A Study Evaluating the Efficacy of Obinutuzumab and Bendamustine Treatment in Participants With Refractory or Relapsed Chronic Lymphocytic Leukemia

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02071225
• Collaborator: (none)
• Enrollment: 72
• Locations: 21
• Arm: 1
• Actual Duration (Months): 55.4
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial was designed to evaluate the efficacy of obinutuzumab and bendamustine treatment in participants with refractory or relapsed chronic lymphocytic leukemia (CLL). Participants receive up to six 28-day cycles of treatment. Treatment consists of intravenous (IV) administration of obinutuzumab and bendamustine. Treatment time is expected to last 6 months, and participant follow-up will last 2 years.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Drug: bendamustine; Drug: obinutuzumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial to Evaluate The Efficacy of Obinutuzumab (RO5072759) + Bendamustine Treatment in Patients With Refractory Or Relapsed Chronic Lymphocytic Leukemia
• Actual Study Start Date: Apr 9, 2014
• Actual Primary Completion Date: Nov 19, 2018
• Actual Study Completion Date: Nov 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Obinutuzmab + Bendamustine Participants will receive obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles	Drug: bendamustine; 70 milligrams per square meter (mg/m^2) given by intravenous (IV) infusion on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of subsequent cycles.; Drug: obinutuzumab; 1000 mg given by IV infusion on Days 1, 8, and 15 of Cycle 1 and on Day 1 of subsequent cycles.; Other Names: RO5072759

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) as Assessed by the Investigator Using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria [2-3 months after last dose of the study treatment (up to approximately 9 months)]

   ORR was defined as percentage of participants achieving Complete Response (CR), incomplete CR (CRi) or Partial Response (PR). CR: lymphocytes below 4 x 10^9/L, absence of lymphadenopathy, hepatomegaly and splenomegaly, absence of disease or constitutional symptoms, neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L, bone marrow at least normocellular for age. CRi: CR with persistent cytopenia, i.e. anemia, thrombocytopenia and/or neutropenia. PR: reduction ≥ 50% of the lymphocyte count AND reduction ≥ 50% of the lymphadenopathy OR reduction ≥ 50% of the size of the liver if enlarged at baseline OR reduction ≥ 50% of the size of the spleen if enlarged at baseline PLUS one of the following: neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L or increase ≥ 50% compared to pre-treatment.

Secondary Outcome Measures

1. Best Response Rate as Assessed by the Investigator Using the IWCLL 2008 Criteria [During study treatment and until 6 months after end of study treatment at approximately 12 months]

   Best overall response was defined as percentage of participants achieving a best response of CR, CRi and PR. CR: lymphocytes below 4 x 10^9/L, absence of lymphadenopathy, hepatomegaly and splenomegaly, absence of disease or constitutional symptoms, neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L, bone marrow at least normocellular for age. CRi: CR with persistent cytopenia, i.e. anemia, thrombocytopenia and/or neutropenia. PR: reduction ≥ 50% of the lymphocyte count AND reduction ≥ 50% of the lymphadenopathy OR reduction ≥ 50% of the size of the liver if enlarged at baseline OR reduction ≥ 50% of the size of the spleen if enlarged at baseline PLUS one of the following: neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L or increase ≥ 50% compared to pre-treatment.

2. Progression Free Survival (PFS) [From start of treatment up to disease progression or relapse or death, whichever occurred first (up to approximately 4.5 years)]

   PFS is defined as the time from the start of treatment to disease progression (DP), relapse or death from any cause, whichever occurs first, as assessed by the investigator. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal chronic lymphocytic leukemia (CLL) cells.

3. Overall Survival (OS) [From start of treatment up to death of any cause (up to approximately 4.5 years)]

   OS was defined as the time from the start of study treatment to death from any cause.

4. Event Free Survival (EFS) [From start of treatment up to disease progression or relapse or death or start of a new anti-leukemic therapy, whichever occurred first (up to approximately 4.5 years)]

   EFS was defined as the time from the start of treatment to DP/relapse, death from any cause or start of a new anti-leukemia therapy. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal CLL cells.

