CLL11: A Study of Obinutuzumab (RO5072759 [GA101]) With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 1a)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01010061
• Collaborator: German CLL Study Group (Other), Genentech, Inc. (Industry)
• Enrollment: 787
• Locations: 262
• Arms: 3
• Actual Duration (Months): 92.1
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This open-label, randomized, 3-arm study will evaluate the efficacy and safety of obinutuzumab (RO5072759) in combination with chlorambucil as compared to rituximab plus chlorambucil or chlorambucil alone in patients with previously untreated chronic lymphocytic leukemia (CLL). Patients will be randomized 2:2:1 to receive a maximum of six 28-day cycles of either RO5072759 (1000 mg intravenous (iv) infusion, on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6) plus chlorambucil (0.5 mg/kg orally, days 1 and 15 of cycles 1-6), or rituximab (iv infusion day 1, 375 mg/m^{2 cycle 1, 500 mg/m}2 cycles 2-6) plus chlorambucil, or chlorambucil alone. Anticipated time on study treatment is >6 months and follow-up for disease-progression and safety will be at least 5 years. In the US, this trial is sponsored/managed by Genentech.

Condition or Disease	Intervention/Treatment	Phase
Lymphocytic Leukemia, Chronic	Drug: obinutuzumab; Drug: rituximab; Drug: chlorambucil	Phase 3

Detailed Description

Protocol BO21004 is divided into 3 separate Unique Protocol IDs for reporting results on clinicaltrials.gov because there are 3 separate primary analyses conducted at different time-points.

• BO21004 (Stage 1a) [NCT01010061] includes the analysis of 2 of the 3 arms obinutuzumab plus chlorambucil (Glb) compared to chlorambucil (Clb) reported here.

• BO21004 (Stage 1b) [NCT01998880] includes the analysis of 2 of the 3 arms rituximab plus chlorambucil (RClb) compared to chlorambucil (Clb) reported separately.

• BO21004 (Stage 2) [NCT02053610] includes the analysis of 2 of the 3 arms obinutuzumab plus chlorambucil (Glb) compared to rituximab plus chlorambucil (RClb) reported separately.

Study Design

• Study Type: Interventional
• Actual Enrollment: 787 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multi-center, Three Arm Randomized Study to Investigate the Safety and Efficacy on Progression-free Survival of RO5072759 + Chlorambucil (GClb) Compared to Rituximab + Chlorambucil (RClb) or Chlorambucil (Clb) Alone in Previously Untreated CLL Patients With Comorbidities.
• Actual Study Start Date: Dec 21, 2009
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Aug 23, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: obinutuzumab + chlorambucil (GClb) Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	Drug: obinutuzumab; 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in Cycles 2-6 (28-day cycles).; Other Names: RO5072759 GA101 GAZYVA® ; Drug: chlorambucil; Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.
Active Comparator: 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).	Drug: rituximab; 375 mg/m^2 rituximab intravenous (IV) infusion on Day 1 of Cycle 1 (Cycle duration is 28 days) then 500 mg/m^2 IV infusions on Day 1 of Cycles 2-6.; Other Names: Rituxan® MabThera® ; Drug: chlorambucil; Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.
Active Comparator: 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.	Drug: chlorambucil; Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)]

   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 (PD) 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).

2. Percentage of Participants With Progression Free Survival Events [Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)]

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

Secondary Outcome Measures

1. Progression Free Survival Based on Independent Review Committee (IRC) Data [Randomization to clinical cutoff date of 9 May 2013 (median observation 22.8 months)]

   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).

2. Percentage of Participants With Progression Free Survival Events Based on Independent Review Committee (IRC) Data [Randomization to clinical cutoff date of 9 May 2013 (median observation 22.8 months)]

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

3. Percentage of Participants With End of Treatment Response (EOTR) [Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)]

   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.

4. Percentage of Participants With Best Overall Response [Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)]

   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.

5. Event Free Survival [Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)]

   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 as per IWCLL criteria 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).

6. Overall Survival [Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)]

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

7. Duration of Response [Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)]

   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.

8. Percentage of Participants With Molecular Remission at the End of Treatment [Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)]

   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 chronic lymphocytic leukemia (CLL) cell in 10000 leukocytes (MRD value < 0.0001) based on the method of allele specific polymerase chain reaction (ASO-PCR).

9. Time to Re-Treatment/New-antileukemic Therapy [Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)]

   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.

10. Pharmacokinetics of Obinutuzumab (RO5072759) in Combination With Chlorambucil (Clb) [Pre- and post-dose sampling on day 1 of cycles 1-6 (Up to 26.8 months)]

    Blood samples were collected from all patients allocated to the GClb treatment arm pre- and post-dose Day 1 of Cycles 1 to 6 and were sent to a laboratory. The concentration of obinutzumab in serum was determined using a validated enzyme-linked immunosorbent assay (ELISA) and was reported in micrograms/milliliter (μg/mL).

11. European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score [Baseline and Cycle 4 Day 1 (Cy4D1)]

    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.

