Clinical Trial Results:
A Randomized, Open-label, Controlled Phase 3 Trial to Investigate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab as Consolidation Therapy Versus Conventional Consolidation Chemotherapy in Pediatric Subjects With High-risk First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)
Summary
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EudraCT number |
2014-002476-92 |
Trial protocol |
DE CZ BE IT SE PT DK AT GB PL ES FR NL Outside EU/EEA GR NO HU RO |
Global end of trial date |
21 Nov 2022
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Results information
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Results version number |
v2(current) |
This version publication date |
30 Jun 2023
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First version publication date |
19 May 2023
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Other versions |
v1 |
Version creation reason |
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 |
20120215
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02393859 | ||
WHO universal trial number (UTN) |
- | ||
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,
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Public contact |
Study Director, Amgen Inc., +1 8665726436, medinfo@amgen.com
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Scientific contact |
Study Director, Amgen Inc., +1 8665726436, medinfo@amgen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000574-PIP02-12 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Nov 2022
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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 |
21 Nov 2022
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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 event-free survival (EFS) after blinatumomab when compared to standard of care (SOC) chemotherapy.
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Protection of trial subjects |
The study was conducted in accordance with the International Council for Harmonisation Good Clinical Practice and applicable national or regional regulations/guidelines.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
10 Nov 2015
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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 |
36 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 |
Australia: 4
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
Czechia: 2
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Country: Number of subjects enrolled |
Denmark: 2
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Country: Number of subjects enrolled |
Israel: 3
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Country: Number of subjects enrolled |
Netherlands: 2
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Country: Number of subjects enrolled |
Poland: 2
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Country: Number of subjects enrolled |
France: 11
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Country: Number of subjects enrolled |
Germany: 22
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Country: Number of subjects enrolled |
Italy: 42
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Country: Number of subjects enrolled |
Portugal: 4
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Country: Number of subjects enrolled |
Spain: 8
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Country: Number of subjects enrolled |
United Kingdom: 7
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Worldwide total number of subjects |
111
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EEA total number of subjects |
97
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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) |
3
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Children (2-11 years) |
88
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Adolescents (12-17 years) |
20
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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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 48 centers across 13 countries (Europe, Australia, Israel). The first participant was enrolled on 10 November 2015. The last participant enrolled on 30 August 2019. The primary completion date was 17 July 2019 and the study completion date was 21 November 2022. | |||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
After a 3-week screening period, participants were enrolled and randomized 1:1 into 1 of 2 treatment groups: High Risk Consolidation 3 (HC3) chemotherapy or blinatumomab. Randomization was stratified by age and bone marrow/minimal residual disease (MRD) status. | |||||||||||||||||||||||||||||||||
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 |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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HC3 Chemotherapy | |||||||||||||||||||||||||||||||||
Arm description |
One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m^2/day intravenous [IV] on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and pegylated [PEG]-asparaginase (1000 U/m^2 IV for 2 hours or intramuscularly [IM] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses). | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SOC chemotherapy
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use, Intramuscular use
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Dosage and administration details |
The standard intensive consolidation chemotherapy course HC3 included dexamethasone (10 mg/m^2/day IV on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and PEG-asparaginase (1000 U/m^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses).
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Arm title
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Blinatumomab | |||||||||||||||||||||||||||||||||
Arm description |
One 4-week cycle of blinatumomab 15 μg/m^2/day as a continuous intravenous infusion (CIVI). | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Blinatumomab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion, Powder for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Blinatumomab was administered as CIVI at a constant daily flow rate of 15 µg/m^2/day over 4 weeks (1 cycle).
