Clinical Trial Results:
An Open-label, Multicenter Phase 2 Study to Investigate the Efficacy, Safety, and Tolerability of the Bi-specific T-cell Engager (BiTE®) MT103 in Patients with Minimal Residual Disease (MRD) of Positive B-precursor Acute Lymphoblastic Leukemia (ALL)
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Summary
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EudraCT number |
2006-006520-19 |
Trial protocol |
DE |
Global end of trial date |
03 Nov 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Jun 2016
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First version publication date |
04 Jun 2016
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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 |
MT103-202
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00560794 | ||
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 |
03 Nov 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
01 Sep 2009
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Nov 2014
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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 purpose of this study is to determine whether the bispecific T-cell engager (BiTE®) blinatumomab (MT103) is effective in the treatment of patients with ALL and minimal residual disease.
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Protection of trial subjects |
This study was conducted in accordance with applicable laws and regulations, Good Clinical Practice (GCP), and the ethical principles that have their origin in the Declaration of Helsinki. All informed consent documents were compliant with the International Conference on Harmonisation (ICH) guidelines on GCP.
The study protocol including any amendments (if applicable), informed consent form,
and any accompanying material provided to the subject (such as information or descriptions of the study used to obtain informed consent) were reviewed and approved by the IEC. A copy of the written approval of the protocol and informed consent form received by Amgen before recruitment of subjects into the study and shipment of Amgen investigational product.
The subject’s free and expressed informed consent was to be obtained in writing prior to any enrollment into the study according to all applicable regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 Jan 2008
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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 |
5 Years | ||
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 |
Germany: 21
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Worldwide total number of subjects |
21
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EEA total number of subjects |
21
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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) |
15
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 32 subjects were enrolled and screened in this study; 11 subjects screen failed and 21 subjects received ≥ 1 infusion of investigational product and were included in the safety analysis set. | ||||||||||||||||||||
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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 as continuous intravenous infusion at constant flow rate over 4 weeks followed by a 2-week treatment-free period (defined as one treatment cycle), for up to a maximum of 10 cycles. The initial dose was 15 μg/m²/day. A dose increase to 30 μg/m²/day was permitted with evidence for insufficient response to blinatumomab treatment. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Blinatumomab
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Investigational medicinal product code |
MT103
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Other name |
BLINCYTO™
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Pharmaceutical forms |
Powder for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Administered by continuous intravenous infusion (CIV) over 4 weeks per cycle
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Baseline characteristics reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
Participants received blinatumomab as continuous intravenous infusion at constant flow rate over 4 weeks followed by a 2-week treatment-free period (defined as one treatment cycle), for up to a maximum of 10 cycles. The initial dose was 15 μg/m²/day. A dose increase to 30 μg/m²/day was permitted with evidence for insufficient response to blinatumomab 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 as continuous intravenous infusion at constant flow rate over 4 weeks followed by a 2-week treatment-free period (defined as one treatment cycle), for up to a maximum of 10 cycles. The initial dose was 15 μg/m²/day. A dose increase to 30 μg/m²/day was permitted with evidence for insufficient response to blinatumomab treatment. | ||
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End point title |
Percentage of Participants with a Minimal Residual Disease (MRD) Response Within 4 Cycles of Treatment [1] | ||||||||
End point description |
MRD Response is defined as:
- If Philadelphia Chromosome (Ph) positive (+) or translocation (t) (4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10^-4.
- If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10^-4.
The full analysis set included all participants who received ≥ 1 infusion of blinatumomab who completed at least the first treatment cycle and for whom at least one minimal residual disease (MRD) response assessment was available.
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End point type |
Primary
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End point timeframe |
Within 4 treatment cycles, 24 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: The EudraCT system does not allow statistical analyses to be entered for studies with just one treatment arm. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with an MRD Response After Each Treatment Cycle | ||||||||||||||||
End point description |
MRD Response is defined as:
- If Philadelphia Chromosome (Ph)+ or t(4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10^-4.
- If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10^-4.
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End point type |
Secondary
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End point timeframe |
At the end of each treatment cycle - Weeks 4, 10, 16, and 22.