5. Disease Free Survival (DFS) [From occurrence of complete response up to disease progression or death, whichever occurred first (up to approximately 4.5 years)]

   DFS was defined for all participants who achieved complete response (CRi or CR). DFS lasted from the date on which CRi or CR was recorded until the date on which the first DP or death from any cause occurred. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal CLL cells.

6. Duration of Response (DR) [From occurrence of CR or PR up to disease progression or death, whichever occurred first (up to approximately 4.5 years)]

   DR was defined for participants with CRi, CR or PR. DR spanned from the date on which response was recorded until the date on which DP or death from any cause occurred. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal CLL cells.

7. Time to Re-treatment/New Anti-leukemia Therapy [Up to 4.5 years]

   Time to re-treatment/new leukemia therapy was defined as the time between the start of treatment and the date of the first administration of re-treatment or new leukemia therapy.

8. Percentage of Participants With Minimal Residual Disease (MRD) Negativity [At approximately 9 months]

   MRD negativity was defined as the presence of less than 1 cell of CLL per 10,000 leukocytes (= category 0, <0.01%) assessed in bone marrow (BM) and peripheral blood (PB) by flow cytometry after the end of the treatment at the final response assessment.

9. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to approximately 4.5 years]

   An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs. An SAE was any AE that was any of the following: fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/ birth defect, and was considered a significant medical event by the investigator.

10. Percentage of Participants With AEs of Special Interest (AESIs) [Up to approximately 4.5 years]

    AESIs included any of the following: SAEs associated with the infusion of obinutuzumab: obinutuzumab serious infusion-related reactions, which were defined as AEs occurring during or within 24 hours following the administration of an infusion of obinutuzumab and considered related to obinutuzumab; serious infection; serious neutropenia; any tumor lysis syndrome (TLS); second malignancies.

11. Percentage of Participants With Infusion-related Reactions (IRRs) [Up to end of treatment at 6 months]

    IRRs were defined as AEs occurring during or within 24 hours following the administration of an infusion and considered related to drug treatment.

12. Percentage of Participants Who Discontinued Treatment Prematurely [Up to end of treatment at 6 months]

13. Percentage of Participants With Previous/Concomitant Diseases [Up to approximately 4.5 years]

14. Percentage of Participants With Concomitant Medication [From 7 days prior to screening to the end of treatment at 6 months]

    Concomitant therapies included any medication (prescription medication, over-the-counter medications, herbal/homeopathic remedies, nutritional supplements) used by subjects in the 7 days prior to screening until the end of treatment. The following treatments were not permitted during the study treatment period: investigational or unauthorized or unapproved medicinal products, immunotherapy or radioimmunotherapy (other than the trial immunotherapy, obinutuzumab), chemotherapy (other than the trial chemotherapy, bendamustine) and radiotherapy.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age 18 years or older

• Diagnosed CD20+ B- chronic lymphocytic leukemia (CLL) according to National Cancer Institute (NCI) criteria

• Active disease meeting at least 1 of the International Workshop on CLL (IWCLL) 2008 criteria for treatment

• Refractory CLL (i.e. treatment failure or progression during treatment or within 6 months after the last treatment) or relapse CLL (i.e. participants who met criteria for CR or PR, but progressed beyond 6 months post-treatment)

• At least 1 prior purine analogue or bendamustine containing therapy

• Life expectancy greater than (>) 6 months

• Use of effective contraception as described in the study protocol

Exclusion Criteria:

• Prior Alogenic Bone Marrow Transplant

• Greater than or equal to (>/=) 3 previous lines of chemotherapy and/or immunotherapy for the CLL

• Previous obinutuzumab-containing regimen

• Treatment failure or progression within 6 months of bendamustine-containing regimen

• Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL; Richter's transformation) Patients with prolymphocytic transformation cannot entry the study either

• Active haemolytic anaemia

• Inadequate liver function

• History of other malignancy which could affect compliance with the protocol or interpretation of results. Patients with a history of malignancy that has been treated but not with curative intent will be excluded, unless the malignancy has been in remission without treatment for >/= 2 years prior to enrolment. Patients with a history of adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage localized prostate cancer treated surgically with curative intent; good prognosis ductal carcinoma in situ (DCIS) of the breast treated with lumpectomy alone with curative intent are eligible

• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or pulmonary disease

• Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis

• Regular treatment with corticosteroids during the 4 weeks prior to study start, unless administered for another condition at a dose equivalent to less than or equal to (</=) 30 milligrams per day (mg/day) prednisone

• Known active infection or any infection requiring treatment with IV antibiotics or hospitalization within 4 weeks prior to study start

• Patients with HIV, human T cell leukemia virus 1 (HTLV-1), hepatitis B or hepatitis C

• Pregnancy or breast-feeding

• Vaccination with a live vaccine within 4 weeks prior to baseline visit

• Receipt of any other study drug within 4 weeks prior to study start

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital De Txagorritxu; Servicio de Hematologia	Vitoria	Alava	Spain	01009
2	Hospital General Universitario de Elche; Servicio de Hematologia	Elche	Alicante	Spain	03203
3	Hospital de Cabueñes; Servicio de Hematología y Hemoterapia	Gijon	Asturias	Spain	33203
4	Hospital Univ. Central de Asturias; servicio de Hematologia	Oviedo	Asturias	Spain	33011
5	Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia	Badalona	Barcelona	Spain	08915
6	Hospital Mutua de Terrassa; Servicio de Hematologia	Terrassa	Barcelona	Spain	08221
7	Hospital de Navarra, Servicio de Hematología	Pamplona	Navarra	Spain	31008
8	Complejo Hospitalario Nuestra Señora de la Candelaria; Servicio de Hematologia	Santa Cruz de Tenerife	Tenerife	Spain	38010
9	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona		Spain	08035
10	Hospital Clínic i Provincial; Servicio de Hematología y Oncología	Barcelona		Spain	08036
11	Hospital General de Castellon; Servicio de Hematologia	Castellon		Spain	12004
12	Hospital Universitario Virgen de las Nieves; Servicio de Hematologia	Granada		Spain	18014
13	Hospital de Gran Canaria Dr. Negrin; Servicio de Hematologia	Las Palmas		Spain	35020
14	Hospital Universitario la Paz; Servicio de Hematologia	Madrid		Spain	28046
15	Hospital Universitario Puerta de Hierro; Servicio de Hematologia	Madrid		Spain	28222
16	Hospital Costa del Sol; Servicio de Hematologia	Malaga		Spain	29600
17	Hospital Universitario Virgen Macarena; Servicio de Hematologia	Sevilla		Spain	41009
18	Hospital Univ. Nuestra Señora de Valme; Servicio de Hematologia	Sevilla		Spain	41014
19	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia		Spain	46010
20	Hospital Universitario Dr. Peset; Servicio de Hematologia	Valencia		Spain	46017
21	Hospital Clinico Universitario Lozano Blesa; Servicio de Hematologia	Zaragoza		Spain	50009

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 31, 2017

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02071225
• Other Study ID Numbers: ML29167; 2013-003388-79
• First Posted: Feb 25, 2014
• Last Update Posted: Feb 7, 2020
• Last Verified: Feb 1, 2020

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

Study Results

Participant Flow

Recruitment Details	A total of 72 participants were recruited at 20 sites in Spain.
Pre-assignment Detail	Participants enrolled in the study had documented CD20-positive B-cell type relapsed or refractory chronic lymphocytic leukemia (CLL).

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Period Title: Overall Study
STARTED	72
COMPLETED	42
NOT COMPLETED	30

Baseline Characteristics

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Overall Participants	72
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	67.9
Sex: Female, Male (Count of Participants)
Female	24 33.3%
Male	48 66.7%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	71 98.6%
Indian	1 1.4%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR) as Assessed by the Investigator Using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria
Description	ORR was defined as percentage of participants achieving Complete Response (CR), incomplete CR (CRi) or Partial Response (PR). CR: lymphocytes below 4 x 10^9/L, absence of lymphadenopathy, hepatomegaly and splenomegaly, absence of disease or constitutional symptoms, neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L, bone marrow at least normocellular for age. CRi: CR with persistent cytopenia, i.e. anemia, thrombocytopenia and/or neutropenia. PR: reduction ≥ 50% of the lymphocyte count AND reduction ≥ 50% of the lymphadenopathy OR reduction ≥ 50% of the size of the liver if enlarged at baseline OR reduction ≥ 50% of the size of the spleen if enlarged at baseline PLUS one of the following: neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L or increase ≥ 50% compared to pre-treatment.
Time Frame	2-3 months after last dose of the study treatment (up to approximately 9 months)

Outcome Measure Data

Analysis Population Description

Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab).

