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CLL11: A Study of Obinutuzumab (RO5072759 [GA101]) With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 2)

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT02053610
Collaborator
German CLL Study Group (Other), Genentech, Inc. (Industry)
787
Enrollment
262
Locations
3
Arms
91.7
Actual Duration (Months)
3
Patients Per Site
0
Patients Per Site Per Month

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/m2 cycle 1, 500 mg/m2 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
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 separately.

  • 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) includes the analysis of 2 of the 3 arms obinutuzumab plus chlorambucil (Glb) compared to rituximab plus chlorambucil (RClb) reported here.

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 31, 2009
Actual Primary Completion Date :
Aug 31, 2013
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®
  • Gazyvaro

    • 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 (median observation 59.4 months)]

      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).

    2. Percentage of Participants With Progression Free Survival Events [Randomization to clinical cutoff (median observation 59.4 months)]

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

    Secondary Outcome Measures

    1. Progression Free Survival Based on Independent Review Committee (IRC) Data [Randomization to clinical cutoff of 09 May 2013 (median observation 18.7 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 of 09 May 2013 (median observation 18.7 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 (median observation 59.4 months)]

      EOTR was the first response assessment 56 days from the last dose according to the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) guidelines. Complete Response (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. Partial Response (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 (median observation 59.4 months)]

      Best overall response according to IWCLL guidelines was defined as the percentage of patients with CR, CRi, PR or nodular Partial Response (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 (median observation 59.4 months)]

      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 (median observation 59.4 months)]

      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 (median observation 59.4 months)]

      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 (median observation 59.4 months)]

      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 Anti-leukemic Therapy [Randomization to clinical cutoff (median observation 59.4 months)]

      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. European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire [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.

    11. European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire [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 lumpectomy 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 Cosenza Calabria Italy 87100
    167 Ferrara Emilia-Romagna Italy 44100
    168 Modena Emilia-Romagna Italy 41100
    169 Roma Lazio Italy 00144
    170 Roma Lazio Italy 00161
    171 Roma Lazio Italy 00168
    172 Genova Liguria Italy 16132
    173 Milano Lombardia Italy 20132
    174 Milano Lombardia Italy 20162
    175 Orbassano Piemonte Italy 10043
    176 Torino Piemonte Italy 10126
    177 Cagliari Sardegna Italy 09121
    178 Messina Sicilia Italy 98165
    179 Terni Umbria Italy 05100
    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:
    NCT02053610
    Other Study ID Numbers:
    • BO21004 (Stage 2)
    • 2009-012476-28; CLL1
    First Posted:
    Feb 3, 2014
    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. Stage 1 was divided for analysis into: Stage 1a [NCT01010061] and Stage 1b [NCT01998880]. 663 participants were included in the Stage 2 Analysis reported here.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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).
    Period Title: Overall Study
    STARTED 330 333
    Received Study Drug 326 331
    COMPLETED 288 266
    NOT COMPLETED 42 67

    Baseline Characteristics

    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb) Total
    Arm/Group Description 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). 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). Total of all reporting groups
    Overall Participants 330 333 663
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    71.5
    (8.82)
    71.9
    (8.68)
    71.7
    (8.75)
    Sex: Female, Male (Count of Participants)
    Female
    126
    38.2%
    130
    39%
    256
    38.6%
    Male
    204
    61.8%
    203
    61%
    407
    61.4%

    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 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 (median observation 59.4 months)

    Outcome Measure Data

    Analysis Population Description
    Intent--to-treat population (ITT) included all randomized participants. Data for patients without disease progression or death was censored at the time of the last response assessment, or, if no response assessments were performed after the baseline visit, at the time of randomization plus one day.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Median (95% Confidence Interval) [months]
    15.7
    28.9
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rituximab + Chlorambucil (RClb), Obinutuzumab + Chlorambucil (GClb)
    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 (HR)
    Estimated Value 0.49
    Confidence Interval (2-Sided) 95%
    0.41 to 0.58
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title Percentage of Participants With Progression Free Survival Events
    Description Percentage of Participants with Progression Free Survival Events: progression, relapse, or death.
    Time Frame Randomization to clinical cutoff (median observation 59.4 months)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized participants.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Number [percentage of participants]
    88.5
    26.8%
    73.3
    22%
    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 of 09 May 2013 (median observation 18.7 months)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat population (ITT) included all randomized participants. Data for patients without disease progression or death was censored at the time of the last response assessment, or, if no response assessments were performed after the baseline visit, at the time of randomization plus one day.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Median (95% Confidence Interval) [months]
    14.9
    26.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rituximab + Chlorambucil (RClb), Obinutuzumab + Chlorambucil (GClb)
    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 (HR)
    Estimated Value 0.42
    Confidence Interval (2-Sided) 95%
    0.33 to 0.54
    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 of 09 May 2013 (median observation 18.7 months)

