Trial Outcomes & Findings for CLL11: A Study of Rituximab With Chlorambucil or Chlorambucil Alone in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 1b) (NCT NCT01998880)

NCT ID: NCT01998880

Last Updated: 2018-09-14

Results Overview

PFS was defined as the time from randomization to the first occurrence of progression, relapse, or death from any cause as assessed by the investigator. Progressive disease required at least one of the following: ≥50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes (\>15 mm in longest diameter) or any new extra nodal lesion, ≥50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, ≥50% increase in the enlargement of the liver and/or spleen, Transformation to a more aggressive histology or After treatment, the progression of any cytopenia (a decrease of hemoglobin levels \>20 g/L or \<10 g/dL or a decrease of platelet counts \>50% or \<100 x 10\^9/L or by a decrease of neutrophil counts \>50% or \<1.0 x 10\^9/L).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

787 participants

Primary outcome timeframe

Randomization to clinical cutoff (median observation 57.7 months)

Results posted on

2018-09-14

Participant Flow

787 patients were enrolled in the study. Following a 6 patient safety run-in prior to randomization, 781 patients were randomized.

589 patients were randomized to 1 of 3 treatment groups in 2:2:1 ratio: GClb (n=238), RClb (n=233) or Clb (n=118) in Stage 1 plus 192 randomized to GClb or RClb in Stage 2 \[NCT02053610\]. Stage 1 was divided for analysis into: Stage 1a \[NCT01010061\] (GClb vs Clb) reported separately and Stage 1b \[NCT01998880\] (RClb vs Clb) (n=351) reported here.

Participant milestones

Participant milestones
Measure	Rituximab + Chlorambucil (RClb) Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Overall Study STARTED	233	118
Overall Study Received Study Drug	230	116
Overall Study COMPLETED	205	78
Overall Study NOT COMPLETED	28	40

Reasons for withdrawal

Reasons for withdrawal
Measure	Rituximab + Chlorambucil (RClb) Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Overall Study Adverse Events or Intercurrent Illness	16	16
Overall Study Disease Progression	1	8
Overall Study Withdrew Consent	2	1
Overall Study Death	3	6
Overall Study Insufficient Therapeutic Response	1	5
Overall Study Administrative/Other	1	1
Overall Study Refused Treatment/Did Not Cooperate	1	0
Overall Study Violation of Selection Criteria at Entry	0	1
Overall Study Did Not Receive Treatment	3	2

Baseline Characteristics

CLL11: A Study of Rituximab With Chlorambucil or Chlorambucil Alone in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 1b)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.	Total n=351 Participants Total of all reporting groups
Age, Customized <65 years	47 participants n=5 Participants	26 participants n=7 Participants	73 participants n=5 Participants
Age, Customized >=65 years	186 participants n=5 Participants	92 participants n=7 Participants	278 participants n=5 Participants
Sex: Female, Male Female	84 Participants n=5 Participants	43 Participants n=7 Participants	127 Participants n=5 Participants
Sex: Female, Male Male	149 Participants n=5 Participants	75 Participants n=7 Participants	224 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization to clinical cutoff (median observation 57.7 months)

Population: Intent-to-treat population included all randomized participants. Patients without PFS events were censored.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Progression-free Survival (PFS)	16.5 Months Interval 14.3 to 17.7	11.1 Months Interval 10.7 to 11.3

PRIMARY outcome

Timeframe: Randomization to clinical cutoff (median observation 57.7 months)

Population: Intent-to-treat population included all randomized participants.

Percentage of Participants with Progression Free Survival Events: progression, relapse, or death.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Percentage of Participants With Progression Free Survival Events	90.1 Percentage of participants	90.7 Percentage of participants

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 57.7 months)

Population: Intent-to-treat population included all randomized participants. Patients without EFS events were censored.