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Baseline characteristics reporting groups
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Reporting group title |
HC3 Chemotherapy
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Reporting group description |
One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m^2/day intravenous [IV] on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and pegylated [PEG]-asparaginase (1000 U/m^2 IV for 2 hours or intramuscularly [IM] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Blinatumomab
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Reporting group description |
One 4-week cycle of blinatumomab 15 μg/m^2/day as a continuous intravenous infusion (CIVI). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
HC3 Chemotherapy
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Reporting group description |
One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m^2/day intravenous [IV] on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and pegylated [PEG]-asparaginase (1000 U/m^2 IV for 2 hours or intramuscularly [IM] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses). | ||
Reporting group title |
Blinatumomab
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Reporting group description |
One 4-week cycle of blinatumomab 15 μg/m^2/day as a continuous intravenous infusion (CIVI). | ||
Subject analysis set title |
HC3 Chemotherapy (Primary Analysis)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants in the full analysis set at the primary completion date randomized to HC3 chemotherapy. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m^2/day intravenous [IV] on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and pegylated [PEG]-asparaginase (1000 U/m^2 IV for 2 hours or intramuscularly [IM] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses).
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Subject analysis set title |
Blinatumomab (Primary Analysis)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants in the full analysis set at the primary completion date randomized to blinatumomab
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End point title |
Kaplan Meier Estimate: EFS (Primary Analysis) | ||||||||||||
End point description |
EFS is calculated from the time of randomization until the date of relapse or M2 marrow after having achieved a complete remission (CR), failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. Participants who failed to achieve a CR following treatment with investigational product (IP) or who died before the disease assessment at the end of treatment were considered treatment failures and assigned an EFS duration of 1 day. Participants still alive and event-free were censored on their last disease assessment date. Participants were said to be in CR when they had the following: M1 marrow, peripheral blood without blasts, absence of extramedullary leukemic involvement. Full analysis set (FAS): randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received (primary analysis population).
99999 = data was not estimable.
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End point type |
Primary
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End point timeframe |
As of the primary analysis data cutoff date (17 July 2019), overall median follow-up time for EFS was 22.4 months.
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Statistical analysis title |
Stratified log-rank test | ||||||||||||
Comparison groups |
HC3 Chemotherapy (Primary Analysis) v Blinatumomab (Primary Analysis)
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Number of subjects included in analysis |
108
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
< 0.001 [2] | ||||||||||||
Method |
Stratified log-rank test | ||||||||||||
Confidence interval |
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Notes [1] - Normal score = -11.54 (A normal score < 0 indicates fewer than expected events for blinatumomab relative to HC3 and therefore a longer event-free survival time.) [2] - Stratification factors were: age (1 to 9 years vs other [< 1 year and > 9 years]), and marrow/MRD status (M1 with MRD level < 10^-3 vs M1 with MRD level ≥ 10^-3 vs M2). |
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Statistical analysis title |
Stratified HR with time-dependent covariate | ||||||||||||
Statistical analysis description |
Cox proportional hazard model including time from randomization to allogeneic hematopoietic stem cell transplant. Stratification factors: age and marrow/MRD status. (HR <1.0=lower average event rate and longer EFS for blinatumomab relative to HC3.)
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Comparison groups |
HC3 Chemotherapy (Primary Analysis) v Blinatumomab (Primary Analysis)
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Number of subjects included in analysis |
108
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Stratified HR | ||||||||||||
Point estimate |
0.36
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.2 | ||||||||||||
upper limit |
0.64 | ||||||||||||
Statistical analysis title |
Unstratified HR | ||||||||||||
Statistical analysis description |
Cox proportional hazard model. (HR < 1.0 indicates a lower average event rate and a longer EFS for blinatumomab relative to HC3.)