    Outcome Measure Data

    Analysis Population Description
    ITT participants included all randomized participants.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Number [percentage of participants]
    55.5
    16.8%
    30.9
    9.3%
    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. Complete Response (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. Partial Response (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 (median observation 59.4 months)

    Outcome Measure Data

    Analysis Population Description
    Participants from the ITT population, all randomized participants, with data available for analysis. Participants who had not reached the 3-month follow-up visit at the time of the clinical cut-off were excluded from analysis.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Complete Response (CR)
    4.8
    1.5%
    15.6
    4.7%
    Complete Response incomplete (CRi)
    1.5
    0.5%
    3.6
    1.1%
    Partial Response (PR)
    53.9
    16.3%
    52.0
    15.6%
    Nodular Partial Response (nPR)
    5.2
    1.6%
    7.5
    2.3%
    Stable Disease
    15.2
    4.6%
    4.5
    1.4%
    Progressive Disease
    11.2
    3.4%
    4.5
    1.4%
    No Response Assessment
    8.2
    2.5%
    12.3
    3.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rituximab + Chlorambucil (RClb), Obinutuzumab + Chlorambucil (GClb)
    Comments Includes participants with EOTR: CR, CRi, PR or nPR.
    Type of Statistical Test Superiority or Other
    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 13.22
    Confidence Interval (2-Sided) 95%
    6.3 to 20.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    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 nodular Partial Response (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 (median observation 59.4 months)

    Outcome Measure Data

    Analysis Population Description
    Participants from the ITT population, all randomized participants, with data available for analysis. Participants who had not reached the 3-month follow-up visit at the time of the clinical cut-off were excluded from analysis.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Complete Response (CR)
    7.0
    2.1%
    23.7
    7.1%
    Complete Response incomplete (CRi)
    1.2
    0.4%
    1.8
    0.5%
    Partial Response (PR)
    55.5
    16.8%
    50.8
    15.3%
    Nodular Partial Response (nPR)
    2.7
    0.8%
    3.0
    0.9%
    Stable Disease
    14.5
    4.4%
    3.9
    1.2%
    Progressive Disease
    11.5
    3.5%
    4.5
    1.4%
    No Response Assessment
    7.6
    2.3%
    12.3
    3.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rituximab + Chlorambucil (RClb), Obinutuzumab + Chlorambucil (GClb)
    Comments Includes participants with best overall response: CR, CRi, PR or nPR.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Difference in Response Rates
    Estimated Value 12.92
    Confidence Interval (2-Sided) 95%
    6.1 to 19.8
    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 (median observation 59.4 months)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized participants. Participants were censored at the date of last tumor assessment. In cases where no tumor assessment is available, participants were censored at the date of randomization plus one day.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Median (95% Confidence Interval) [months]
    15
    26.5
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rituximab + Chlorambucil (RClb), Obinutuzumab + Chlorambucil (GClb)
    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 (HR)
    Estimated Value 0.51
    Confidence Interval (2-Sided) 95%
    0.43 to 0.61
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    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 (median observation 59.4 months)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized participants. Participants who were not reported as having died at the time of the analysis were censored at the date when they were last known to be alive.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Median (95% Confidence Interval) [months]
    73.1
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rituximab + Chlorambucil (RClb), Obinutuzumab + Chlorambucil (GClb)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0245
    Comments
    Method Log Rank, Stratified
    Comments Stratified by Binet stage at Baseline.
    Method of Estimation Estimation Parameter Hazard Ratio (stratified)
    Estimated Value 0.76
    Confidence Interval (2-Sided) 95%
    0.60 to 0.97
    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 (median observation 59.4 months)

    Outcome Measure Data

    Analysis Population Description
    Participants from the ITT population, all randomized participants, with response.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 220 271
    Median (95% Confidence Interval) [months]
    11.8
    23.8
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rituximab + Chlorambucil (RClb), Obinutuzumab + Chlorambucil (GClb)
    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 (HR)
    Estimated Value 0.50
    Confidence Interval (2-Sided) 95%
    0.41 to 0.61
    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 (median observation 59.4 months)