Event-free survival (EFS) was defined as the time between date of randomization and the date of disease progression/relapse, death, or start of a new anti-leukemic therapy. Progressive disease required at least one of the following: ≥50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes (\>15 mm in longest diameter) or any new extra nodal lesion, ≥50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, ≥50% increase in the enlargement of the liver and/or spleen, Transformation to a more aggressive histology or After treatment, the progression of any cytopenia (a decrease of hemoglobin levels \>20 g/L or \<10 g/dL or a decrease of platelet counts \>50% or \<100 x 10\^9/L or by a decrease of neutrophil counts \>50% or \<1.0 x 10\^9/L).

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Event Free Survival	15.7 Months Interval 14.2 to 17.2	10.8 Months Interval 8.0 to 11.1

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 57.7 months)

Population: Intent-to-treat population included all randomized participants. Patients without OS events were censored.

Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Overall Survival	74.9 Months Interval 60.8 to The upper limit of 95% CI could not be estimated due to a low number of deaths.	66.7 Months Interval 50.9 to The upper limit of 95% CI could not be estimated due to a low number of deaths.

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 57.7 months)

Population: Participants from the Intent-to-treat population (all randomized participants) with data available for analysis. Participants who did not reach the 3 month Follow-up visit at the time of the clinical cutoff are excluded.

EOTR was the first response assessment 56 days from the last dose according to the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) guidelines. CR required: Peripheral blood lymphocytes below 4 x 10\^9/L, Absence of significant lymphadenopathy, No hepatomegaly, No splenomegaly, Absence of disease, Blood counts above the following values (Neutrophils \>1.5 x 10\^9/L, Platelets \>100 x 10\^9/L, Hemoglobin \>11g/dL) and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. PR required the following for at least 2 months from end of treatment: ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value AND Either a ≥ 50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement PLUS at least one of the following: Neutrophils \>1.5 x 10\^9/ or ≥50% increase, Platelets \>100 x 10\^9/L or ≥50% increase, Hemoglobin 11 g/dL or ≥50% increase.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Percentage of Participants With End of Treatment Response (EOTR) Complete Response (CR)	4.7 Percentage of participants Interval 2.4 to 8.3	0.0 Percentage of participants Interval 0.0 to 3.1
Percentage of Participants With End of Treatment Response (EOTR) Complete Response incomplete (CRi)	2.1 Percentage of participants Interval 0.7 to 4.9	0.0 Percentage of participants Interval 0.0 to 3.1
Percentage of Participants With End of Treatment Response (EOTR) Partial Response (PR)	55.4 Percentage of participants Interval 48.7 to 61.9	28.8 Percentage of participants Interval 20.8 to 37.9
Percentage of Participants With End of Treatment Response (EOTR) Nodular Partial Response (nPR)	3.4 Percentage of participants Interval 1.5 to 6.7	2.5 Percentage of participants Interval 0.5 to 7.3
Percentage of Participants With End of Treatment Response (EOTR) Stable Disease	13.7 Percentage of participants Interval 9.6 to 18.8	22.9 Percentage of participants Interval 15.7 to 31.5
Percentage of Participants With End of Treatment Response (EOTR) Progressive Disease	12.4 Percentage of participants Interval 8.5 to 17.4	28.8 Percentage of participants Interval 20.8 to 37.9
Percentage of Participants With End of Treatment Response (EOTR) No Response Assessment	8.2 Percentage of participants 95 % CI was not estimated for participants with no response assessment.	16.9 Percentage of participants 95 % CI was not estimated for participants with no response assessment.

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 57.7 months)

Population: Participants from the Intent-to-treat population (all randomized participants) with MRD data available for analysis. Participants who did not reach the 3 month Follow-up visit at the time of the clinical cutoff are excluded.

Molecular remission was defined as a minimal residual disease (MRD)-negative result at the end of treatment (assessment that occurred between 56 days and 6 months of last treatment). Molecular remission was assessed for all patients using a blood sample. Additionally, a bone marrow sample was obtained from patients whom the investigator assumed to have a complete response, consistent with the IWCLL guidelines. A combined analysis of blood and bone marrow results was conducted. A patient was considered MRD negative if result was less than 1 CLL cell in 10000 leukocytes (MRD value \< 0.0001) based on the method of allele specific polymerase chain reaction (ASO-PCR).