12. European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score [Baseline and Cycle 4 Day 1 (Cy4D1)]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults >/=18 years

• Documented Cluster of Differentiation Antigen 20 (CD20) + B-Cell Chronic Lymphocytic Lymphoma (B-CLL)

• Previously untreated Chronic Lymphocytic Leukemia (CLL) requiring treatment according to the National Cancer Institute (NCI) criteria

• Total Cumulative Illness Rating Scale (CIRS) > 6 and/or creatinine clearance < 70 ml/min

Exclusion Criteria:

• Prior CLL therapy

• Transformation of CLL to aggressive Non-Hodgkin's Lymphoma (NHL) (Richter's transformation)

• History of other malignancy unless the malignancy has been in remission without treatment for >/=2 years prior to enrolment, and except for carcinoma in situ of the cervix, basal or squamous cell skin cancer, surgically treated low-grade prostate cancer, or ductal carcinoma in situ (DCIS) of the breast treated with lymphectomy alone

• Positive hepatitis serology (HBV, HCV) or positive HIV or Human T Cell Leukemia Virus (HTLV) testing

• Patients with active infection requiring systemic treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		San Diego	California	United States	92123
2		Chicago	Illinois	United States	60637
3		Baltimore	Maryland	United States	21215
4		Green Bay	Wisconsin	United States	54311
5		Waukesha	Wisconsin	United States	53188
6		Buenos Aires		Argentina	1406
7		Buenos Aires		Argentina	1425
8		Buenos Aires		Argentina	C1114AAN
9		Buenos Aires		Argentina	C1180AAX
10		Buenos Aires		Argentina	C1221ADC
11		Buenos Aires		Argentina	C1431FWO
12		Rosario		Argentina	2000
13		Adelaide	New South Wales	Australia	5011
14		Gosford	New South Wales	Australia	2250
15		Kogarah	New South Wales	Australia	2217
16		Liverpool	New South Wales	Australia	2170
17		St. Leonards	New South Wales	Australia	2065
18		Sydney	New South Wales	Australia	2139
19		Greenslopes	Queensland	Australia	4120
20		Southport	Queensland	Australia	4215
21		Woolloongabba	Queensland	Australia	4102
22		Kurralta Park	South Australia	Australia	5037
23		Frankston	Victoria	Australia	3199
24		Melbourne	Victoria	Australia	3168
25		Graz		Austria	8036
26		Innsbruck		Austria	6020
27		Wien		Austria	1090
28		Wien		Austria	1160
29		Goiania	GO	Brazil	74140-050
30		Belo Horizonte	MG	Brazil	31270-901
31		Porto Alegre	RS	Brazil	90880-480
32		Santo Andre	SP	Brazil	09060-650
33		Sao Paulo	SP	Brazil	05403-000
34		Pleven		Bulgaria	5800
35		Plovdiv		Bulgaria	4002
36		Sofia		Bulgaria	1756
37		Varna		Bulgaria	9010
38		Vratsa		Bulgaria	3000
39		Calgary	Alberta	Canada	T2N 4N2
40		Edmonton	Alberta	Canada	T6G 1Z2
41		Winnipeg	Manitoba	Canada	R0C 2Z0
42		Halifax	Nova Scotia	Canada	B3H 2Y9
43		Barrie	Ontario	Canada	L4M 6M2
44		Ottawa	Ontario	Canada	K1H 8L6
45		Montreal	Quebec	Canada	H2L 4M1
46		Rimouski	Quebec	Canada	G5L 5T1
47		Zagreb		Croatia	10000
48		Brno		Czechia	625 00
49		Hradec Kralove		Czechia	500 05
50		Praha 2		Czechia	128 08
51		Aalborg		Denmark	9000
52		København		Denmark	2100
53		Odense		Denmark	5000
54		Vejle		Denmark	7100
55		Århus		Denmark	8000
56		Cairo		Egypt	11796
57		Tallinn		Estonia	13419
58		Tartu		Estonia	51014
59		Angers		France	49933
60		Bobigny		France	93009
61		Caen		France	14076
62		Clermont Ferrand		France	63003
63		Creteil		France	94010
64		Le Mans		France	72015
65		Lille		France	59037
66		Lyon		France	69373
67		Marseille		France	13273
68		Montpellier		France	34295
69		Nantes		France	44093
70		Paris		France	75475
71		Paris		France	75651
72		Pessac		France	33604
73		Pierre Benite		France	69495
74		Poitiers		France	86021
75		Reims		France	51092
76		Rennes		France	35033
77		Rouen		France	76038
78		Toulouse		France	31059
79		Tours		France	37044
80		Vandoeuvre Les Nancy		France	54511
81		Ahaus		Germany	48683
82		Amberg		Germany	92224
83		Ansbach		Germany	91522
84		Bamberg		Germany	96049
85		Berlin		Germany	12200
86		Bonn		Germany	53113
87		Bremen		Germany	28177
88		Bremen		Germany	28209
89		Bremen		Germany	28239
90		Delitzsch		Germany	04509
91		Detmold		Germany	32756
92		Dresden		Germany	01127
93		Dresden		Germany	01307
94		Duisburg		Germany	47051
95		Erlangen		Germany	91052
96		Erlangen		Germany	91054
97		Eschweiler		Germany	52249
98		Essen		Germany	45122
99		Essen		Germany	45239
100		Esslingen		Germany	73730
101		Frankfurt am Main		Germany	60389
102		Frankfurt an der Oder		Germany	15236
103		Frankfurt		Germany	60596
104		Frechen		Germany	50226
105		Freiburg		Germany	79106
106		Giessen		Germany
107		Greifswald		Germany	17475
108		Göttingen		Germany	37075
109		Hamburg		Germany	20095
110		Hamburg		Germany	20099
111		Hamburg		Germany	20246