    Outcome Measure Data

    Analysis Population Description
    Participants from the ITT population, all randomized participants, with data available for analysis. Participants who had not reached the 3-month follow-up visit at the time of the clinical cut-off were excluded from analysis.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 246 237
    Number (95% Confidence Interval) [percentage of participants]
    2
    0.6%
    24
    7.2%
    11. Secondary Outcome
    Title Time to Re-Treatment/New Anti-leukemic 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 (median observation 59.4 months)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized participants. Participants who were reported as not having started re-treatment or new anti-leukemic therapy were censored at the last visit date they were assessed with regard to start of new treatment or the date of death.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Median (95% Confidence Interval) [months]
    34.9
    56.4
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rituximab + Chlorambucil (RClb), Obinutuzumab + Chlorambucil (GClb)
    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 0.58
    Confidence Interval (2-Sided) 95%
    0.46 to 0.73
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire
    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 category.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Appetite Loss Scale: Baseline (n=314, 312)
    15.4
    (26.02)
    19
    (29.37)
    Appetite Loss Scale: Cy4D1 (n=277, 258)
    12
    (23.22)
    10.9
    (21.47)
    Cognitive Functioning Scale: Baseline(n=312, 315)
    83.0
    (20.02)
    80.4
    (22.52)
    Cognitive Functioning Scale: Cy4D1 (n=277, 259)
    83.6
    (17.26)
    83.9
    (20.25)
    Constipation Scale: Baseline (n=311, 312)
    15.2
    (24.62)
    14.9
    (23.54)
    Constipation Scale: Cy4D1 (n=276,257)
    14.3
    (23.05)
    15.3
    (25.16)
    Diarrhoea Scale: Baseline (n=311,313)
    8.4
    (18.78)
    9.5
    (19.58)
    Diarrhoea Scale: Cy4D1 (n=276,257)
    8.8
    (19.66)
    9.2
    (20.32)
    Dyspnoea Scale: Baseline (n=312,312)
    27.5
    (28.62)
    27.8
    (29.97)
    Dyspnoea: Cy4D1 (n=277,257)
    20.8
    (26.69)
    16.5
    (23.75)
    Emotional Functioning Scale: Baseline (n=312,314)
    77.1
    (21.32)
    73.9
    (23.14)
    Emotional Functioning Scale: Cy4D1 (n=277,259)
    82.7
    (18.29)
    82.5
    (19.18)
    Fatigue Scale: Baseline (n=313,312)
    36.9
    (25.86)
    38.5
    (26.05)
    Fatigue Scale: Cy4D1 (n=278,258)
    30.4
    (22.32)
    29.8
    (21.43)
    Financial Difficulties Scale: Baseline (n=309,312)
    10.5
    (21.53)
    10.5
    (22.14)
    Financial Difficulties Scale: Cy4D1(n=273,258)
    9.6
    (20.02)
    8.4
    (19.35)
    Nausea, Vomiting Scale: Baseline (n=313,315)
    4.5
    (12.66)
    5.3
    (12.9)
    Nausea, Vomiting Scale: Cy4D1 (n=278,258)
    4.1
    (10.18)
    5.2
    (10.96)
    Pain scale: Baseline (n=313,316)
    22.5
    (27.59)
    22.9
    (27.73)
    Pain scale: Cy4D1 (n=278,259)
    15.6
    (22.48)
    18.1
    (24.60)
    Physical Functioning Scale: Baseline (n=313,316)
    75.8
    (19.34)
    73.3
    (20.77)
    Physical Functioning Scale: Cy4D1 (n=278,258)
    77.8
    (18.5)
    78.5
    (18.90)
    Global Health Status Scale: Baseline (n=310,313)
    58.1
    (22.74)
    58.0
    (23.81)
    Global Health Status Scale: Cy4D1 (n=275,256)
    65.8
    (20.22)
    66.7
    (20.27)
    Role Functioning Scale: Baseline (n=313,315)
    76.4
    (28.68)
    74.3
    (27.62)
    Role Functioning Scale: Cy4D1 (n=277,258)
    79.9
    (25.4)
    78.7
    (24.56)
    Social Functioning Scale: Baseline (n=312,314)
    82.9
    (23.81)
    83.7
    (24.96)
    Social Functioning Scale: Cy4D1(n=276,259)
    85.4
    (21)
    86.6
    (20.71)
    Insomnia: Baseline (n=312,316)
    25.6
    (30.91)
    29.9
    (31.18)
    Insomnia: Cy4D1(n=276,258)
    20.9
    (26.71)
    21.6
    (27.97)
    13. Secondary Outcome
    Title European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire
    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 category.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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 330 333
    Disease Effects Scale: Baseline (n=276,284)
    22.8
    (17.94)
    22.7
    (18.49)
    Disease Effects Scale: Cy4D1 (n=243, 233)
    15.4
    (15)
    14.7
    (15.34)
    Fatigue Scale: Baseline (n=276, 284)
    27.7
    (23.48)
    31.1
    (25.32)
    Fatigue Scale: Cy4D1 (n=243, 233)
    21
    (20.52)
    20.6
    (20.82)
    Future Health: Baseline (n=275, 280)
    47.5
    (32.17)
    49.8
    (32.79)
    Future Health: Cy4D1 (n=240, 231)
    33.9
    (29.72)
    30.3
    (31.17)
    Infection Scale: Baseline (n=275, 284)
    11.8
    (15.83)
    12.7
    (16.67)
    Infection Scale: Cy4D1 (n=243, 233)
    9.4
    (13.94)
    9
    (12.2)
    Social Problems: Baseline (n=271, 281)
    25.2
    (32.45)
    23.6
    (31.12)
    Social Problems: Cy4D1 (n=242, 232)
    19.3
    (26.03)
    19.5
    (27.94)
    Treatment Side Effects Scale: Baseline(n=276, 284)
    17.9
    (15.69)
    19.9
    (17.59)
    Treatment Side Effect Scale: Cy4D1(n=243, 233)
    14.2
    (13.57)
    14.6
    (14.89)

