants
Sex: Female, Male Male	59 Participants n=10 Participants	63 Participants n=10 Participants	122 Participants n=20 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=10 Participants	3 Participants n=10 Participants	4 Participants n=20 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	101 Participants n=10 Participants	99 Participants n=10 Participants	200 Participants n=20 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=10 Participants	3 Participants n=10 Participants	7 Participants n=20 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=10 Participants	0 Participants n=10 Participants	0 Participants n=20 Participants
Race (NIH/OMB) Asian	0 Participants n=10 Participants	1 Participants n=10 Participants	1 Participants n=20 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=10 Participants	0 Participants n=10 Participants	0 Participants n=20 Participants
Race (NIH/OMB) Black or African American	0 Participants n=10 Participants	0 Participants n=10 Participants	0 Participants n=20 Participants
Race (NIH/OMB) White	101 Participants n=10 Participants	101 Participants n=10 Participants	202 Participants n=20 Participants
Race (NIH/OMB) More than one race	1 Participants n=10 Participants	0 Participants n=10 Participants	1 Participants n=20 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=10 Participants	3 Participants n=10 Participants	7 Participants n=20 Participants
Region of Enrollment CZECH REPUBLIC	9 Participants n=10 Participants	13 Participants n=10 Participants	22 Participants n=20 Participants
Region of Enrollment DENMARK	7 Participants n=10 Participants	5 Participants n=10 Participants	12 Participants n=20 Participants
Region of Enrollment FRANCE	4 Participants n=10 Participants	3 Participants n=10 Participants	7 Participants n=20 Participants
Region of Enrollment ISRAEL	6 Participants n=10 Participants	12 Participants n=10 Participants	18 Participants n=20 Participants
Region of Enrollment NETHERLANDS	1 Participants n=10 Participants	6 Participants n=10 Participants	7 Participants n=20 Participants
Region of Enrollment POLAND	12 Participants n=10 Participants	10 Participants n=10 Participants	22 Participants n=20 Participants
Region of Enrollment RUSSIAN FEDERATION	23 Participants n=10 Participants	16 Participants n=10 Participants	39 Participants n=20 Participants
Region of Enrollment SPAIN	10 Participants n=10 Participants	9 Participants n=10 Participants	19 Participants n=20 Participants
Region of Enrollment SWEDEN	2 Participants n=10 Participants	0 Participants n=10 Participants	2 Participants n=20 Participants
Region of Enrollment TURKEY	8 Participants n=10 Participants	13 Participants n=10 Participants	21 Participants n=20 Participants
Region of Enrollment UNITED KINGDOM	8 Participants n=10 Participants	4 Participants n=10 Participants	12 Participants n=20 Participants
Region of Enrollment UNITED STATES	2 Participants n=10 Participants	2 Participants n=10 Participants	4 Participants n=20 Participants

PRIMARY outcome

Timeframe: Up to 2 years 10 months

Population: The intent-to-treat (ITT) analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Progression Free Survival (PFS)	NA Months Interval 31.24 to Here "NA" indicates that median and upper limit of 95% CI was not estimable due to insufficient number of events.	20.96 Months Interval 16.59 to 24.67

SECONDARY outcome

Timeframe: Up to 2 years 10 months

Population: The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.

MRD-negative rate is defined as the percentage of participants who achieved MRD-negative status (that is, less than \[\<\] 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or \<0.01 percentage \[%\]) in the bone marrow as assessed by next-generation sequencing (NGS). Participants with missing MRD data were considered MRD positive.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Minimal Residual Disease (MRD) Negative Rate	55.7 Percentage of participants Interval 46.2 to 65.1	21.0 Percentage of participants Interval 13.2 to 28.7

SECONDARY outcome

Timeframe: Up to 2 years 10 months

Population: The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.

Complete response rate is defined as the percentage of participants who achieved complete response or complete response with an incomplete marrow recovery (CRi) on or prior to initiation of subsequent anti-leukemic therapy per the IRC assessment. International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils \>1.5\*10\^9/liter (L), platelets \>100\*10\^9/L, Hgb \>11 gram per deciliter (g/dL), absolute lymphocyte count \<4000/microliter (mcL) and normocellular bone marrow with \<30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Complete Response Rate (CRR)	38.7 Percentage of Participants Interval 29.4 to 48.0	11.4 Percentage of Participants Interval 5.3 to 17.5

SECONDARY outcome

Timeframe: Up to 2 years 10 months

Population: The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received. Participants with missing post-randomization data were considered non-responders.