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Time to Hematological Relapse | ||||||||
End point description |
The time to hematological relapse is defined as the time between start of first infusion of blinatumomab and the first result of hematological relapse. Participants without an event of hematological relapse were censored on their last available date of bone marrow aspiration/biopsy.
Hematological relapse is defined as > 5% leukemia cells in bone marrow.
Time to hematological relapse was analyzed using Kaplan-Meier methods. "99999" indicates data not estimable.
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End point type |
Secondary
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End point timeframe |
Up to the data cut-off date of 14 January 2010; maximum duration of follow-up was 564 days.
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to MRD Progression | ||||||||
End point description |
Time to MRD progression is defined for participants who do not show MRD response at any time during the study as the time from start of first infusion until the first result of MRD progression or hematological relapse, if no MRD progression was diagnosed before hematological relapse. For participants who showed MRD response during the study the time to MRD progression is defined as the time from the date of the first MRD response to the date of MRD relapse. Participants without an event of MRD progression were censored on the day of their last bone marrow aspiration/biopsy. Participants who received a bone marrow transplant were censored on the last day of bone marrow aspiration/biopsy before transplantation.
MRD progression is defined as the increase in the MRD level by 1 log as compared to the baseline level (equal to a 10-fold increase in the number of MRD cells), and had to be confirmed within 6 weeks.
"99999" indicates data not estimable.
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End point type |
Secondary
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End point timeframe |
Up to the data cut-off date of 14 January 2010; Median follow-up time was 155 days
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to MRD Relapse | ||||||||
End point description |
Time to MRD relapse is defined only for participants with an MRD response during the study, defined as the time between the date of the first MRD response and the date of MRD relapse. If a participant experienced hematological relapse without having shown MRD positivity before then the time point of MRD relapse is defined as the time point of hematological relapse. Participants without an event of MRD relapse or hematological relapse were censored on the day of their last available bone marrow aspiration/biopsy. If a participant received a bone marrow transplant the last day of bone marrow aspiration/biopsy before transplantation was used as time point for censoring.
MRD relapse is defined as reappearance of bcr/abl, and/or t(4;11) translocation at any detection level, and/or by individual rearrangements of immunoglobulin or T-cell receptor genes ≥10^-4 for at least 1 individual marker measured by an assay with a sensitivity of minimum 10^-4 and should be confirmed within 6 weeks.
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End point type |
Secondary
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End point timeframe |
Up to the data cut-off date of 14 January 2010; Median follow-up time was 116.5 days
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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 |
The severity (or intensity) of AEs was evaluated according to the grading scale provided in the Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, or according to the following: Grade 1 – Mild AE; Grade 2 – Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death.
The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab.
A serious adverse event (SAE) is any untoward medical occurrence or effect that, at any dose results in death, is life-threatening, requires or prolongs hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. In addition, all laboratory abnormalities of grade four severity that occur during or after administration of the investigational drug, any overdose and a pregnancy or fathering were reported as SAEs.
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End point type |
Secondary
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End point timeframe |
From the start of study treatment until up to 4 weeks after the end of study treatment. The median treatment duration was 87.3 days.
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Screening Value in B-cell Count During Cycle 1 | ||||||||||||||||||||||||||||||||
End point description |
B-cells were measured by flow cytometry.
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End point type |
Secondary
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End point timeframe |
At Screening and in Cycle 1 at the start of infusion, 45 minutes, 2, 6, 12, 24 hours and at Days 2, 7, 14, 21, 28 and 35 after the start of infusion.
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Change From Screening Value in T-cell Count During Cycle 1 | ||||||||||||||||||||||||||||||||
End point description |
T-cells were measured by flow cytometry.
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End point type |
Secondary
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End point timeframe |
At Screening and in Cycle 1 at the start of infusion, 45 minutes, 2, 6, 12, 24 hours and at Days 2, 7, 14, 21, 28 and 35 after the start of infusion.