    Adverse Events

    Time Frame 5.5 years
    Adverse Event Reporting Description Safety Population included all randomized participants who received at least one dose of study drug. 4 patients randomized to RClb and 2 patients randomized to GClb did not receive study drug. In addition, 5 participants in the RClb arm received at least 1 dose of obinutuzumab and are included in the GClb arm for safety analyses.
    Arm/Group Title Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Arm/Group Description 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). 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).
    All Cause Mortality
    Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 124/321 (38.6%) 150/336 (44.6%)
    Blood and lymphatic system disorders
    Febrile neutropenia 3/321 (0.9%) 6/336 (1.8%)
    Neutropenia 2/321 (0.6%) 4/336 (1.2%)
    Anaemia 2/321 (0.6%) 3/336 (0.9%)
    Thrombocytopenia 1/321 (0.3%) 4/336 (1.2%)
    Autoimmune haemolytic anaemia 1/321 (0.3%) 2/336 (0.6%)
    Pancytopenia 2/321 (0.6%) 1/336 (0.3%)
    Cytopenia 1/321 (0.3%) 0/336 (0%)
    Haemolytic anaemia 0/321 (0%) 1/336 (0.3%)
    Immune thrombocytopenic purpura 0/321 (0%) 1/336 (0.3%)
    Leukopenia 0/321 (0%) 1/336 (0.3%)
    Cardiac disorders
    Cardiac failure 2/321 (0.6%) 4/336 (1.2%)
    Myocardial infarction 0/321 (0%) 4/336 (1.2%)
    Atrial fibrillation 1/321 (0.3%) 2/336 (0.6%)
    Cardiac arrest 3/321 (0.9%) 0/336 (0%)
    Acute coronary syndrome 1/321 (0.3%) 1/336 (0.3%)
    Acute myocardial infarction 2/321 (0.6%) 0/336 (0%)
    Angina pectoris 1/321 (0.3%) 0/336 (0%)
    Aortic valve stenosis 1/321 (0.3%) 0/336 (0%)
    Arrhythmia 1/321 (0.3%) 0/336 (0%)
    Atrial thrombosis 0/321 (0%) 1/336 (0.3%)
    Cardiac failure chronic 0/321 (0%) 1/336 (0.3%)
    Cardiac failure congestive 0/321 (0%) 1/336 (0.3%)
    Myocardial ischaemia 1/321 (0.3%) 0/336 (0%)
    Nodal rhythm 0/321 (0%) 1/336 (0.3%)
    Supraventricular tachycardia 1/321 (0.3%) 0/336 (0%)
    Ventricular extrasystoles 1/321 (0.3%) 0/336 (0%)
    Congenital, familial and genetic disorders
    Hereditary non-polyposis colorectal cancer syndrome 0/321 (0%) 1/336 (0.3%)
    Gastrointestinal disorders
    Diarrhoea 0/321 (0%) 3/336 (0.9%)
    Colitis 1/321 (0.3%) 1/336 (0.3%)
    Abdominal pain 1/321 (0.3%) 0/336 (0%)
    Anal fistula 1/321 (0.3%) 0/336 (0%)
    Ascites 0/321 (0%) 1/336 (0.3%)
    Constipation 0/321 (0%) 1/336 (0.3%)
    Dysphagia 1/321 (0.3%) 0/336 (0%)
    Enterocolitis 0/321 (0%) 1/336 (0.3%)
    Food poisoning 1/321 (0.3%) 0/336 (0%)
    Gastric ulcer 1/321 (0.3%) 0/336 (0%)
    Gastritis 0/321 (0%) 1/336 (0.3%)
    Intestinal obstruction 1/321 (0.3%) 0/336 (0%)