112		Hamburg		Germany	22081
113		Hamburg		Germany	22087
114		Hamburg		Germany	22767
115		Hamm		Germany	59063
116		Hannover		Germany	30449
117		Heidelberg		Germany	69120
118		Homburg/Saar		Germany	66241
119		Kaiserslautern		Germany	67655
120		Karlsruhe		Germany	76133
121		Kempten		Germany	87439
122		Kiel		Germany	24116
123		Koblenz		Germany	56068
124		Koeln		Germany	50674
125		Kronach		Germany	96317
126		Köln		Germany	50924
127		Landshut		Germany	84028
128		Lebach		Germany	66822
129		Leer		Germany	26789
130		Lemgo		Germany	32657
131		Lörrach		Germany	79539
132		Lüdenscheid		Germany	58515
133		Magedburg		Germany	39104
134		Mainz		Germany	55131
135		Mannheim		Germany	68161
136		Muenchen		Germany	81377
137		Mutlangen		Germany	73557
138		München		Germany	80335
139		München		Germany	81241
140		München		Germany	81479
141		München		Germany	81675
142		Neunkirchen/Saar		Germany	66538
143		Nürnberg		Germany	90449
144		Oldenburg		Germany	26121
145		Porta Westfalica		Germany	32457
146		Ravensburg		Germany	88212
147		Recklinghausen		Germany	45657
148		Regensburg		Germany	93049
149		Regensburg		Germany	93053
150		Rostock		Germany	18057
151		Rüsselsheim		Germany	65428
152		Saarbruecken		Germany	66113
153		Sindelfingen		Germany	71065
154		Stuttgart		Germany	70199
155		Trier		Germany	54290
156		Tübingen		Germany	72076
157		Ulm		Germany	89081
158		Villingen-Schwenningen		Germany	78052
159		Weilheim		Germany	82362
160		Wendlingen		Germany	73240
161		Witten		Germany	58452
162		Worms		Germany	67547
163		Wuerzburg		Germany	97080
164		Würzburg		Germany	97080
165		Hong Kong		Hong Kong
166		Cagliari		Italy	09121
167		Cosenza		Italy	87100
168		Ferrara		Italy	44100
169		Genova		Italy	16132
170		Messina		Italy	98165
171		Milano		Italy	20132
172		Milano		Italy	20162
173		Modena		Italy	41100
174		Orbassano		Italy	10043
175		Roma		Italy	00144
176		Roma		Italy	00161
177		Roma		Italy	00168
178		Terni		Italy	05100
179		Torino		Italy	10126
180		Aguascalientes		Mexico	20127
181		Culiacan		Mexico	80230
182		Hermosillo		Mexico	83000
183		Monterrey		Mexico	64460
184		San Luis Potosi		Mexico	78218
185		Delftzijl		Netherlands	9934 JD
186		Enschede		Netherlands	7511 JX
187		Leeuwarden		Netherlands	8934 AD
188		Nieuwegein		Netherlands	3430 EM
189		Auckland		New Zealand	1009
190		Christchurch		New Zealand	8011
191		Bucharest		Romania	022328
192		Bucuresti		Romania	030171
193		Targu-mures		Romania	540136
194		Kazan		Russian Federation	420029
195		Nizhny Novgorod		Russian Federation	603126
196		Penza		Russian Federation	440071
197		Perm		Russian Federation	614077
198		Rostov-na-donu		Russian Federation	344022
199		UFA		Russian Federation	450005
200		Bratislava		Slovakia	833 10
201		Oviedo	Asturias	Spain	33006
202		Manresa	Barcelona	Spain	08240
203		Sabadell	Barcelona	Spain	08208
204		Jerez de La Frontera	Cadiz	Spain	11407
205		Santander	Cantabria	Spain	39008
206		San Sebastian	Guipuzcoa	Spain	20014
207		La Coruna	LA Coruña	Spain	15006
208		Santiago de Compostela	LA Coruña	Spain	15706
209		Pamplona	Navarra	Spain	31008
210		La Laguna	Tenerife	Spain	38320
211		Gandia	Valencia	Spain	46702
212		Barcelona		Spain	08003
213		Barcelona		Spain	08025
214		Barcelona		Spain	08035
215		Barcelona		Spain	08036
216		Jaen		Spain	23007
217		Las Palmas		Spain	35020
218		Madrid		Spain	28006
219		Madrid		Spain	28031
220		Madrid		Spain	28033
221		Madrid		Spain	28034
222		Madrid		Spain	28041
223		Madrid		Spain	28046
224		Madrid		Spain	28222
225		Madrid		Spain	28905
226		Malaga		Spain	29010
227		Malaga		Spain	29600
228		Murcia		Spain	30008
229		Murcia		Spain	30120
230		Salamanca		Spain	37007
231		Sevilla		Spain	41014
232		Toledo		Spain	45004
233		Toledo		Spain	45600
234		Valencia		Spain	46009
235		Valencia		Spain	46010
236		Valencia		Spain	46014
237		Valencia		Spain	46015
238		Valencia		Spain	46017
239		Zaragoza		Spain	50009
240		Aarau		Switzerland	5001
241		Basel		Switzerland	4031
242		Bern		Switzerland	3010
243		Chur		Switzerland	7000
244		Luzern		Switzerland	6000
245		St. Gallen		Switzerland	9007
246		Zürich		Switzerland	8091
247		Bangkok		Thailand	10330
248		Bangkok		Thailand	10400
249		Bangkok		Thailand	10700
250		Khon Kaen		Thailand	40002
251		Bournemouth		United Kingdom	BH7 7DW
252		Cambridge		United Kingdom	CB2 0QQ
253		Canterbury		United Kingdom	CT1 3NG
254		Cardiff		United Kingdom	CF14 4XN
255		Cottingham		United Kingdom	HU16 5JG
256		Edinburgh		United Kingdom	EH4 2XU
257		Glasgow		United Kingdom	G12 0YN
258		Leicester		United Kingdom	LE1 5WW
259		London		United Kingdom	EC1M 6BQ
260		London		United Kingdom	NW3 2QG
261		Nottingham		United Kingdom	NG5 1PB
262		Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