ORR: percentage of participants who achieved best overall response of either CR, CRi, nodular PR (nPR) and partial response (PR). iWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils \>1.5\*10\^9/liter (L), platelets \>100\*10\^9/L, Hgb \>11 g/dL and ALC \<4000/mcL, normocellular bone marrow with \<30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but bone marrow biopsy shows B-lymphoid nodules (reflecting residual disease); PR-2 of following when abnormal at baseline: \>=50% decrease in ALC, \>=50% decrease in sum of products of multiple nodes, \>=50% decrease in enlargement of spleen or liver; and 1 of following: neutrophils \>1.5\*10\^9/L, Platelets \>100\*10\^9/L and Hgb\>11 g/dL or \>=50% improvement over baseline in any of these; 50% reduction in bone marrow infiltrates or B lymphoid nodules; no new enlarged nodes or new hepatosplenomegaly.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Overall Response Rate (ORR)	86.8 Percentage of participants Interval 80.3 to 93.2	84.8 Percentage of participants Interval 77.9 to 91.6

SECONDARY outcome

Timeframe: Up to 4 years 10 months

Population: The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

OS is defined as the time from date of randomization to date of death from any cause.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=17 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=36 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Overall Survival (OS)	NA Months Here "NA" indicates that median and 95% CI was not estimable due to insufficient number of events.	NA Months Here "NA" indicates that median and 95% CI was not estimable due to insufficient number of events.

SECONDARY outcome

Timeframe: Up to 2 years 10 months

Population: Population analyzed included ITT amongst who were responders (PR or better).

DOR is defined as the interval between the date of initial documentation of a response including partial response with lymphocytosis (PRL) and the date of first documented evidence of PD or death or date of censoring per the IRC assessment. iWCLL 2008 criteria for PD: New enlarged nodes \>1.5 cm, new hepatomegaly or splenomegaly, or other organ infiltrates; \>= 50% increase from nadir in existing lymph node or \>=50% increase from nadir in sum of product of diameters of multiple nodes; \>=50% increase from nadir in enlargement of liver or spleen; \>=50% increase from baseline in lymphocyte count (and to \>=5\*10\^9/L) unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=92 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=89 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Duration of Response (DOR)	28.85 Months Interval 28.68 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.	21.13 Months Interval 15.93 to 25.1

SECONDARY outcome

Timeframe: Up to 2 years 10 months

Population: The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.

Time-to-next treatment was measured from the date of randomization to the start date of any subsequent anti-leukemic therapy.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Time-to-Next Treatment	NA Months Here "NA" indicates that median and 95% CI was not estimable due to insufficient number of events.	NA Months Interval 31.54 to Here "NA" indicates that median and upper limit of 95% CI was not estimable due to insufficient number of events.

SECONDARY outcome

Timeframe: Up to 2 years 10 months

Population: The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.

Time to worsening= time interval (months) from randomization to first observation of deterioration. EQ-5D-5L consists of a 5-item descriptive system and the EuroQol visual analog scale (EQ-5D VAS). EQ-5D-VAS self-rating records respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Worsening is defined as a decrease of \>= 7 points (on a 0-100 scale). EQ-5D-5L descriptive system comprises 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe participant's current health state. Responses for 5 dimensions are combined into a 5-digit number describing respondents health state that can be converted into a single index value or utility score (using the United Kingdom weights), ranging from -1 to 1, where lower scores indicate a worse health status. Worsening is defined as a decrease of \>=0.08 points (on a 0-1 scale).

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L) EQ-5D-5L: Visual Analogue Score	8.34 Months Interval 5.65 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.	24.18 Months Interval 11.27 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.
Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L) EQ-5D-5L: Utility Score	14.29 Months Interval 8.15 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.	24.11 Months Interval 8.34 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.

SECONDARY outcome

Timeframe: Up to 2 years 10 months

Population: The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.