    Pancreatitis acute 0/321 (0%) 1/336 (0.3%)
    Proctitis 1/321 (0.3%) 0/336 (0%)
    Varices oesophageal 1/321 (0.3%) 0/336 (0%)
    General disorders
    Death 3/321 (0.9%) 0/336 (0%)
    Pyrexia 2/321 (0.6%) 2/336 (0.6%)
    Chest pain 2/321 (0.6%) 1/336 (0.3%)
    General physical health deterioration 3/321 (0.9%) 1/336 (0.3%)
    Asthenia 1/321 (0.3%) 1/336 (0.3%)
    Oedema peripheral 2/321 (0.6%) 0/336 (0%)
    Adhesion 1/321 (0.3%) 0/336 (0%)
    Chills 1/321 (0.3%) 0/336 (0%)
    Fatigue 0/321 (0%) 1/336 (0.3%)
    Impaired healing 0/321 (0%) 1/336 (0.3%)
    Malaise 0/321 (0%) 1/336 (0.3%)
    Hepatobiliary disorders
    Cholecystitis 0/321 (0%) 1/336 (0.3%)
    Cholelithiasis 0/321 (0%) 1/336 (0.3%)
    Hepatitis 0/321 (0%) 1/336 (0.3%)
    Liver disorder 0/321 (0%) 1/336 (0.3%)
    Immune system disorders
    Anaphylactic reaction 0/321 (0%) 1/336 (0.3%)
    Infections and infestations
    Pneumonia 19/321 (5.9%) 14/336 (4.2%)
    Respiratory tract infection 2/321 (0.6%) 3/336 (0.9%)
    Bronchitis 3/321 (0.9%) 1/336 (0.3%)
    Lower respiratory tract infection 1/321 (0.3%) 3/336 (0.9%)
    Neutropenic sepsis 1/321 (0.3%) 3/336 (0.9%)
    Upper respiratory tract infection 3/321 (0.9%) 1/336 (0.3%)
    Urinary tract infection 1/321 (0.3%) 3/336 (0.9%)
    Cellulitis 3/321 (0.9%) 0/336 (0%)
    Infection 2/321 (0.6%) 1/336 (0.3%)
    Diverticulitis 1/321 (0.3%) 1/336 (0.3%)
    Endocarditis 1/321 (0.3%) 1/336 (0.3%)
    Erysipelas 0/321 (0%) 2/336 (0.6%)
    Escherichia infection 1/321 (0.3%) 1/336 (0.3%)
    Hepatitis B 1/321 (0.3%) 0/336 (0%)
    Infective exacerbation of chronic obstructive airways disease 2/321 (0.6%) 0/336 (0%)
    Sepsis 1/321 (0.3%) 1/336 (0.3%)
    Septic shock 0/321 (0%) 2/336 (0.6%)
    Streptococcal sepsis 1/321 (0.3%) 1/336 (0.3%)
    Varicella 2/321 (0.6%) 0/336 (0%)
    Wound infection 1/321 (0.3%) 1/336 (0.3%)
    Cystitis 1/321 (0.3%) 0/336 (0%)
    Dacryocystitis 0/321 (0%) 1/336 (0.3%)
    Device related sepsis 0/321 (0%) 1/336 (0.3%)
    Epididymitis 0/321 (0%) 1/336 (0.3%)
    Escherichia sepsis 0/321 (0%) 1/336 (0.3%)
    Furuncle 1/321 (0.3%) 0/336 (0%)
    Gangrene 0/321 (0%) 1/336 (0.3%)
    Gastroenteritis 0/321 (0%) 1/336 (0.3%)
    Gastroenteritis clostridial 1/321 (0.3%) 0/336 (0%)
    Herpes simplex 1/321 (0.3%) 0/336 (0%)
    Herpes zoster 1/321 (0.3%) 0/336 (0%)
    Infected skin ulcer 1/321 (0.3%) 0/336 (0%)
    Infectious colitis 0/321 (0%) 1/336 (0.3%)
    Infective exacerbation of bronchiectasis 0/321 (0%) 1/336 (0.3%)
    Intervertebral discitis 0/321 (0%) 1/336 (0.3%)
    Laryngitis 1/321 (0.3%) 0/336 (0%)
    Liver abscess 0/321 (0%) 1/336 (0.3%)
    Lung infection 1/321 (0.3%) 0/336 (0%)
    Ophthalmic herpes zoster 0/321 (0%) 1/336 (0.3%)
