Clinical Trial Results:
A Phase 2 Single Arm, Multicenter Trial to Evaluate the Efficacy of the BiTE® Antibody Blinatumomab in Adult Subjects With Relapsed/Refractory Philadelphia Positive B-precursor Acute Lymphoblastic Leukemia (Alcantara Study)
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Summary
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EudraCT number |
2013-000706-36 |
Trial protocol |
IT GB DE |
Global end of trial date |
06 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Dec 2017
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First version publication date |
30 Dec 2017
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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 |
20120216
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02000427 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Amgen Inc.
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Sponsor organisation address |
One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
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Public contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
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Scientific contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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 |
06 Jan 2017
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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 |
06 Jan 2017
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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 |
The primary objective was to evaluate the rate of complete remission (CR)/complete remission with partial hematological recovery (CRh*) in adult subjects with relapsed/refractory Philadelphia chromosome (Ph)-positive B-precursor acute lymphoblastic leukemia (ALL).
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and United States Food and Drug Administration regulations/guidelinese.
The study protocol and all amendments were reviewed by an independent ethics committee (IEC) or institutional review board (IRB).
Before a subject’s participation in the clinical study, the investigator was responsible for obtaining written informed consent from the subject or legally acceptable representative after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before any protocol-specific screening procedures or any investigational products were administered.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Jan 2014
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy | ||
Long term follow-up duration |
18 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
United States: 11
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Country: Number of subjects enrolled |
Italy: 14
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Country: Number of subjects enrolled |
France: 11
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
United Kingdom: 3
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Worldwide total number of subjects |
45
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EEA total number of subjects |
34
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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) |
33
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From 65 to 84 years |
12
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted at 19 centers in 4 European countries and the United States: 3 centers in France, 3 in Germany, 5 in Italy, 1 in the United Kingdom, and 7 in the United States. The first participant enrolled on 03 January 2014 and the last participant enrolled on 12 January 2015. | ||||||||||
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Pre-assignment
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Screening details |
This was a single-arm, Simon 2-stage design, multicenter study that consisted of a 3-week screening and prephase period for the administration of dexamethasone to reduce both tumor burden and the incidence of tumor lysis syndrome, an induction phase of 2 cycles of blinatumomab, a consolidation phase, and a long-term follow-up phase. | ||||||||||
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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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Blinatumomab | ||||||||||
Arm description |
Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Blinatumomab
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Investigational medicinal product code |
MT103
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Other name |
AMG 103
Blincyto®
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Blinatumomab is administered as a continuous intravenous infusion (CIV). A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks of blinatumomab followed by a 2-week treatment-free interval.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment. | ||
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End point title |
Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery (CR/CRh*) During the First Two Treatment Cycles [1] | ||||||||
End point description |
Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts.
Complete remission was defined as meeting all 3 of the following criteria:
• less than or equal to 5% blasts in the bone marrow;
• no evidence of disease
• full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl.
Complete remission with partial hematological recovery (CRh*) was defined as meeting all 3 of the following criteria:
• less than or equal to 5% blasts in the bone marrow
• no evidence of disease
• partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl.
The analysis was based on the full analysis set which included all participants who received an infusion of blinatumomab. Participants without a post-baseline disease assessment were considered non-responders.
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End point type |
Primary
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End point timeframe |
Approximately 12 weeks
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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: Statistical analyses were not performed in this single-arm study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Minimal Residual Disease (MRD) Remission During the First 2 Cycles of Treatment | ||||||||
End point description |
Bone marrow samples were evaluated for MRD remission by a central laboratory using bcr-abl fusion gene reverse transcription polymerase chain reaction (RT-PCR).
An MRD response was defined as MRD < 10^-4 measured by PCR.
The analysis was based on the full analysis set. Participants with no post-baseline MRD assessment were considered non-responders.
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End point type |
Secondary
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End point timeframe |
Approximately 12 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of CR or CRh* Response | ||||||||
End point description |
Duration of response was measured for participants in remission (CR/CRh*), and was measured from the time the participant first achieved remission until first documented relapse or death from disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of the last bone marrow assessment or the last survival follow-up visit to confirm remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their date of death.
The analysis was based on the full analysis set with a CR or CRh* response during the first 2 treatment cycles. "99999" indicates data that could not be estimated.
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End point type |
Secondary
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End point timeframe |
Up to the final analysis cut-off date; median observation time was 16.1 months
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Complete Remission (CR) During the First Two Treatment Cycles | ||||||||
End point description |
Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts.
Complete remission was defined as meeting all 3 of the following criteria:
• less than or equal to 5% blasts in the bone marrow;
• no evidence of disease;
• full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl.
The analysis was based on the full analysis set. Participants without a post-baseline disease assessment were considered non-responders.
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End point type |
Secondary
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End point timeframe |
Approximately 12 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Complete Remission With Partial Hematological Recovery (CRh*) During the First Two Treatment Cycles | ||||||||
End point description |
Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts.