• Hoffmann-La Roche
• German CLL Study Group
• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01010061
• Other Study ID Numbers: BO21004 (Stage 1a); 2009-012476-28; CLL11; NCT02035462
• First Posted: Nov 9, 2009
• Last Update Posted: Sep 14, 2018
• Last Verified: Aug 1, 2018

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Obinutuzumab; Chlorambucil

Study Results

Participant Flow

Recruitment Details	787 patients were enrolled in the study. Following a 6 patient safety run-in prior to randomization, 781 patients were randomized.
Pre-assignment Detail	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 and an additional 192 randomized to GClb or RClb in Stage 2 [NCT02053610]. Stage 1 was divided for analysis into: Stage 1a (GClb vs Clb) n=356 reported here and Stage 1b (RClb vs Clb) [NCT01998880] reported separately.

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Period Title: Overall Study
STARTED	238	118
Received Study Drug	236	116
COMPLETED	190	78
NOT COMPLETED	48	40

Baseline Characteristics

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)	Total
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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 of all reporting groups
Overall Participants	238	118	356
Age, Customized (participants) [Number]
<65 years	42 17.6%	26 22%	68 19.1%
>=65 years	196 82.4%	92 78%	288 80.9%
Sex: Female, Male (Count of Participants)
Female	98 41.2%	43 36.4%	141 39.6%
Male	140 58.8%	75 63.6%	215 60.4%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	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 (PD) 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).
Time Frame	Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Median (95% Confidence Interval) [Months]	31.1	11.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil (GClb), Chlorambucil (Clb)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Type I error controlled through closed test procedure.
	Method	Log Rank, Stratified
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95%; 0.16 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by Binet stage at Baseline.

2. Primary Outcome

Title	Percentage of Participants With Progression Free Survival Events
Description	Percentage of Participants with Progression Free Survival Events: disease progression, relapse, or death.
Time Frame	Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Number [Percentage of participants]	72.7 30.5%	90.7 76.9%

3. Secondary Outcome

Title	Progression Free Survival Based on Independent Review Committee (IRC) Data
Description	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).
Time Frame	Randomization to clinical cutoff date of 9 May 2013 (median observation 22.8 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Median (95% Confidence Interval) [Months]	27.2	11.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil (GClb), Chlorambucil (Clb)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank, Stratified
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; 0.14 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by Binet stage at Baseline.

4. Secondary Outcome

Title	Percentage of Participants With Progression Free Survival Events Based on Independent Review Committee (IRC) Data
Description	Percentage of Participants with Progression Free Survival Events: progression, relapse, or death from any cause as assessed by an Independent Review Committee.
Time Frame	Randomization to clinical cutoff date of 9 May 2013 (median observation 22.8 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Number [Percentage of participants]	37.4 15.7%	76.3 64.7%

5. Secondary Outcome

Title	Percentage of Participants With End of Treatment Response (EOTR)
Description	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.
Time Frame	Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Complete Response (CR)	17.2 7.2%	0.0 0%
Complete Response incomplete (CRi)	4.2 1.8%	0.0 0%
Partial Response (PR)	48.3 20.3%	28.8 24.4%
Nodular Partial Response (nPR)	7.6 3.2%	2.5 2.1%
Stable Disease	5 2.1%	22.9 19.4%
Progressive Disease	4.2 1.8%	28.8 24.4%
No Response Assessment	13.4 5.6%	16.9 14.3%