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=170 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=90 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Percentage of Participants With Molecular Remission at the End of Treatment	2 Percentage of participants Interval 0.6 to 5.9	0 Percentage of participants Interval 0.0 to 4.0

SECONDARY outcome

Timeframe: Randomization to clinical cutoff date of 9 May 2013 (median observation 22.7 months)

Population: Intent-to-treat population included all randomized participants. Patients without PFS events were censored.

PFS was defined as the time from randomization to the first occurrence of progression, relapse, or death from any cause as assessed by Independent Review Committee. Progressive disease required at least one of the following: ≥50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes (\>15 mm in longest diameter) or any new extra nodal lesion, ≥50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, ≥50% increase in the enlargement of the liver and/or spleen, Transformation to a more aggressive histology or After treatment, the progression of any cytopenia (a decrease of hemoglobin levels \>20 g/L or \<10 g/dL or a decrease of platelet counts \>50% or \<100 x 10\^9/L or by a decrease of neutrophil counts \>50% or \<1.0 x 10\^9/L).

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Progression Free Survival Based on Independent Review Committee (IRC) Data	16.1 months Interval 14.3 to 17.2	11.2 months Interval 11.0 to 12.1

SECONDARY outcome

Timeframe: Randomization to clinical cutoff date of 9 May 2013 (median observation 22.7 months)

Population: Intent-to-treat population included all randomized participants. Participants without PFS events were censored.

Percentage of Participants with Progression Free Survival Events: progression, relapse, or death from any cause as assessed by an Independent Review Committee.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Percentage of Participants With Progression Free Survival Events Based on Independent Review Committee (IRC) Data	64.8 Percentage of participants	76.3 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and Cycle 4 Day 1 (Cy4D1)

Population: ITT population. Here, n signifies the number of participants who were evaluated for specified categories.