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Comparison groups |
HC3 Chemotherapy (Primary Analysis) v Blinatumomab (Primary Analysis)
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Number of subjects included in analysis |
108
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Unstratified HR | ||||||||||||
Point estimate |
0.39
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.22 | ||||||||||||
upper limit |
0.7 | ||||||||||||
Statistical analysis title |
Unstratified log-rank test | ||||||||||||
Comparison groups |
HC3 Chemotherapy (Primary Analysis) v Blinatumomab (Primary Analysis)
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Number of subjects included in analysis |
108
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.001 | ||||||||||||
Method |
Unstratified log-rank test | ||||||||||||
Confidence interval |
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Notes [3] - Normal score: -11.16. (A normal score < 0 indicates fewer than expected events for blinatumomab relative to HC3 and therefore a longer event-free survival time.) |
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Statistical analysis title |
Stratified hazard ratio (HR) | ||||||||||||
Statistical analysis description |
Cox proportional hazard model. Stratification factors were: age and marrow/MRD status. (HR < 1.0 indicates a lower average event rate and a longer EFS for blinatumomab relative to HC3.)
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Comparison groups |
HC3 Chemotherapy (Primary Analysis) v Blinatumomab (Primary Analysis)
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Number of subjects included in analysis |
108
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Stratified HR | ||||||||||||
Point estimate |
0.36
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.19 | ||||||||||||
upper limit |
0.66 |
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End point title |
Kaplan Meier Estimate: EFS (Final Analysis) | ||||||||||||
End point description |
EFS is calculated from the time of randomization until the date of relapse or M2 marrow after having achieved a CR, failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. Participants who failed to achieve a CR following treatment with IP or who died before the disease assessment at the end of treatment were considered treatment failures and assigned an EFS duration of 1 day. Participants still alive and event-free were censored on their last disease assessment date. Participants were said to be in CR when they had the following: M1 marrow, peripheral blood without blasts, absence of extramedullary leukemic involvement. FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received (final analysis population).
99999 = data was not estimable.
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End point type |
Primary
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End point timeframe |
At final analysis, overall median follow-up time for EFS was 51.9 months.
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Statistical analysis title |
Stratified log-rank test | ||||||||||||
Comparison groups |
HC3 Chemotherapy v Blinatumomab
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Number of subjects included in analysis |
111
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||
P-value |
< 0.001 [5] | ||||||||||||
Method |
Stratified log-rank test | ||||||||||||
Confidence interval |
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Notes [4] - Normal score: -13.90 (A normal score < 0 indicates fewer than expected events for blinatumomab relative to HC3 and therefore a longer event-free survival time.) [5] - Stratification factors were: age (1 to 9 years vs other [< 1 year and > 9 years]), and marrow/MRD status (M1 with MRD level < 10^-3 vs M1 with MRD level ≥ 10^-3 vs M2). |
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Statistical analysis title |
Unstratified log-rank test | ||||||||||||
Comparison groups |
HC3 Chemotherapy v Blinatumomab
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Number of subjects included in analysis |
111
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Analysis specification |
Pre-specified
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Analysis type |
superiority [6] | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Unstratified log-rank test | ||||||||||||
Confidence interval |
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Notes [6] - Normal score: -13.61 (A normal score < 0 indicates fewer than expected events for Blinatumomab relative to HC3 and therefore a longer event free survival time.) |
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Statistical analysis title |
Unstratified HR | ||||||||||||
Statistical analysis description |
Cox proportional hazard model. (HR < 1.0 indicates a lower average event rate and a longer EFS for blinatumomab relative to HC3.)
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Comparison groups |
HC3 Chemotherapy v Blinatumomab
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Number of subjects included in analysis |
111
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Unstratified HR | ||||||||||||
Point estimate |
0.38
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.22 | ||||||||||||
upper limit |
0.65 | ||||||||||||
Statistical analysis title |
Stratified HR with time-dependent covariate | ||||||||||||
Statistical analysis description |
Cox proportional hazard model including time from randomization to allogeneic hematopoietic stem cell transplant. Stratification factors: age and marrow/MRD status. (HR <1.0=lower average event rate and longer EFS for blinatumomab relative to HC3.)