6. Secondary Outcome

Title	Percentage of Participants With Best Overall Response
Description	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.
Time Frame	Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Complete Response (CR)	26.5 11.1%	0.0 0%
Complete Response incomplete (CRi)	2.5 1.1%	1.7 1.4%
Partial Response (PR)	47.1 19.8%	31.4 26.6%
Nodular Partial Response (nPR)	2.1 0.9%	0 0%
Stable Disease	4.2 1.8%	21.2 18%
Progressive Disease	4.2 1.8%	28.8 24.4%
No Response Assessment	13.4 5.6%	16.9 14.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil (GClb), Chlorambucil (Clb)
	Comments	Includes subjects with best overall response: CR, CRi, PR or nPR.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in Response Rates
	Estimated Value	45.1
	Confidence Interval	(2-Sided) 95%; 34.7 to 55.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Event Free Survival
Description	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 as per IWCLL criteria 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).
Time Frame	Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Median (95% Confidence Interval) [Months]	28.7	10.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil (GClb), Chlorambucil (Clb)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank, Stratified
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; 0.15 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified by Binet stage at Baseline.

8. Secondary Outcome

Title	Overall Survival
Description	Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause.
Time Frame	Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Median (95% Confidence Interval) [Months]	NA	66.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil (GClb), Chlorambucil (Clb)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0196
	Comments
	Method	Log Rank, Stratified
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Duration of Response
Description	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.
Time Frame	Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	191	41
Median (95% Confidence Interval) [Months]	24.8	5.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil (GClb), Chlorambucil (Clb)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank, Stratified
	Comments	Stratified by Binet stage at Baseline.
Method of Estimation	Estimation Parameter	Hazard Ratio (stratified)
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; 0.13 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Participants With Molecular Remission at the End of Treatment
Description	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 chronic lymphocytic leukemia (CLL) cell in 10000 leukocytes (MRD value < 0.0001) based on the method of allele specific polymerase chain reaction (ASO-PCR).
Time Frame	Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	166	90
Number (95% Confidence Interval) [Percentage of participants]	25 10.5%	0 0%

11. Secondary Outcome

Title	Time to Re-Treatment/New-antileukemic Therapy
Description	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.
Time Frame	Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Median (95% Confidence Interval) [Months]	55.7	15.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil (GClb), Chlorambucil (Clb)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank, Stratified
	Comments	Stratified by Binet stage at Baseline.
Method of Estimation	Estimation Parameter	Hazard Ratio (stratified)
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; 0.19 to 0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Pharmacokinetics of Obinutuzumab (RO5072759) in Combination With Chlorambucil (Clb)
Description	Blood samples were collected from all patients allocated to the GClb treatment arm pre- and post-dose Day 1 of Cycles 1 to 6 and were sent to a laboratory. The concentration of obinutzumab in serum was determined using a validated enzyme-linked immunosorbent assay (ELISA) and was reported in micrograms/milliliter (μg/mL).
Time Frame	Pre- and post-dose sampling on day 1 of cycles 1-6 (Up to 26.8 months)

Outcome Measure Data

Analysis Population Description

PK population includes all participants with PK data available at the given time-point.

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).
Measure Participants	220
Post-dose Cycle 1 (n=201)	247 (41.6)
Pre-dose Cycle 2 (n=198)	227 (57.9)
Post-dose Cycle 2 (n=197)	587 (36.5)
Pre-dose Cycle 3 (n=193)	165 (68.7)
Post-dose Cycle 3 (n=192)	527 (39.7)
Pre-dose Cycle 4 (n=191)	156 (74.3)
Post-dose Cycle 4 (n=189)	535 (41.0)
Pre-dose Cycle 5 (n=185)	163 (72.4)
Post-dose Cycle 5 (n=181)	534 (39.1)
Pre-dose Cycle 6 (n=185)	181 (69.0)
Post-dose Cycle 6 (n=183)	525 (39.6)