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	70
Number (95% Confidence Interval) [percentage of participants]	78.6 109.2%

2. Secondary Outcome

Title	Best Response Rate as Assessed by the Investigator Using the IWCLL 2008 Criteria
Description	Best overall response was defined as percentage of participants achieving a best response of CR, CRi and PR. CR: lymphocytes below 4 x 10^9/L, absence of lymphadenopathy, hepatomegaly and splenomegaly, absence of disease or constitutional symptoms, neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L, bone marrow at least normocellular for age. CRi: CR with persistent cytopenia, i.e. anemia, thrombocytopenia and/or neutropenia. PR: reduction ≥ 50% of the lymphocyte count AND reduction ≥ 50% of the lymphadenopathy OR reduction ≥ 50% of the size of the liver if enlarged at baseline OR reduction ≥ 50% of the size of the spleen if enlarged at baseline PLUS one of the following: neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L or increase ≥ 50% compared to pre-treatment.
Time Frame	During study treatment and until 6 months after end of study treatment at approximately 12 months

Outcome Measure Data

Analysis Population Description

Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab). Reported here is the number of participants for whom data for best response achieved were available.

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	54
CR	46.3 64.3%
CRi	1.9 2.6%
PR	42.6 59.2%

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS is defined as the time from the start of treatment to disease progression (DP), relapse or death from any cause, whichever occurs first, as assessed by the investigator. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal chronic lymphocytic leukemia (CLL) cells.
Time Frame	From start of treatment up to disease progression or relapse or death, whichever occurred first (up to approximately 4.5 years)

Outcome Measure Data

Analysis Population Description

Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab).

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	70
Median (95% Confidence Interval) [months]	24.14

4. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from the start of study treatment to death from any cause.
Time Frame	From start of treatment up to death of any cause (up to approximately 4.5 years)

Outcome Measure Data

Analysis Population Description

Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab).

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	70
Median (95% Confidence Interval) [months]	NA

5. Secondary Outcome

Title	Event Free Survival (EFS)
Description	EFS was defined as the time from the start of treatment to DP/relapse, death from any cause or start of a new anti-leukemia therapy. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal CLL cells.
Time Frame	From start of treatment up to disease progression or relapse or death or start of a new anti-leukemic therapy, whichever occurred first (up to approximately 4.5 years)

Outcome Measure Data

Analysis Population Description

Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab).

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	70
Median (95% Confidence Interval) [months]	24.14

6. Secondary Outcome

Title	Disease Free Survival (DFS)
Description	DFS was defined for all participants who achieved complete response (CRi or CR). DFS lasted from the date on which CRi or CR was recorded until the date on which the first DP or death from any cause occurred. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal CLL cells.
Time Frame	From occurrence of complete response up to disease progression or death, whichever occurred first (up to approximately 4.5 years)

Outcome Measure Data

Analysis Population Description

Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab). Included in the analysis are participants who achieved CRi or CR.

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	25
Median (95% Confidence Interval) [months]	23.02

7. Secondary Outcome

Title	Duration of Response (DR)
Description	DR was defined for participants with CRi, CR or PR. DR spanned from the date on which response was recorded until the date on which DP or death from any cause occurred. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal CLL cells.
Time Frame	From occurrence of CR or PR up to disease progression or death, whichever occurred first (up to approximately 4.5 years)

Outcome Measure Data

Analysis Population Description

Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab). Included in the analysis are participants who achieved CRi, CR or PR.

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	54
Median (95% Confidence Interval) [months]	21.41

8. Secondary Outcome

Title	Time to Re-treatment/New Anti-leukemia Therapy
Description	Time to re-treatment/new leukemia therapy was defined as the time between the start of treatment and the date of the first administration of re-treatment or new leukemia therapy.
Time Frame	Up to 4.5 years

Outcome Measure Data

Analysis Population Description

Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab).

