Clinical Trial Results:
Phase II Trial to Evaluate the Efficacy of Obinutuzumab (RO5072759) + Bendamustine Treatment in Patients With Refractory or Relapsed Chronic Lymphocytic Leukemia
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Summary
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EudraCT number |
2013-003388-79 |
Trial protocol |
ES |
Global end of trial date |
19 Nov 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Nov 2019
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First version publication date |
27 Nov 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ML29167
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02071225 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Scientific contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, + 41 616878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
19 Nov 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Nov 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy of obinutuzumab and bendamustine treatment in subjects with refractory or relapsed chronic lymphocytic leukemia (CLL).
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Apr 2014
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
55 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 72
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Worldwide total number of subjects |
72
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EEA total number of subjects |
72
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
26
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From 65 to 84 years |
46
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 72 subjects were recruited at 20 sites in Spain. | ||||||||||||||||
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Pre-assignment
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Screening details |
Subjects enrolled in the study had documented CD20-positive B-cell type relapsed or refractory chronic lymphocytic leukemia (CLL). | ||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Arm title
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Obinutuzumab + Bendamustine | ||||||||||||||||
Arm description |
Subjects received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Bendamustine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
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.
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Investigational medicinal product name |
Obinutuzmab
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Investigational medicinal product code |
RO5072759
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
1000 mg given by IV infusion on Days 1, 8, and 15 of Cycle 1 and on Day 1 of subsequent cycles.
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Baseline characteristics reporting groups
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Reporting group title |
Obinutuzumab + Bendamustine
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Reporting group description |
Subjects received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles. | |||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Obinutuzumab + Bendamustine
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Reporting group description |
Subjects received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles. | ||
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End point title |
Overall Response Rate (ORR) as Assessed by the Investigator Using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria [1] | ||||||||
End point description |
ORR was defined as percentage of subjects 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. Efficacy population included all subjects, who received at least one dose of both treatments (bendamustine and obinutuzumab).
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End point type |
Primary
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End point timeframe |
2-3 months after last dose of the study treatment (up to approximately 9 months)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analyses were planned for this one arm study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Best Response Rate (BRR) as Assessed by the Investigator Using the IWCLL 2008 Criteria | ||||||||||||||
End point description |
Best overall response was defined as percentage of subjects achieving a BR of CR, CRi and PR. CR: lymphocytes below 4x10^9/L, absence of lymphadenopathy, hepatomegaly and splenomegaly, absence of disease or constitutional symptoms, neutrophils >1.5x10^9/L, platelets >100x10^9/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 liver if enlarged at baseline OR reduction ≥50% of the size of the spleen if enlarged at baseline PLUS one of the following: neutrophils >1.5x10^9/L, platelets >100x10^9/L, hemoglobin >110 g/L or increase ≥50% compared to pre-treatment. Efficacy population included all subjects, who received at least one dose of both treatments (bendamustine and obinutuzumab). Reported here is the number of subjects for whom data for BR achieved were available.
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End point type |
Secondary
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End point timeframe |
During study treatment and until 6 months after end of study treatment at approximately 12 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Progression Free Survival (PFS) | ||||||||
End point 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 5x10^9/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 100x10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0x10^9/L if the marrow biopsy also shows infiltration of clonal CLL cells. Efficacy population included all subjects, who received at least one dose of both treatments (bendamustine and obinutuzumab).
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End point type |
Secondary
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End point timeframe |
From start of treatment up to disease progression or relapse or death, whichever occurred first (up to approximately 4.5 years)
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (OS) | ||||||||
End point description |
OS was defined as the time from the start of study treatment to death from any cause. Efficacy population included all subjects, who received at least one dose of both treatments (bendamustine and obinutuzumab). Here, 99999 indicates that median of OS for efficacy population was not reached.
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End point type |
Secondary
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End point timeframe |
From start of treatment up to death of any cause (up to approximately 4.5 years)
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| No statistical analyses for this end point | |||||||||
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End point title |
Event Free Survival (EFS) | ||||||||
End point 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. Efficacy population included all subjects, who received at least one dose of both treatments (bendamustine and obinutuzumab).