13. Secondary Outcome

Title	European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score
Description	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.
Time Frame	Baseline and Cycle 4 Day 1 (Cy4D1)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Appetite Loss Scale: Baseline (n=226, 111)	18.1 (28.46)	19.8 (29.26)
Appetite Loss Scale: Cy4D1 (n=189, 92)	10.2 (21.77)	14.5 (24.36)
Cognitive Functioning Scale: Baseline (n=227, 111)	80.6 (21.35)	81.8 (22.76)
Cognitive Functioning Scale:Cy4D1 (n=190,93)	83.9 (20.31)	85.8 (18.54)
Constipation Scale: Baseline (n=225, 111)	14.8 (23.94)	16.8 (26.92)
Constipation Scale: Cy4D1 (n=188, 93)	15.1 (25.16)	12.5 (23.53)
Diarrhoea Scale: Baseline (n=226, 110)	9.3 (20.05)	8.8 (18.98)
Diarrhoea Scale: Cy4D1 (n=189, 93)	9.3 (19.47)	6.5 (14.95)
Dyspnoea Scale: Baseline (n=225, 109)	27.1 (29.89)	23.9 (27.63)
Dyspnoea: Cy4D1 (n=189, 91)	15.9 (23.71)	22.3 (26.78)
Emotional Functioning Scale: Baseline (n=226, 111)	73.8 (23.45)	72.9 (25.7)
Emotional Functioning Scale: Cy4D1(n=190,93)	82.5 (18.62)	80.6 (18.48)
Fatigue Scale: Baseline (n=226, 111)	38 (25.72)	36.9 (27.01)
Fatigue Scale: Cy4D1(n=189, 93)	29.2 (20.39)	30.8 (23.00)
Financial Difficulties Scale: Baseline (n=224,110)	8.9 (20.69)	13.6 (25.26)
Financial Difficulty Scale: Cy4D1(n=189,93)	7.4 (17.64)	9.3 (19.88)
Nausea, Vomiting Scale: Baseline (n=227, 111)	5 (11.18)	7.4 (18.49)
Nausea, Vomiting Scale: Cy4D1 (n=189,93)	5.5 (11.51)	7.5 (17.81)
Pain scale: Baseline (n=228, 111)	22.9 (27.57)	21.5 (25.66)
Pain scale: Cy4D1 (n=190, 93)	17.9 (24.09)	17.7 (25.98)
Physical Functioning Scale: Baseline (n=228, 111)	73.7 (19.86)	77.3 (18.87)
Physical Functioning Scale: Cy4D1(n=189,93)	78.6 (18.71)	80.9 (16.24)
Global Health Status Scale: Baseline (n=226, 111)	58.4 (22.8)	57.4 (22.9)
Global Health Status Scale: Cy4D1(n=189,93)	66.7 (20.03)	63.4 (20.56)
Role Functioning Scale: Baseline(n=227,110)	76.1 (26.18)	74.7 (28.35)
Role Functioning Scale: Cy4D1(n=189,93)	79.7 (23.64)	81.5 (21.35)
Social Functioning Scale:Baseline(n=226,110)	86.3 (22.52)	83.3 (25.34)
Social Functioning Scale: Cy4D1(n=190,93)	87.8 (19.97)	85.5 (19.38)
Insomnia Scale: Baseline (n=228,111)	29.4 (31.12)	31.5 (32.98)
Insomnia Scale: Cy4D1(n=189,93)	20.6 (27.13)	24.4 (29.13)

14. Secondary Outcome

Title	European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score
Description	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.
Time Frame	Baseline and Cycle 4 Day 1 (Cy4D1)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)	Chlorambucil (Clb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).	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.
Measure Participants	238	118
Disease Effects Scale: Baseline (n=209, 102)	23 (18.89)	23.7 (20.18)
Disease Effects Scale: Cy4D1 (n=176, 86)	15.0 (15.12)	15.9 (14.16)
Fatigue Scale: Baseline (n=209, 102)	31.2 (25.83)	27.6 (24.65)
Fatigue Scale: Cy4D1 (n=176, 86)	20.9 (21.51)	23.4 (22.20)
Future Health: Baseline (n=206, 101)	47.7 (32.14)	50.8 (33.53)
Future Health: Cy4D1 (n=175, 86)	29.5 (31.74)	39.1 (30.33)
Infection Scale: Baseline (n=209, 102)	12 (15.91)	14.6 (17.97)
Infection Scale: Cy4D1 (n=176, 86)	8.9 (11.65)	8.5 (10.70)
Social Problems: Baseline (n=206, 100)	24.3 (31.99)	26.3 (33.26)
Social Problems: Cy4D1 (n=175, 85)	19.4 (27.75)	22.0 (27.00)
Treatment Side Effects Scale: Baseline (n=209,102)	19.8 (17.7)	17.2 (15.27)
Treatment Side Effect Scale: Cy4D1(n=176,86)	14.7 (14.68)	15.6 (16.11)