Time to worsening= time interval from randomization to first observation of deterioration. EORTC QLQ-C30 includes 30 separate items: 5 functional scales (physical, role, emotional, cognitive, and social Functioning), 1 global health status (GHS) and QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each item, except GHS, is answered on 4-point scale (1=not at all to 4=very much) and GHS is measured on 1-7 scale: 1=very poor and 7=excellent. Scores derived using validated scoring algorithms as per EORTC QLQ-C30 Manual and linearly transformed in a range from 0-100. For functional and global QoL scales, higher scores=better level of functioning/QoL. For symptom-oriented scales, higher score=more severe symptoms. Worsening in functional and global health scores=decrease of \>=10 points (on 0-100 scale) and in symptom scores=increase of \>=10 points (on 0-100 scale).

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) Physical Functioning	NA Months Interval 19.42 to Here "NA" indicates that median and upper limit of 95% CI was not estimable due to insufficient number of events.	NA Months Interval 14.03 to Here "NA" indicates that median and upper limit of 95% CI was not estimable due to insufficient number of events.
Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) Pain (Symptom Scale)	8.31 Months Interval 5.45 to 13.9	11.01 Months Interval 5.65 to 17.87
Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) Global Health Status	14.95 Months Interval 8.38 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.	24.18 Months Interval 13.86 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.
Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) Cognitive Functioning	11.07 Months Interval 5.95 to 24.05	14.03 Months Interval 7.16 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.
Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) Emotional Functioning	NA Months Interval 17.31 to Here "NA" indicates that median and upper limit of 95% CI was not estimable due to insufficient number of events.	25.00 Months Interval 16.62 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events
Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) Role Functioning	11.10 Months Interval 6.28 to 14.95	8.48 Months Interval 5.62 to 16.69
Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) Social Functioning	11.10 Months Interval 8.34 to 16.69	17.87 Months Interval 11.07 to 25.3
Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) Fatigue (Symptom Scale)	8.38 Months Interval 5.62 to 14.95	17.87 Months Interval 8.44 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.
Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) Nausea/Vomiting (Symptom Scale)	11.07 Months Interval 8.28 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.	NA Months Interval 20.44 to Here "NA" indicates that median and upper limit of 95% CI was not estimable due to insufficient number of events.

SECONDARY outcome

Timeframe: Up to 2 years 10 months

Population: The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.

Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). Time to Worsening is defined as time interval (months) from randomization to first observation of deterioration. Worsening is defined as a decrease \>= 3 points (on a 0-52 scale). Time to improvement is defined as the time interval (months) from randomization to the first observation of improvement. Improvement is defined as an increase \>=3 points (on a 0-52 scale).

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Time to Worsening and Time to Improvement as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score Time to Worsening	8.15 Months Interval 3.98 to 10.94	14.03 Months Interval 8.61 to Here "NA" indicates that upper limit of 95% CI was not estimable due to insufficient number of events.
Time to Worsening and Time to Improvement as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score Time to Improvement	5.59 Months Interval 3.81 to 11.2	3.75 Months Interval 2.2 to 5.75

SECONDARY outcome

Timeframe: Up to 4 years 10 months

Population: The safety analysis set is defined as all randomized participants who received at least one dose of any one of the four study drugs (ibrutinib, venetoclax, chlorambucil, or obinutuzumab).

An adverse event (AE) is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability	105 Participants	99 Participants

SECONDARY outcome

Timeframe: Up to 4 years 10 months

Population: The safety analysis set is defined as all randomized participants who received at least one dose of any one of the four study drugs (ibrutinib, venetoclax, chlorambucil, or obinutuzumab).

Number of participants with abnormal clinical laboratory findings (hematology and serum chemistry) were reported.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Alanine Transaminase (ALT) (Increase)	22 Participants	26 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Aspartate Aminotransferase (AST) (Increase)	23 Participants	30 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Alkaline Phosphatase (Increase)	19 Participants	21 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Bilirubin (Increase)	36 Participants	25 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Creatinine (Increase)	33 Participants	17 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Creatinine Clearance (Decrease)	40 Participants	17 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Hypercalcemia	13 Participants	3 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Hypoalbuminemia	36 Participants	20 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Hypocalcemia	27 Participants	30 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Phosphate (Decrease)	16 Participants	6 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Potassium (Decrease)	25 Participants	9 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Potassium (Increase)	31 Participants	22 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Sodium (Decrease)	25 Participants	26 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Sodium (Increase)	12 Participants	8 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Chemistry: Uric Acid (Increase)	37 Participants	19 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Hematology: Hemoglobin (Decrease)	38 Participants	42 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Hematology: Platelets (Decrease)	52 Participants	78 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Hematology: Any hemoglobin, platelet, or ANC decrease	94 Participants	103 Participants
Number of Participants With Abnormal Clinical Laboratory Findings Hematology: Absolute Neutrophils Counts (Decrease)	81 Participants	95 Participants