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Disease Free Survival (DFS) | ||||||||
End point description |
DFS was defined for all subjects who achieved CRi or CR. DFS lasted from the date on which CRi or CR was recorded until date on which first DP or death from any cause occurred. DP: at least one: increase ≥50% in lymphocytes up to at least 5x10^9/L, appearance of new palpable lymph nodes, increase ≥50% of longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥50% of size of 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 100x10^9/L and/or decrease in neutrophil counts by more than 50% or to below 1.0x10^9/L if marrow biopsy also shows infiltration of clonal CLL cells. Efficacy population included all subjects, who received at least one dose of both treatments (bendamustine and obinutuzumab). Included in the analysis are subjects who achieved CRi or CR.
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End point type |
Secondary
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End point timeframe |
From occurrence of complete response up to disease progression or death, whichever occurred first (up to approximately 4.5 years)
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Response (DR) | ||||||||
End point description |
DR was defined for subjects with CRi, CR or PR. DR spanned from date on which response was recorded until the date on which DP or death from any cause occurred. DP: at least one: increase ≥50% in lymphocytes up to at least 5x10^9/L, appearance of new palpable lymph nodes, increase ≥50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥50% of size of 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 100x10^9/L and/or decrease in neutrophil counts by more than 50% or to below 1.0 x 10^9/L if marrow biopsy also shows infiltration of clonal CLL cells. Efficacy population included all subjects, who received at least one dose of both treatments (bendamustine and obinutuzumab). Included in the analysis are subjects who achieved CRi, CR or PR.
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End point type |
Secondary
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End point timeframe |
From occurrence of CR or PR up to disease progression or death, whichever occurred first (up to approximately 4.5 years)
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Re-treatment/New Anti-leukemia Therapy | ||||||||
End point 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. Efficacy population included all subjects, who received at least one dose of both treatments (bendamustine and obinutuzumab). Here, 99999 indicates that median of time to re-treatment for efficacy population was not reached.
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End point type |
Secondary
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End point timeframe |
Up to 4.5 years
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects With Minimal Residual Disease (MRD) Negativity | ||||||||||||
End point 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. Intent-to-treat (ITT) population included all subjects, who received at least one dose of any treatment.
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End point type |
Secondary
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End point timeframe |
At approximately 9 months
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | ||||||||||||
End point description |
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavourable 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 hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/ birth defect, and was considered a significant medical event by the investigator. Safety population included all subjects, who received at least one dose of any treatment.
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End point type |
Secondary
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End point timeframe |
Up to approximately 4.5 years
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects With AEs of Special Interest (AESIs) | ||||||||
End point 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. Safety population included all subjects, who received at least one dose of any treatment.
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End point type |
Secondary
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End point timeframe |
Up to approximately 4.5 years
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects With Infusion-related Reactions (IRRs) | ||||||||
End point description |
IRRs were defined as AEs occurring during or within 24 hours following the administration of an infusion and considered related to drug treatment. Safety population included all subjects, who received at least one dose of any treatment.
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End point type |
Secondary
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End point timeframe |
Up to end of treatment at 6 months
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects Who Discontinued Treatment Prematurely | ||||||||
End point description |
Safety population included all subjects, who received at least one dose of any treatment.
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End point type |
Secondary
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End point timeframe |
Up to end of treatment at 6 months
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects With Previous/Concomitant Diseases | ||||||||
End point description |
Safety population included all subjects, who received at least one dose of any treatment.
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End point type |
Secondary
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End point timeframe |
Up to approximately 4.5 years
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects With Concomitant Medication | ||||||||
End point 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. Safety population included all subjects, who received at least one dose of any treatment.