The EORTC Quality of Life Questionnaire QLQ-C30 was used to assess patient-reported outcomes (PRO) and symptom burden. The QLQ-C30 contains 30 items including the functional scales of physical functioning (5 items), role functioning (2 items), emotional functioning (4 items), cognitive functioning (2 items), social functioning (2 items) and symptom scales including fatigue (3 items), nausea and vomiting (2 items), and pain (4 items) and six single item scales on dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact. Final scores are transformed such that they range from 0 - 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be of minimally important difference to participants. A positive change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Appetite Loss Scale: Baseline (n=220, 111)	15.8 unit on a scale Standard Deviation 27.11	19.8 unit on a scale Standard Deviation 29.26
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Appetite Loss Scale: Cy4D1 (n=196, 92)	10.9 unit on a scale Standard Deviation 21.50	14.5 unit on a scale Standard Deviation 24.36
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Cognitive Functioning Scale: Baseline (n=221, 111)	82.7 unit on a scale Standard Deviation 20.77	81.8 unit on a scale Standard Deviation 22.76
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Cognitive Functioning Scale: Cy4D1 (n=190,93)	83.0 unit on a scale Standard Deviation 17.86	85.8 unit on a scale Standard Deviation 18.54
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Constipation Scale: Baseline (n=219, 111)	15.1 unit on a scale Standard Deviation 25.37	16.8 unit on a scale Standard Deviation 26.92
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Constipation Scale: Cy4D1 (n=195, 93)	13.3 unit on a scale Standard Deviation 22.04	12.5 unit on a scale Standard Deviation 23.53
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Diarrhoea Scale: Baseline (n=220, 110)	7.6 unit on a scale Standard Deviation 18.66	8.8 unit on a scale Standard Deviation 18.98
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Diarrhoea Scale: Cy4D1 (n=195, 93)	9.2 unit on a scale Standard Deviation 20.45	6.5 unit on a scale Standard Deviation 14.95
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Dyspnoea Scale: Baseline (n=220, 109)	26.1 unit on a scale Standard Deviation 28.09	23.9 unit on a scale Standard Deviation 27.63
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Dyspnoea: Cy4D1 (n=196, 91)	19.7 unit on a scale Standard Deviation 25.19	22.3 unit on a scale Standard Deviation 26.78
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Emotional Functioning Scale: Baseline (n=221, 111)	77.3 unit on a scale Standard Deviation 21.23	72.9 unit on a scale Standard Deviation 25.70
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Emotional Functioning Scale:Change Cy4D1(n=196,93)	82.8 unit on a scale Standard Deviation 17.52	80.6 unit on a scale Standard Deviation 18.48
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Fatigue Scale: Baseline (n=221, 111)	35.8 unit on a scale Standard Deviation 24.60	36.9 unit on a scale Standard Deviation 27.01
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Fatigue Scale: Cy4D1(n=197, 93)	29.6 unit on a scale Standard Deviation 22.24	30.8 unit on a scale Standard Deviation 23.00
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Financial Difficulties Scale: Baseline (n=220,110)	10.9 unit on a scale Standard Deviation 22.12	13.6 unit on a scale Standard Deviation 25.26
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Financial Difficulty Scale: Cy4D1(n=193,93)	10.2 unit on a scale Standard Deviation 20.26	9.3 unit on a scale Standard Deviation 19.88
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Nausea, Vomiting Scale: Baseline (n=221, 111)	4.4 unit on a scale Standard Deviation 12.04	7.4 unit on a scale Standard Deviation 18.49
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Nausea, Vomiting Scale: Cy4D1 (n=197,93)	3.6 unit on a scale Standard Deviation 8.99	7.5 unit on a scale Standard Deviation 17.81
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Pain scale: Baseline (n=221, 111)	21.5 unit on a scale Standard Deviation 27.37	21.5 unit on a scale Standard Deviation 25.66
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Pain scale: Cy4D1 (n=197, 93)	15.1 unit on a scale Standard Deviation 22.41	17.7 unit on a scale Standard Deviation 25.98
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Physical Functioning Scale: Baseline (n=221, 111)	76.1 unit on a scale Standard Deviation 18.95	77.3 unit on a scale Standard Deviation 18.87
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Physical Functioning Scale: Cy4D1(n=197,93)	77.6 unit on a scale Standard Deviation 18.27	80.9 unit on a scale Standard Deviation 16.24
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Global Health Status Scale: Baseline (n=219, 111)	58.7 unit on a scale Standard Deviation 22.28	57.4 unit on a scale Standard Deviation 22.90
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Global Health Status Scale: Cy4D1(n=195,93)	65.7 unit on a scale Standard Deviation 20.13	63.4 unit on a scale Standard Deviation 20.56
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Role Functioning Scale: Baseline(n=221,110)	76.9 unit on a scale Standard Deviation 28.70	74.7 unit on a scale Standard Deviation 28.35
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Role Functioning Scale: Cy4D1(n=197,93)	79.4 unit on a scale Standard Deviation 25.97	81.5 unit on a scale Standard Deviation 21.35
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Social Functioning Scale:Baseline(n=221,110)	82.1 unit on a scale Standard Deviation 24.49	83.3 unit on a scale Standard Deviation 25.34
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Social Functioning Scale: Cy4D1(n=195,93)	85.5 unit on a scale Standard Deviation 20.79	85.5 unit on a scale Standard Deviation 19.38
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Insomnia Scale: Baseline (n=220,111)	24.8 unit on a scale Standard Deviation 30.03	31.5 unit on a scale Standard Deviation 32.98
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score Insomnia Scale: Cy4D1(n=195,93)	18.8 unit on a scale Standard Deviation 25.77	24.4 unit on a scale Standard Deviation 29.13

SECONDARY outcome

Timeframe: Baseline and Cycle 4 Day 1 (Cy4D1)

Population: ITT population. Here, n signifies the number of participants who were evaluated for specified categories.