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Serum Cytokine Peak Levels in Cycle 1 | ||||||||||||||||||||||
End point description |
The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-γ using fluorescence-activated cell sorter (FACS)-based cytometric bead array (CBA) system. The limit of detection (LOD) for the cytokine determination was 20 pg/mL, the limit of quantification (LOQ) was 125 pg/mL.
"99999" indicates levels less than the limit of quantification or detection.
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End point type |
Secondary
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End point timeframe |
Cycle 1 at pre-dose and at post infusion start at 45 minutes; 2, 6, 12, 24, and 48 hours; 7, 14, 21, and 28 days.
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Serum Blinatumomab Concentration at Steady State | ||||||||
End point description |
The mean serum concentration of blinatumomab during cycle 1.
The LOQ of the assay was 100 pg/mL, and the limit of detection (LOD) was 3 pg/mL.
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End point type |
Secondary
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End point timeframe |
Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Drug Concentration-time Curve From Time Zero to Infinity | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Apparent Volume of Distribution | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Terminal Half-life of Blinatumomab | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Clearance of Blinatumomab | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Hematological Relapse Free Survival (RFS) | ||||||||
End point description |
RFS was calculated from time of start of first infusion until hematological relapse or death. Hematological relapse was defined as ≥ 5% leukemia cells in the bone marrow.
Subjects without an event were censored on their last available date of bone marrow aspiration/biopsy. "99999" indicates data not estimable.
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End point type |
Secondary
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End point timeframe |
Up to 5 years (median follow-up time was 1550 days)
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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 start of study treatment until up to 4 weeks after the end of study treatment. The median treatment duration was 87.3 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 |
11.0
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Reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
Participants received blinatumomab as continuous intravenous infusion at constant flow rate over 4 weeks followed by a 2 week treatment-free period (defined as one treatment cycle), for up to a maximum of 10 cycles. The initial dose was 15 μg/m²/day. A dose increase to 30 μg/m²/day was permitted with evidence for insufficient response to blinatumomab 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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21 Apr 2008 |
- removal of subject upper age limit for inclusion in study
- bone marrow assessment procedure changed to include bone marrow aspiration for measurement of MRD
- change in necessary number of treatment cycles for evaluation of response for dose escalation (at least 1 cycle required instead of 2 cycles)
- deletion of exclusion criterion #10; such that subjects with fulfilled criteria and available donor for allogeneic stem cell transplantation eligible for enrollment
- modification of exclusion criterion #2; changed to current "relevant" CNS pathology
- modification of exclusion criterion #7; added "low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, steroids" as acceptable prior therapy)
- adjustment of infusion restart timepoint rules (corrected to day 0 and day 1)
- modification of the formulation of the blinatumomab IV bag diluent (to minimize the formation of yellow color due to the oxidation of polysorbate 80, the IV Bag Diluent was formulated with 25 mM citric acid as an additional excipient)
- shelf life extension for blinatumomab (up to 48 months) |
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27 Oct 2008 |
- extension of inclusion criterion #2 to bcr/abl and/or t(4;11) translocation at any detection level measured by RT-PCR
- modification of exclusion criterion #15 to threshold of the antithrombin activity for exclusion of subjects from < lower limit of normal (LLN) to < 70%
- modification of exclusion criterion #16 to allow subjects with history of malignancy other than ALL
- change in the time of mandatory anticoagulation during study treatment to first 7 days of each treatment cycle
- change in criteria for dose escalation
- addition of secondary endpoint of MRD response after any treatment cycle |
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24 Mar 2009 |
- recommendation of intrathecal prophylaxis during treatment
- reduction of number of PD and PK assessments
- prolongation of hospitalization for monitoring following dose escalation
- adaption of informed consent form
- change of principal investigator at Dresden site |
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25 Jan 2010 |
- change in post-study follow-up period assessments and times
- change from electronic CRFs to paper version in post study follow-up period
- specification of duration of subject participation/duration of study to up to 62 weeks for core study
- change in planned statistical analysis to remove comparison of time to event analyses to historical control data |
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02 Mar 2011 |
- prolong the administration period of blinatumomab final solution from 7 to 10 days
- administrative changes regarding study site personnel contact information |
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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 | |||