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End point type |
Secondary
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End point timeframe |
From 7 days prior to screening to the end of treatment at 6 months
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to approximately 4.5 years
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Adverse event reporting additional description |
Safety population included all subjects, who received at least one dose of any treatment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
Obinutuzumab + Bendamustine
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Reporting group description |
Subjects received obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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27 Mar 2014 |
Protocol was amended to reflect changes in the safety profile of obinutuzumab with regard to a higher incidence of thrombocytopenia and haemorrhagic events during the first cycle in patients with CLL treated with obinutuzumab plus chlorambucil, as compared to patients treated with rituximab plus chlorambucil or chlorambucil alone, in the phase 3 pivotal study BO21004/2009-012476-28. Patients who experienced Grade 3 or 4 neutropenia were to be monitored until neutrophil values returned to at least Grade 2. The use of G-CSF was allowed for treatment of neutropenia in this study. Primary prophylaxis with G-CSF was recommended according to the American Society of Clinical Oncology (ASCO), the European Organisation for Research and Treatment of Cancer (EORTC), and European Society for Medical Oncology (ESMO) guidelines, namely for patients who were >/= 60 years old and/or with co-morbidities. Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after the infusion) had been observed during treatment with obinutuzumab. Fatal haemorrhagic events had also been reported in subjects treated with obinutuzumab. It seemed that the first cycle was the greatest risk of haemorrhage in obinutuzumab-treated subjects. A clear relationship between thrombocytopenia and haemorrhagic events had not been established. Subjects treated with concomitant medication, which could possibly worsen thrombocytopenia-related events such as platelet inhibitors and anticoagulants, could be at greater risk of bleeding. Subjects were to be closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests were to be performed until the event resolved, and dose delays were to be considered in case of severe or life-threatening thrombocytopenia. Transfusion of blood products (i.e. platelet transfusion) according to institutional practice was at the discretion of the treating physician. |
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29 Jan 2015 |
Protocol was amended to add clarity to elements that were causing confusion at study sites based on experiences and to correct errors. Additional guidance was added to improve management and increase the safety of patients. The amendment also sought to communicate the risk of tumor lysis syndrome (TLS) and reinforced adherence to the protocol when treating subjects in the study: Guidance was clarified to improve the management and emphasis on the monitoring of patients who were at high risk for tumor lysis syndrome (TLS). Bendamustine is contraindicated in subjects with severe blood count alterations. Therefore, subjects who received bendamustine had to have a leukocyte count > 3,000/mcL at baseline. Patients with prolymphocytic transformation could not be enrolled in the study. For Grade 3 or 4 adverse events when obinutuzumab was administered on Days 1, 2, 8 and 15, up to 2 weeks delay for infusions was allowed during Cycle 1. For subsequent obinutuzumab cycles, a maximum dose delay of 4 weeks was permitted per cycle due to toxicity. A maximum of 8 weeks of cumulative delay due to toxicity was allowed in total per subjects. In patients receiving chemotherapy,
chemotherapy had to be similarly delayed matching any obinutuzumab delay and vice versa. Premedication guidance was clarified according to the recommendations for management of Infusion Related Reactions in the obinutuzumab safety reference document. In order to collect more robust data in this broader patient population, immunoglobulins and beta2-microglobulin were now to be tested. Concerning the study visits there was to be a visit of End of Treatment 28 days after last study drug administration, as well as the Final Response Assessment Visit 2-3 months after last study drug
administration. |
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06 Oct 2015 |
Protocol was amended in order to extend the exploratory study of the prognostic markers as well as to be consistent with updated safety information regarding gastrointestinal (GI) perforation as an important identified risk associated with obinutuzumab. Cases of GI perforation were reported in patients receiving obinutuzumab, mainly in Non-Hodgkin Lymphoma (NHL). Patients with GI involvement had to be monitored for signs of GI perforation. |
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31 Mar 2016 |
Protocol was amended to implement additional risk minimization measures in patients with chronic lymphocytic leukemia (CLL) at risk of tumor lysis syndrome (TLS) treated with a combination of obinutuzumab and bendamustine. These measures included additional monitoring and laboratory assessments during Cycle 1. If the Howard criteria for TLS were fulfilled (two or more electrolyte laboratory abnormalities present simultaneously) or if a medically relevant laboratory abnormality in TLS-related parameters or a sign of clinical TLS
(e.g. increased serum creatinine or cardiac dysrhythmia) were noted, study drugs were to be withheld and patients were to be hospitalized and adequately treated until normalisation of laboratory abnormalities. After normalisation, treatment could be restarted. Patients were to be informed about symptoms or signs of TLS and advised to contact the investigator immediately if any such symptoms occurred. |
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31 May 2017 |
Protocol was amended to consider second malignancies as an adverse event of special interest (AESI) and report these events indefinitely, regardless of relationship to study treatment (even if the study has been closed). |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