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	70
Median (95% Confidence Interval) [months]	NA

9. Secondary Outcome

Title	Percentage of Participants With Minimal Residual Disease (MRD) Negativity
Description	MRD negativity was defined as the presence of less than 1 cell of CLL per 10,000 leukocytes (= category 0, <0.01%) assessed in bone marrow (BM) and peripheral blood (PB) by flow cytometry after the end of the treatment at the final response assessment.
Time Frame	At approximately 9 months

Outcome Measure Data

Analysis Population Description

ITT population included all participants, who received at least one dose of any treatment.

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	72
MRD in BM: Cat 0	36.4 50.6%
MRD in PB: Cat 0	53.4 74.2%

10. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs. An SAE was any AE that was any of the following: fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/ birth defect, and was considered a significant medical event by the investigator.
Time Frame	Up to approximately 4.5 years

Outcome Measure Data

Analysis Population Description

Safety population included all participants, who received at least one dose of any treatment.

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	72
AEs	94.4 131.1%
SAEs	51.4 71.4%

11. Secondary Outcome

Title	Percentage of Participants With AEs of Special Interest (AESIs)
Description	AESIs included any of the following: SAEs associated with the infusion of obinutuzumab: obinutuzumab serious infusion-related reactions, which were defined as AEs occurring during or within 24 hours following the administration of an infusion of obinutuzumab and considered related to obinutuzumab; serious infection; serious neutropenia; any tumor lysis syndrome (TLS); second malignancies.
Time Frame	Up to approximately 4.5 years

Outcome Measure Data

Analysis Population Description

Safety population included all participants, who received at least one dose of any treatment.

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	72
Number [percentage of participants]	45.8 63.6%

12. Secondary Outcome

Title	Percentage of Participants With Infusion-related Reactions (IRRs)
Description	IRRs were defined as AEs occurring during or within 24 hours following the administration of an infusion and considered related to drug treatment.
Time Frame	Up to end of treatment at 6 months

Outcome Measure Data

Analysis Population Description

Safety population included all participants, who received at least one dose of any treatment.

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	72
Number [percentage of participants]	20.8 28.9%

13. Secondary Outcome

Title	Percentage of Participants Who Discontinued Treatment Prematurely
Time Frame	Up to end of treatment at 6 months

Outcome Measure Data

Analysis Population Description

Safety population included all participants, who received at least one dose of any treatment.

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	72
Number [percentage of participants]	41.7 57.9%

14. Secondary Outcome

Title	Percentage of Participants With Previous/Concomitant Diseases
Time Frame	Up to approximately 4.5 years

Outcome Measure Data

Analysis Population Description

Safety population included all participants, who received at least one dose of any treatment.

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	72
Number [percentage of participants]	97.2 135%

15. Secondary Outcome

Title	Percentage of Participants With Concomitant Medication
Description	Concomitant therapies included any medication (prescription medication, over-the-counter medications, herbal/homeopathic remedies, nutritional supplements) used by subjects in the 7 days prior to screening until the end of treatment. The following treatments were not permitted during the study treatment period: investigational or unauthorized or unapproved medicinal products, immunotherapy or radioimmunotherapy (other than the trial immunotherapy, obinutuzumab), chemotherapy (other than the trial chemotherapy, bendamustine) and radiotherapy.
Time Frame	From 7 days prior to screening to the end of treatment at 6 months

Outcome Measure Data

Analysis Population Description

Safety population included all participants, who received at least one dose of any treatment.

Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
Measure Participants	72
Number [percentage of participants]	54.2 75.3%

Adverse Events

Time Frame	Up to approximately 4.5 years
Adverse Event Reporting Description	Safety population included all participants, who received at least one dose of any treatment.
Arm/Group Title	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles.
All Cause Mortality
	Obinutuzumab + Bendamustine
	Affected / at Risk (%)	# Events
Total	25/72 (34.7%)
Serious Adverse Events
	Obinutuzumab + Bendamustine
	Affected / at Risk (%)	# Events
Total	37/72 (51.4%)
Blood and lymphatic system disorders
Neutropenia	9/72 (12.5%)
Febrile neutropenia	8/72 (11.1%)
Acute myeloid leukaemia	1/72 (1.4%)
Acute myelomonocytic leukaemia	1/72 (1.4%)
Haemophagocytic lymphohistiocytosis	1/72 (1.4%)
Thrombocytopenia	1/72 (1.4%)
Cardiac disorders
Dyspnoea	1/72 (1.4%)
Gastrointestinal disorders
Diarrhoea	2/72 (2.8%)
Gastroenteritis	1/72 (1.4%)
Upper gastrointestinal haemorrhage	1/72 (1.4%)
General disorders
Pyrexia	8/72 (11.1%)
Infusion related reaction	2/72 (2.8%)
Multiple organ dysfunction syndrome	2/72 (2.8%)
Cachexia	1/72 (1.4%)
Malaise	1/72 (1.4%)
Mucosal inflammation	1/72 (1.4%)
Infections and infestations
Pneumonia	8/72 (11.1%)
Respiratory tract infection	6/72 (8.3%)
Septic shock	3/72 (4.2%)
Bronchitis	2/72 (2.8%)
Sepsis	2/72 (2.8%)
Abdominal Sepsis	1/72 (1.4%)
Bronchopulmonary aspergillosis	1/72 (1.4%)
Lung Infection	1/72 (1.4%)
Periorbital cellulitis	1/72 (1.4%)
Respiratory syncytial virus infection	1/72 (1.4%)
Rotavirus infection	1/72 (1.4%)
Serratia sepsis	1/72 (1.4%)
Tuberculosis	1/72 (1.4%)
Upper respiratory tract infection	1/72 (1.4%)
Urinary tract infection	1/72 (1.4%)
Metabolism and nutrition disorders
Hyponatraemia	1/72 (1.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastrointestinal stromal tumour	1/72 (1.4%)
Glioblastoma multiforme	1/72 (1.4%)
Laryngeal squamous cell carcinoma	1/72 (1.4%)
Lung neoplasm malignant	1/72 (1.4%)
Squamous cell carcinoma of lung	1/72 (1.4%)
Respiratory, thoracic and mediastinal disorders
Bronchiolitis	1/72 (1.4%)
Interstitial lung disease	1/72 (1.4%)
Vascular disorders
Hypertensive crisis	1/72 (1.4%)
Other (Not Including Serious) Adverse Events
	Obinutuzumab + Bendamustine
	Affected / at Risk (%)	# Events
Total	67/72 (93.1%)
Blood and lymphatic system disorders
Neutropenia	48/72 (66.7%)
Thrombocytopenia	30/72 (41.7%)
Anaemia	14/72 (19.4%)
Cardiac disorders
Dyspnoea	6/72 (8.3%)
Chest pain	4/72 (5.6%)
Gastrointestinal disorders
Nausea	17/72 (23.6%)
Diarrhoea	16/72 (22.2%)
Constipation	9/72 (12.5%)
Vomiting	8/72 (11.1%)
Abdominal pain	5/72 (6.9%)
Abdominal pain upper	4/72 (5.6%)
General disorders
Asthenia	28/72 (38.9%)
Pyrexia	27/72 (37.5%)
Infusion related reaction	13/72 (18.1%)
Hepatobiliary disorders
Hypertransaminasaemia	4/72 (5.6%)
Infections and infestations
Respiratory tract infection	19/72 (26.4%)
Urinary tract infection	6/72 (8.3%)
Herpes zoster	5/72 (6.9%)
Metabolism and nutrition disorders
Decreased appetite	5/72 (6.9%)
Nervous system disorders
Headache	4/72 (5.6%)
Tremor	4/72 (5.6%)
Respiratory, thoracic and mediastinal disorders
Cough	11/72 (15.3%)
Nasopharyngitis	9/72 (12.5%)
Skin and subcutaneous tissue disorders
Pruritus	9/72 (12.5%)
Rash	6/72 (8.3%)
Vascular disorders
Hypotension	4/72 (5.6%)

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.