SECONDARY outcome

Timeframe: Up to 2 years 10 months

Population: The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.

Sustained hemoglobin improvement is defined as the percentage of participants who achieved an increase in hemoglobin levels from baseline by \>= 2 grams per deciliter (g/dL) and lasts for at least 56 days without blood transfusion or growth factors.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Percentage of Participants With Sustained Hemoglobin Improvement	44.3 Percentage of Participants	50.5 Percentage of Participants

SECONDARY outcome

Timeframe: Up to 2 years 10 months

Population: The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.

Sustained platelet improvement is defined as the percentage of participants who achieved an increase in platelet levels from baseline by \>= 50% and lasts for at least 56 days without blood transfusion or growth factors.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=106 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) n=105 Participants Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Percentage of Participants With Sustained Platelet Improvement	24.5 Percentage of Participants	29.5 Percentage of Participants

SECONDARY outcome

Timeframe: Ibrutinib: Pre-dose-Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days), Venetoclax: Pre-dose-Day 1 of Cycles 5 and 6

Population: The pharmacokinetics (PK) analysis set is defined as all randomized participants in Treatment Arm A who received at least one dose of ibrutinib and/or venetoclax and had at least one valid blood sample drawn for PK analysis. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this endpoint. Here, "n (number analyzed)" is defined as number of participants analyzed for specified category.

Plasma concentrations of ibrutinib and venetoclax were determined by validated liquid chromatography-tandem mass spectrometry.

Outcome measures

Outcome measures
Measure	Treatment Arm A (Ibrutinib + Venetoclax) n=79 Participants Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.	Treatment Arm B (Chlorambucil + Obinutuzumab) Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Plasma Concentration of Ibrutinib and Venetoclax Ibrutinib: Pre-dose Day 1 Cycle 2 (Ibrutinib Alone)	5.70 Nanograms per milliliter (ng/mL) Standard Deviation 5.58	—
Plasma Concentration of Ibrutinib and Venetoclax Ibrutinib: Pre-dose Day 1 Cycle 3 (Ibrutinib Alone)	6.20 Nanograms per milliliter (ng/mL) Standard Deviation 7.78	—
Plasma Concentration of Ibrutinib and Venetoclax Ibrutinib: Pre-dose Day 1 Cycle 5 (Ibrutinib and Venetoclax)	6.37 Nanograms per milliliter (ng/mL) Standard Deviation 6.71	—
Plasma Concentration of Ibrutinib and Venetoclax Ibrutinib: Pre-dose Day 1 Cycle 6 (Ibrutinib and Venetoclax)	5.90 Nanograms per milliliter (ng/mL) Standard Deviation 6.74	—
Plasma Concentration of Ibrutinib and Venetoclax Venetoclax: Pre-dose Day 1 Cycle 5 (Ibrutinib + Venetoclax)	1139 Nanograms per milliliter (ng/mL) Standard Deviation 959	—
Plasma Concentration of Ibrutinib and Venetoclax Venetoclax: Pre-dose Day 1 Cycle 6 (Ibrutinib + Venetoclax)	1765 Nanograms per milliliter (ng/mL) Standard Deviation 1573	—

Adverse Events

Treatment Arm A (Ibrutinib + Venetoclax)

Serious events: 49 serious events

Other events: 98 other events

Deaths: 17 deaths

Treatment Arm B (Chlorambucil + Obinutuzumab)

Serious events: 30 serious events

Other events: 98 other events

Deaths: 36 deaths

Serious adverse events

Other adverse events

Additional Information

EXECUTIVE MEDICAL DIRECTOR

Janssen Research & Development, LLC

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.
Publication restrictions are in place

Restriction type: OTHER