Adverse Events

Time Frame	Randomization to clinical cutoff (median observation 42 months)
Adverse Event Reporting Description	Safety population included patients who received at least 1 dose of study drug. Adverse Events are reported for Stage 1a (GClb and Clb arms). In Stage 1a, 4 patients randomized to the RClb arm actually received obinutuzumab and were included in the GClb arm for analysis.
Arm/Group Title	Obinutuzumab + Chlorambucil (GClb)		Chlorambucil (Clb)		Crossover Subjects: Obinutuzumab + Chlorambucil (GClb)
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in 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).		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.		Subjects in Clb arm who progressed during/within 6 months after end of Clb treatment had opportunity to cross over to GClb arm at discretion of investigator. Subjects received 1000 mg obinutuzumab IV infusion, on Day 1 [First infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 milligram per kilogram of body weight (mg/kg) orally on Day 1 and 15 of each 28-day cycle (6 Cycles).
All Cause Mortality
	Obinutuzumab + Chlorambucil (GClb)		Chlorambucil (Clb)		Crossover Subjects: Obinutuzumab + Chlorambucil (GClb)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Obinutuzumab + Chlorambucil (GClb)		Chlorambucil (Clb)		Crossover Subjects: Obinutuzumab + Chlorambucil (GClb)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	113/241 (46.9%)		45/116 (38.8%)		8/30 (26.7%)
Blood and lymphatic system disorders
Febrile neutropenia	2/241 (0.8%)		5/116 (4.3%)		1/30 (3.3%)
Anaemia	3/241 (1.2%)		0/116 (0%)		0/30 (0%)
Autoimmune haemolytic anaemia	1/241 (0.4%)		2/116 (1.7%)		0/30 (0%)
Neutropenia	3/241 (1.2%)		0/116 (0%)		0/30 (0%)
Thrombocytopenia	2/241 (0.8%)		0/116 (0%)		0/30 (0%)
Haemolysis	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Haemolytic anaemia	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Immune thrombocytopenic purpura	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Pancytopenia	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Cardiac disorders
Myocardial infarction	4/241 (1.7%)		2/116 (1.7%)		0/30 (0%)
Cardiac failure	3/241 (1.2%)		2/116 (1.7%)		0/30 (0%)
Atrial fibrillation	2/241 (0.8%)		0/116 (0%)		0/30 (0%)
Acute coronary syndrome	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Atrial thrombosis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Cardiac failure congestive	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Nodal rhythm	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Tachyarrhythmia	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Congenital, familial and genetic disorders
Hereditary non-polyposis colorectal cancer syndrome	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Phimosis	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Gastrointestinal disorders
Diarrhoea	2/241 (0.8%)		0/116 (0%)		0/30 (0%)
Abdominal pain	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Ascites	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Colitis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Enterocolitis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Gastritis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Inguinal hernia	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Pancreatitis	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Pancreatitis acute	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Thrombosis mesenteric vessel	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Ileus	0/241 (0%)		0/116 (0%)		1/30 (3.3%)
General disorders
Chest pain	1/241 (0.4%)		1/116 (0.9%)		0/30 (0%)
Asthenia	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Death	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Fatigue	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
General physical health deterioration	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Impaired healing	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Malaise	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Pyrexia	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Hepatobiliary disorders
Biliary colic	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Cholecystitis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Cholelithiasis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Liver disorder	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Immune system disorders
Anaphylactic reaction	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Infections and infestations
Pneumonia	10/241 (4.1%)		4/116 (3.4%)		1/30 (3.3%)
Respiratory tract infection	2/241 (0.8%)		3/116 (2.6%)		0/30 (0%)
Septic shock	2/241 (0.8%)		2/116 (1.7%)		0/30 (0%)
Urinary tract infection	3/241 (1.2%)		1/116 (0.9%)		0/30 (0%)
Erysipelas	1/241 (0.4%)		2/116 (1.7%)		0/30 (0%)
Lower respiratory tract infection	2/241 (0.8%)		1/116 (0.9%)		0/30 (0%)
Neutropenic sepsis	3/241 (1.2%)		0/116 (0%)		0/30 (0%)
Sepsis	0/241 (0%)		4/116 (3.4%)		1/30 (3.3%)
Infection	1/241 (0.4%)		1/116 (0.9%)		0/30 (0%)
Liver abscess	1/241 (0.4%)		1/116 (0.9%)		0/30 (0%)
Upper respiratory tract infection	1/241 (0.4%)		1/116 (0.9%)		0/30 (0%)
Bronchitis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Cellulitis	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Dacryocystitis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Diverticulitis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Endocarditis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Epididymitis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Escherichia sepsis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Gangrene	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Infective exacerbation of bronchiectasis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Intervertebral discitis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Lung infection	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Neutropenic infection	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Ophthalmic herpes zoster	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Oral candidiasis	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Staphylococcal sepsis	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Stenotrophomonas sepsis	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Subcutaneous abscess	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Superinfection bacterial	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Wound infection	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Gastroenteritis	0/241 (0%)		0/116 (0%)		1/30 (3.3%)
Injury, poisoning and procedural complications
Infusion related reaction	27/241 (11.2%)		0/116 (0%)		0/30 (0%)
Tibia fracture	2/241 (0.8%)		0/116 (0%)		0/30 (0%)