    Peritonitis 1/321 (0.3%) 0/336 (0%)
    Pneumocystis jirovecii pneumonia 1/321 (0.3%) 0/336 (0%)
    Pneumonia influenzal 0/321 (0%) 1/336 (0.3%)
    Pulmonary sepsis 0/321 (0%) 1/336 (0.3%)
    Septic arthritis staphylococcal 0/321 (0%) 1/336 (0.3%)
    Staphylococcal infection 1/321 (0.3%) 0/336 (0%)
    Subcutaneous abscess 0/321 (0%) 1/336 (0.3%)
    Superinfection bacterial 0/321 (0%) 1/336 (0.3%)
    Tooth abscess 1/321 (0.3%) 0/336 (0%)
    Urosepsis 1/321 (0.3%) 0/336 (0%)
    Hepatitis B Reactivation 1/321 (0.3%) 0/336 (0%)
    Injury, poisoning and procedural complications
    Infusion related reaction 5/321 (1.6%) 34/336 (10.1%)
    Fall 1/321 (0.3%) 3/336 (0.9%)
    Femur fracture 3/321 (0.9%) 0/336 (0%)
    Femoral neck fracture 1/321 (0.3%) 1/336 (0.3%)
    Post procedural haemorrhage 2/321 (0.6%) 0/336 (0%)
    Tibia fracture 0/321 (0%) 2/336 (0.6%)
    Fracture displacement 0/321 (0%) 1/336 (0.3%)
    Hip fracture 1/321 (0.3%) 0/336 (0%)
    Laceration 0/321 (0%) 1/336 (0.3%)
    Lower limb fracture 1/321 (0.3%) 0/336 (0%)
    Pubis fracture 0/321 (0%) 1/336 (0.3%)
    Shunt thrombosis 0/321 (0%) 1/336 (0.3%)
    Spinal compression fracture 1/321 (0.3%) 0/336 (0%)
    Spinal fracture 0/321 (0%) 1/336 (0.3%)
    Subdural haematoma 0/321 (0%) 1/336 (0.3%)
    Subdural haemorrhage 0/321 (0%) 1/336 (0.3%)
    Tendon rupture 0/321 (0%) 1/336 (0.3%)
    Investigations
    Haemoglobin decreased 0/321 (0%) 1/336 (0.3%)
    Metabolism and nutrition disorders
    Tumour lysis syndrome 0/321 (0%) 5/336 (1.5%)
    Dehydration 0/321 (0%) 1/336 (0.3%)
    Hyperglycaemia 0/321 (0%) 1/336 (0.3%)
    Musculoskeletal and connective tissue disorders
    Back pain 1/321 (0.3%) 1/336 (0.3%)
    Gouty arthritis 0/321 (0%) 1/336 (0.3%)
    Musculoskeletal chest pain 0/321 (0%) 1/336 (0.3%)
    Spinal column stenosis 0/321 (0%) 1/336 (0.3%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin 6/321 (1.9%) 6/336 (1.8%)
    Basal cell carcinoma 4/321 (1.2%) 8/336 (2.4%)
    Squamous cell carcinoma 7/321 (2.2%) 4/336 (1.2%)
    Myelodysplastic syndrome 3/321 (0.9%) 1/336 (0.3%)
    Malignant melanoma 2/321 (0.6%) 2/336 (0.6%)
    Prostate cancer 3/321 (0.9%) 2/336 (0.6%)
    Adenocarcinoma of colon 1/321 (0.3%) 2/336 (0.6%)
    Colon adenoma 1/321 (0.3%) 1/336 (0.3%)
    Colon cancer 1/321 (0.3%) 1/336 (0.3%)
    Keratoacanthoma 1/321 (0.3%) 1/336 (0.3%)
    Metastatic squamous cell carcinoma 2/321 (0.6%) 0/336 (0%)
    Renal cell carcinoma 0/321 (0%) 1/336 (0.3%)
    Skin cancer 2/321 (0.6%) 0/336 (0%)
    Squamous cell carcinoma of lung 1/321 (0.3%) 2/336 (0.6%)
    Acute myeloid leukaemia 2/321 (0.6%) 0/336 (0%)
    Adenocarcinoma 1/321 (0.3%) 0/336 (0%)