Complete remission with partial hematological recovery (CRh*) was defined as meeting all 3 of the following criteria:
• less than or equal to 5% blasts in the bone marrow;
• no evidence of disease;
• partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl.
The analysis was based on the full analysis set. Participants without a post-baseline disease assessment were considered non-responders.
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End point type |
Secondary
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End point timeframe |
Approximately 12 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi) During the First Two Treatment Cycles | ||||||||
End point description |
Complete remission was defined as meeting the following criteria:
• less than or equal to 5% blasts in the bone marrow;
• no evidence of disease;
• full recovery of peripheral blood counts: platelets > 100,000/μl, and ANC > 1000/μl.
Complete remission with partial hematological recovery was defined as meeting the following criteria:
• less than or equal to 5% blasts in the bone marrow;
• no evidence of disease;
• partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl.
Complete remission with incomplete hematologic recovery was defined as meeting all of the following criteria:
• less than or equal to 5% blasts in the bone marrow;
• no evidence of disease;
• incomplete recovery of peripheral blood counts: platelets > 100,000/μl or ANC > 1000/μl.
The analysis was based on the full analysis set. Participants without a post-baseline disease assessment were considered non-responders.
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End point type |
Secondary
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End point timeframe |
Approximately 12 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival | ||||||||
End point description |
Overall survival was assessed from the date the participant received the first infusion of blinatumomab until death from any cause or the date of the last follow-up.
Participants still alive at the data cut-off date were censored on the last documented visit date or the date of the last contact when the patient was last known to have been alive.
The analysis was based on the full analysis set.
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End point type |
Secondary
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End point timeframe |
From first dose of blinatumomab until the final analysis data cut-off date; median observation time was 25.1 months.
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission | ||||||||
End point description |
Participants who achieved remission (CR/CRh*) during the first 2 cycles of treatment and received an allogeneic HSCT.
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End point type |
Secondary
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End point timeframe |
Up to the final analysis data cut-off date; maximum duration on study was 26.1 months.
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| No statistical analyses for this end point | |||||||||
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End point title |
100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant | ||||||||
End point description |
The analysis of 100-day mortality after allogeneic HSCT was assessed for participants who received an allogeneic HSCT while in remission (CR/CRh*) after 2 cycles of blinatumomab treatment and did not receive any additional antileukemic treatment. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT.
The 100-day mortality rate after allogeneic HSCT was defined as the percentage of participants having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive.
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End point type |
Secondary
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End point timeframe |
From the date of allogeneic HSCT until the final analysis data cut-off date; maximum observation time was 16.9 months.
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants With Adverse Events | ||||||||||||||||||||||||||||||||||
End point description |
Adverse events (AEs) were graded for severity according to the CTCAE version 4.0, where Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living.
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living.
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
Treatment-related adverse events (TRAEs) were those assessed by the investigator as possibly related to blinatumomab based on response to the question: Is there a reasonable possibility that the event may have been caused by blinatumomab or other protocol-specified therapies/procedures?
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End point type |
Secondary
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End point timeframe |
From the first dose of blinatumomab until 30 days after the last dose; the median duration of treatment was 53.8 days.
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||
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End point title |
Number of Participants Who Developed Anti-blinatumomab Antibodies | ||||||||
End point description |
Anti-blinatumomab binding antibodies were evaluated with a validated blinatumomab anti-drug antibody assay with the electrochemiluminescence detection technology.
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End point type |
Secondary
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End point timeframe |
Day 29 of each treatment period and 30 days after the last dose
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| Notes [2] - Participants with available post-baseline antibody results |
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| No statistical analyses for this end point | |||||||||
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End point title |
Steady State Concentration of Blinatumomab | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Cycle 1, day 8, 6 to 8 hours after the dose step to 28 μg/day, and Cycle 2, day 1, 6 to 8 hours after blinatumomab infusion
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| Notes [3] - Participants with available serum concentration data |
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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 |
From the first dose of blinatumomab until 30 days after the last dose; the median duration of treatment was 53.8 days.
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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 |
19.1
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Reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 Jun 2013 |
Added an external independent data monitoring committee (DMC) to oversee the interim analysis and assess safety approximately every 6 months provided an adequate enrollment rate. |
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15 Sep 2014 |
- Clarified timing and scope of study procedures
- Specified that tyrosine kinase inhibitor therapy within 2 weeks before start of blinatumomab was not exclusionary, but was to be completed before start of treatment
- Provided updated information on packaging and presentation of blinatumomab investigational product
- Replaced the term “CNS events” with the term “neurologic events” throughout to describe clinically relevant neurologic events associated with introduction to blinatumomab
- Provided instructions on blinatumomab overdose reporting (> 10%) as a serious adverse event under the criterion of “other medically important serious event”
- Clarified requirements for medical coverage and safety monitoring in the outpatient setting
- Provided specific guidance for blinatumomab dose modifications from grade 3 infection events
- Clarified criteria for discontinuation of blinatumomab and withdrawal of subjects
- Clarified definitions for evaluation of treatment response
- Clarified objectives, endpoints, and scope of statistical
analyses |
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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 | |||