Femoral neck fracture	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Fracture displacement	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Spinal fracture	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Subdural haematoma	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Subdural haemorrhage	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Tendon rupture	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Radius Fracture	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Investigations
Platelet count decreased	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Metabolism and nutrition disorders
Tumour lysis syndrome	3/241 (1.2%)		0/116 (0%)		0/30 (0%)
Dehydration	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Hyperglycaemia	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Musculoskeletal chest pain	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Spinal column stenosis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	7/241 (2.9%)		0/116 (0%)		1/30 (3.3%)
Squamous cell carcinoma of skin	6/241 (2.5%)		0/116 (0%)		0/30 (0%)
Lung adenocarcinoma	1/241 (0.4%)		1/116 (0.9%)		0/30 (0%)
Malignant melanoma	2/241 (0.8%)		0/116 (0%)		0/30 (0%)
Pancreatic carcinoma	1/241 (0.4%)		1/116 (0.9%)		0/30 (0%)
Plasma cell myeloma	1/241 (0.4%)		1/116 (0.9%)		0/30 (0%)
Prostate cancer	1/241 (0.4%)		1/116 (0.9%)		0/30 (0%)
Squamous cell carcinoma	3/241 (1.2%)		1/116 (0.9%)		0/30 (0%)
Adenocarcinoma gastric	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Adenocarcinoma of colon	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Choroid melanoma	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Colon cancer	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Gastrointestinal stromal tumour	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Hepatocellular carcinoma	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Intraocular melanoma	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Keratoacanthoma	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Myelodysplastic syndrome	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Non-small cell lung cancer	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Rectal adenocarcinoma	2/241 (0.8%)		0/116 (0%)		0/30 (0%)
Rectal cancer	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Renal cell carcinoma	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Schwannoma	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Squamous cell carcinoma of lung	2/241 (0.8%)		0/116 (0%)		0/30 (0%)
Superficial spreading melanoma stage unspecified	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Basosquamous Carcinoma of Skin	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Cholangiocarcinoma	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Gastric Cancer	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Skin Cancer	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Bowen's disease	0/241 (0%)		0/116 (0%)		1/30 (3.3%)
Lung Neoplasm	0/241 (0%)		0/116 (0%)		1/30 (3.3%)
Metastatic neoplasm	0/241 (0%)		0/116 (0%)		1/30 (3.3%)
Nervous system disorders
Cerebrovascular accident	3/241 (1.2%)		0/116 (0%)		0/30 (0%)
Syncope	1/241 (0.4%)		1/116 (0.9%)		0/30 (0%)
Central nervous system haemorrhage	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Cerebral haemorrhage	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Haemorrhage intracranial	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Metabolic encephalopathy	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Major depression	0/241 (0%)		0/116 (0%)		1/30 (3.3%)
Renal and urinary disorders
Cystitis haemorrhagic	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Haematuria	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Renal failure	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Reproductive system and breast disorders
Prostatic obstruction	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Testicular hypertrophy	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	2/241 (0.8%)		0/116 (0%)		0/30 (0%)
Pulmonary embolism	2/241 (0.8%)		0/116 (0%)		0/30 (0%)
Chronic obstructive pulmonary disease	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Pneumonitis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Pulmonary oedema	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Respiratory failure	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Skin and subcutaneous tissue disorders
Dermatitis atopic	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Rash maculo-papular	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Surgical and medical procedures
Fracture treatment	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Vascular disorders
Deep vein thrombosis	1/241 (0.4%)		1/116 (0.9%)		0/30 (0%)
Aortic stenosis	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Capillary leak syndrome	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Diabetic macroangiopathy	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Dry gangrene	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Orthostatic hypotension	0/241 (0%)		1/116 (0.9%)		0/30 (0%)
Peripheral artery thrombosis	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Thrombophlebitis superficial	1/241 (0.4%)		0/116 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Obinutuzumab + Chlorambucil (GClb)		Chlorambucil (Clb)		Crossover Subjects: Obinutuzumab + Chlorambucil (GClb)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	215/241 (89.2%)		89/116 (76.7%)		23/30 (76.7%)
Blood and lymphatic system disorders
Neutropenia	99/241 (41.1%)		21/116 (18.1%)		12/30 (40%)
Thrombocytopenia	36/241 (14.9%)		9/116 (7.8%)		7/30 (23.3%)
Anaemia	27/241 (11.2%)		12/116 (10.3%)		3/30 (10%)
Leukopenia	17/241 (7.1%)		0/116 (0%)		5/30 (16.7%)
Gastrointestinal disorders
Nausea	32/241 (13.3%)		29/116 (25%)		3/30 (10%)
Diarrhoea	23/241 (9.5%)		13/116 (11.2%)		3/30 (10%)
Constipation	17/241 (7.1%)		12/116 (10.3%)		2/30 (6.7%)
Vomiting	13/241 (5.4%)		14/116 (12.1%)		0/30 (0%)
General disorders
Pyrexia	25/241 (10.4%)		8/116 (6.9%)		2/30 (6.7%)
Fatigue	16/241 (6.6%)		12/116 (10.3%)		1/30 (3.3%)
Asthenia	17/241 (7.1%)		8/116 (6.9%)		1/30 (3.3%)
Infections and infestations
Bronchitis	10/241 (4.1%)		8/116 (6.9%)		1/30 (3.3%)
Urinary tract infection	14/241 (5.8%)		2/116 (1.7%)		0/30 (0%)
Viral Upper Respiratory Tract Infections	14/241 (5.8%)		6/116 (5.2%)		0/30 (0%)
Herpes Zoster	0/241 (0%)		0/116 (0%)		2/30 (6.7%)
Injury, poisoning and procedural complications
Infusion related reaction	147/241 (61%)		0/116 (0%)		15/30 (50%)
Metabolism and nutrition disorders
Decreased appetite	8/241 (3.3%)		9/116 (7.8%)		2/30 (6.7%)
Nervous system disorders
Headache	19/241 (7.9%)		8/116 (6.9%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	22/241 (9.1%)		8/116 (6.9%)		4/30 (13.3%)
Dyspnoea	5/241 (2.1%)		8/116 (6.9%)		2/30 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.