    Adenocarcinoma gastric 0/321 (0%) 1/336 (0.3%)
    Bowen's disease 1/321 (0.3%) 0/336 (0%)
    Breast cancer 2/321 (0.6%) 0/336 (0%)
    Bronchial carcinoma 0/321 (0%) 1/336 (0.3%)
    Choroid melanoma 0/321 (0%) 1/336 (0.3%)
    Diffuse large B-cell lymphoma 1/321 (0.3%) 0/336 (0%)
    Hepatocellular carcinoma 0/321 (0%) 1/336 (0.3%)
    Intracranial tumour haemorrhage 1/321 (0.3%) 0/336 (0%)
    Intraocular melanoma 0/321 (0%) 1/336 (0.3%)
    Lung adenocarcinoma 0/321 (0%) 1/336 (0.3%)
    Lung neoplasm malignant 1/321 (0.3%) 0/336 (0%)
    Metastatic malignant melanoma 2/321 (0.6%) 0/336 (0%)
    Non-small cell lung cancer 0/321 (0%) 1/336 (0.3%)
    Oropharyngeal cancer 1/321 (0.3%) 0/336 (0%)
    Pancreatic carcinoma 0/321 (0%) 1/336 (0.3%)
    Plasma cell myeloma 0/321 (0%) 1/336 (0.3%)
    Rectal adenocarcinoma 0/321 (0%) 2/336 (0.6%)
    Rectal cancer 0/321 (0%) 1/336 (0.3%)
    Schwannoma 0/321 (0%) 1/336 (0.3%)
    Superficial spreading melanoma stage unspecified 0/321 (0%) 1/336 (0.3%)
    Transitional cell carcinoma 1/321 (0.3%) 0/336 (0%)
    Basosquamous Carcinoma of Skin 0/321 (0%) 1/336 (0.3%)
    Breast Cancer Metastatic 1/321 (0.3%) 0/336 (0%)
    Cholangiocarcinoma 0/321 (0%) 1/336 (0.3%)
    Gastric Cancer 0/321 (0%) 1/336 (0.3%)
    Malignant Melanoma in Situ 1/321 (0.3%) 0/336 (0%)
    Papillary Renal Cell Carcinoma 1/321 (0.3%) 0/336 (0%)
    Polycythaemia Vera 1/321 (0.3%) 0/336 (0%)
    Renal Cancer 1/321 (0.3%) 0/336 (0%)
    Nervous system disorders
    Cerebrovascular accident 2/321 (0.6%) 3/336 (0.9%)
    Central nervous system haemorrhage 0/321 (0%) 1/336 (0.3%)
    Cerebral haematoma 1/321 (0.3%) 0/336 (0%)
    Depressed level of consciousness 1/321 (0.3%) 0/336 (0%)
    Encephalopathy 1/321 (0.3%) 0/336 (0%)
    Haemorrhage intracranial 1/321 (0.3%) 0/336 (0%)
    Hypoaesthesia 1/321 (0.3%) 0/336 (0%)
    Metabolic encephalopathy 0/321 (0%) 1/336 (0.3%)
    Partial seizures 1/321 (0.3%) 0/336 (0%)
    Presyncope 1/321 (0.3%) 0/336 (0%)
    Syncope 0/321 (0%) 1/336 (0.3%)
    Psychiatric disorders
    Delirium 0/321 (0%) 1/336 (0.3%)
    Disorientation 1/321 (0.3%) 0/336 (0%)
    Mania 1/321 (0.3%) 0/336 (0%)
    Renal and urinary disorders
    Acute kidney injury 3/321 (0.9%) 0/336 (0%)
    Acute prerenal failure 0/321 (0%) 1/336 (0.3%)
    Haematuria 1/321 (0.3%) 0/336 (0%)
    Nephritic syndrome 1/321 (0.3%) 0/336 (0%)
    Nephrolithiasis 1/321 (0.3%) 0/336 (0%)
    Renal failure 1/321 (0.3%) 0/336 (0%)
    Reproductive system and breast disorders
    Testicular hypertrophy 0/321 (0%) 1/336 (0.3%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 2/321 (0.6%) 2/336 (0.6%)
    Pulmonary embolism 1/321 (0.3%) 2/336 (0.6%)