EORTC Quality of Life Questionnaire (QLQ-CLL16) module was used to assess patient-reported outcomes and symptom burden. The QLQ-CLL16 module includes three multi-item scales assessing fatigue (2 items), treatment side effects and disease symptoms (8 items), infection (4 items) and two single item scales on social activities and future health worries. Final scores are transformed such that they range from 0 - 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be of minimally important difference to participants. A positive change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Disease Effects Scale: Baseline (n=198, 102)	22.7 unit on a scale Standard Deviation 18.21	23.7 unit on a scale Standard Deviation 20.18
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Disease Effects Scale: Cy4D1 (n=173, 86)	14.1 unit on a scale Standard Deviation 13.71	15.9 unit on a scale Standard Deviation 14.16
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Fatigue Scale: Baseline (n=198, 102)	27.8 unit on a scale Standard Deviation 23.39	27.6 unit on a scale Standard Deviation 24.65
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Fatigue Scale: Cy4D1 (n=173, 86)	20.0 unit on a scale Standard Deviation 20.25	23.4 unit on a scale Standard Deviation 22.20
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Future Health: Baseline (n=197, 101)	45.9 unit on a scale Standard Deviation 31.24	50.8 unit on a scale Standard Deviation 33.53
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Future Health: Cy4D1 (n=171, 86)	33.1 unit on a scale Standard Deviation 28.12	39.1 unit on a scale Standard Deviation 30.33
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Infection Scale: Baseline (n=197, 102)	9.7 unit on a scale Standard Deviation 14.45	14.6 unit on a scale Standard Deviation 17.97
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Infection Scale: Cy4D1 (n=173, 86)	8.9 unit on a scale Standard Deviation 13.08	8.5 unit on a scale Standard Deviation 10.70
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Social Problems: Baseline (n=195, 100)	25.1 unit on a scale Standard Deviation 31.40	26.3 unit on a scale Standard Deviation 33.26
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Social Problems: Cy4D1 (n=173, 85)	19.3 unit on a scale Standard Deviation 25.94	22.0 unit on a scale Standard Deviation 27.00
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Treatment Side Effects Scale: Baseline (n=198,102)	17.5 unit on a scale Standard Deviation 14.98	17.2 unit on a scale Standard Deviation 15.27
European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score Treatment Side Effect Scale: Cy4D1(n=172,86)	13.9 unit on a scale Standard Deviation 12.42	15.6 unit on a scale Standard Deviation 16.11

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 57.7 months)

Population: Intent-to-treat population included all randomized participants. Participants without events (re-treatment or new anti-leukemic therapy) were censored.

Time to re-treatment/new anti-leukemic therapy was defined as time between the date of randomization and the date of first intake of re-treatment or new anti-leukemic therapy.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Time to Re-Treatment/New-antileukemic Therapy	33.2 months Interval 27.8 to 44.4	15.1 months Interval 11.7 to 18.0

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 57.7 months)

Population: Participants from the Intent-to-treat population (all randomized participants) with CR or PR. Participants without response were censored.

Duration of Response was defined as the date the response \[either Complete Response (CR) or Partial Response (PR)\] was first recorded until the date of Disease Progression or death due to any cause. Response was assessed according IWCLL guidelines.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Duration of Response	12.2 Months Interval 9.5 to 14.5	5.1 Months Interval 3.3 to 6.7

SECONDARY outcome

Timeframe: Randomization to clinical cutoff (median observation 57.7 months)

Best overall response according to IWCLL guidelines was defined as the percentage of patients with CR, CRi,PR or nPR. CR required all of the following: Peripheral blood lymphocytes below 4 x 10\^9/L, Absence of significant lymphadenopathy, No hepatomegaly, No splenomegaly, Absence of disease, Blood counts above the following values (Neutrophils \>1.5 x 10\^9/L, Platelets \>100 x 10\^9/L, Hemoglobin \>11g/dL) and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. PR required the following for at least 2 months from end of treatment: ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value AND Either a ≥ 50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement PLUS at least one of the following: Neutrophils \>1.5 x 10\^9/ or ≥50% increase, Platelets \>100 x 10\^9/L or ≥50% increase, Hemoglobin 11 g/dL or ≥50% increase.

Outcome measures

Outcome measures
Measure	Rituximab + Chlorambucil (RClb) n=233 Participants Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=118 Participants Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Percentage of Participants With Best Overall Response Complete Response (CR)	7.7 Percentage of participants Interval 4.6 to 11.9	0.0 Percentage of participants Interval 0.0 to 3.1
Percentage of Participants With Best Overall Response Complete Response Incomplete (CRi)	1.7 Percentage of participants Interval 0.5 to 4.3	1.7 Percentage of participants Interval 0.2 to 6.0
Percentage of Participants With Best Overall Response Partial Response (PR)	54.9 Percentage of participants Interval 48.3 to 61.4	31.4 Percentage of participants Interval 23.1 to 40.5
Percentage of Participants With Best Overall Response Nodular Partial Response (nPR)	1.7 Percentage of participants Interval 0.5 to 4.3	0.0 Percentage of participants Interval 0.0 to 3.1
Percentage of Participants With Best Overall Response Stable Disease	13.3 Percentage of participants Interval 9.2 to 18.4	21.2 Percentage of participants Interval 14.2 to 29.7
Percentage of Participants With Best Overall Response Progressive Disease	12.4 Percentage of participants Interval 8.5 to 17.4	28.8 Percentage of participants Interval 20.8 to 37.9
Percentage of Participants With Best Overall Response No Response Assessment	8.2 Percentage of participants 95% CI was not estimated.	16.9 Percentage of participants 95% CI was not estimated.

Adverse Events

Rituximab + Chlorambucil (RClb)

Serious events: 87 serious events

Other events: 202 other events

Deaths: 0 deaths

Chlorambucil (Clb)

Serious events: 45 serious events

Other events: 89 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffman-LaRoche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Rituximab + Chlorambucil (RClb) n=225 participants at risk Participants received 375 mg/m\^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m\^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).	Chlorambucil (Clb) n=116 participants at risk Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Blood and lymphatic system disorders Neutropenia	31.6% 71/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	18.1% 21/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Blood and lymphatic system disorders Anaemia	12.4% 28/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	10.3% 12/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Blood and lymphatic system disorders Thrombocytopenia	7.1% 16/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	7.8% 9/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Gastrointestinal disorders Nausea	14.2% 32/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	25.0% 29/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Gastrointestinal disorders Diarrhoea	8.4% 19/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	11.2% 13/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Gastrointestinal disorders Vomiting	7.1% 16/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	12.1% 14/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Gastrointestinal disorders Constipation	6.2% 14/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	10.3% 12/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Injury, poisoning and procedural complications Infusion related reaction	38.2% 86/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	0.00% 0/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
General disorders Fatigue	8.9% 20/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	10.3% 12/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
General disorders Asthenia	8.0% 18/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	6.9% 8/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
General disorders Pyrexia	5.8% 13/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	6.9% 8/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Respiratory, thoracic and mediastinal disorders Cough	6.7% 15/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	6.9% 8/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.0% 9/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	6.9% 8/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Infections and infestations Bronchitis	4.0% 9/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	6.9% 8/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Nervous system disorders Headache	7.1% 16/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	6.9% 8/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Metabolism and nutrition disorders Decreased appetite	2.7% 6/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	7.8% 9/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Skin and subcutaneous tissue disorders Rash	5.8% 13/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	2.6% 3/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.
Infections and infestations Viral Upper Respiratory Tract Infection	2.7% 6/225 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.	5.2% 6/116 Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1b (RClb and Clb arms). In Stage 1b: 5 patients randomized to RClb who received obinutuzumab prior to the August 2012 cutoff are not included in the RClb arm.