    Pleural effusion 0/321 (0%) 2/336 (0.6%)
    Acute pulmonary oedema 1/321 (0.3%) 0/336 (0%)
    Asthma 1/321 (0.3%) 0/336 (0%)
    Dyspnoea 1/321 (0.3%) 0/336 (0%)
    Interstitial lung disease 1/321 (0.3%) 0/336 (0%)
    Pneumonitis 0/321 (0%) 1/336 (0.3%)
    Pulmonary alveolar haemorrhage 0/321 (0%) 1/336 (0.3%)
    Pulmonary oedema 0/321 (0%) 1/336 (0.3%)
    Respiratory failure 1/321 (0.3%) 0/336 (0%)
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 0/321 (0%) 1/336 (0.3%)
    Skin disorder 0/321 (0%) 1/336 (0.3%)
    Vascular disorders
    Capillary leak syndrome 0/321 (0%) 1/336 (0.3%)
    Circulatory collapse 1/321 (0.3%) 0/336 (0%)
    Deep vein thrombosis 0/321 (0%) 1/336 (0.3%)
    Diabetic macroangiopathy 0/321 (0%) 1/336 (0.3%)
    Hypertension 1/321 (0.3%) 0/336 (0%)
    Hypertensive crisis 0/321 (0%) 1/336 (0.3%)
    Malignant hypertension 1/321 (0.3%) 0/336 (0%)
    Peripheral artery thrombosis 0/321 (0%) 1/336 (0.3%)
    Peripheral ischaemia 0/321 (0%) 1/336 (0.3%)
    Thrombophlebitis superficial 0/321 (0%) 1/336 (0.3%)
    Venous thrombosis 1/321 (0.3%) 0/336 (0%)
    Other (Not Including Serious) Adverse Events
    Rituximab + Chlorambucil (RClb) Obinutuzumab + Chlorambucil (GClb)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 279/321 (86.9%) 299/336 (89%)
    Blood and lymphatic system disorders
    Neutropenia 104/321 (32.4%) 128/336 (38.1%)
    Anaemia 34/321 (10.6%) 33/336 (9.8%)
    Thrombocytopenia 20/321 (6.2%) 46/336 (13.7%)
    Leukopenia 7/321 (2.2%) 21/336 (6.3%)
    Gastrointestinal disorders
    Nausea 42/321 (13.1%) 40/336 (11.9%)
    Diarrhoea 24/321 (7.5%) 31/336 (9.2%)
    Constipation 16/321 (5%) 27/336 (8%)
    Vomiting 22/321 (6.9%) 19/336 (5.7%)
    General disorders
    Fatigue 30/321 (9.3%) 26/336 (7.7%)
    Pyrexia 22/321 (6.9%) 28/336 (8.3%)
    Asthenia 25/321 (7.8%) 23/336 (6.8%)
    Infections and infestations
    Urinary Tract Infection 6/321 (1.9%) 17/336 (5.1%)
    Injury, poisoning and procedural complications
    Infusion related reaction 118/321 (36.8%) 197/336 (58.6%)
    Nervous system disorders
    Headache 18/321 (5.6%) 23/336 (6.8%)
    Respiratory, thoracic and mediastinal disorders
    Cough 19/321 (5.9%) 24/336 (7.1%)
    Skin and subcutaneous tissue disorders
    Rash 19/321 (5.9%) 8/336 (2.4%)

    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.

    Results Point of Contact

    Name/Title Medical Communications
    Organization Hoffman-LaRoche
    Phone 800-821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT02053610
    Other Study ID Numbers:
    • BO21004 (Stage 2)
    • 2009-012476-28; CLL1
    First Posted:
    Feb 3, 2014
    Last Update Posted:
    Sep 14, 2018
    Last Verified:
    Aug 1, 2018