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Comparison groups |
HC3 Chemotherapy v Blinatumomab
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Number of subjects included in analysis |
111
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Stratified HR | ||||||||||||
Point estimate |
0.34
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.2 | ||||||||||||
upper limit |
0.59 | ||||||||||||
Statistical analysis title |
Stratified HR | ||||||||||||
Statistical analysis description |
Cox proportional hazard model. Stratification factors were: age and marrow/MRD status. (HR < 1.0 indicates a lower average event rate and a longer EFS for blinatumomab relative to HC3.)
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Comparison groups |
HC3 Chemotherapy v Blinatumomab
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Number of subjects included in analysis |
111
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Stratified HR | ||||||||||||
Point estimate |
0.35
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.2 | ||||||||||||
upper limit |
0.61 |
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End point title |
Kaplan Meier Estimate: Overall Survival (OS) | ||||||||||||
End point description |
OS was calculated from time of randomization until death due to any cause. Participants still alive were censored at the date they were last known to be alive.
FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received.
99999 = data was not estimable.
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End point type |
Secondary
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End point timeframe |
At final analysis, overall median follow-up time for OS was 55.2 months.
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Statistical analysis title |
Stratified log-rank test | ||||||||||||
Comparison groups |
HC3 Chemotherapy v Blinatumomab
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Number of subjects included in analysis |
111
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Analysis specification |
Pre-specified
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Analysis type |
superiority [7] | ||||||||||||
P-value |
= 0.001 [8] | ||||||||||||
Method |
Stratified log-rank test | ||||||||||||
Confidence interval |
|||||||||||||
Notes [7] - Normal score: -10.14 (A normal score < 0 indicates fewer than expected events for blinatumomab relative to HC3 and therefore a longer event-free survival time.) [8] - Stratification factors were: age (1 to 9 years vs other [< 1 year and > 9 years]), and marrow/MRD status (M1 with MRD level < 10^-3 vs M1 with MRD level ≥ 10^-3 vs M2). |
|||||||||||||
Statistical analysis title |
Unstratified HR | ||||||||||||
Statistical analysis description |
Cox proportional hazard model. (HR < 1.0 indicates a lower average event rate and a longer survival for blinatumomab relative to HC3.)
|
||||||||||||
Comparison groups |
HC3 Chemotherapy v Blinatumomab
|
||||||||||||
Number of subjects included in analysis |
111
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
Unstratified HR | ||||||||||||
Point estimate |
0.32
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.16 | ||||||||||||
upper limit |
0.65 | ||||||||||||
Statistical analysis title |
Stratified HR | ||||||||||||
Statistical analysis description |
Cox proportional hazard model. Stratification factors were: age and marrow/MRD status. (HR < 1.0 indicates a lower average event rate and a longer survival for blinatumomab relative to HC3.)
|
||||||||||||
Comparison groups |
HC3 Chemotherapy v Blinatumomab
|
||||||||||||
Number of subjects included in analysis |
111
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
Stratified HR | ||||||||||||
Point estimate |
0.33
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.16 | ||||||||||||
upper limit |
0.66 | ||||||||||||
Statistical analysis title |
Unstratified log-rank test | ||||||||||||
Comparison groups |
HC3 Chemotherapy v Blinatumomab
|
||||||||||||
Number of subjects included in analysis |
111
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [9] | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Unstratified log-rank test | ||||||||||||
Confidence interval |
|||||||||||||
Notes [9] - Normal score: -10.32 (A normal score < 0 indicates fewer than expected events for blinatumomab relative to HC3 and therefore a longer event-free survival time.) |
|
|||||||||||||||||||
End point title |
Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation | ||||||||||||||||||
End point description |
At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory. MRD response was defined as MRD level < 10^-4, by polymerase chain reaction (PCR) or flow cytometry, at the end of treatment (Cycle 1 Day 29) with study drug. Participants who were part of the MRD Evaluable Set and were missing the end of treatment (Cycle 1 Day 29) assessment for a respective MRD assessment method were considered not to have achieved a response. MRD Evaluable Set: participants for whom an evaluable baseline MRD marker can be found with either of the MRD assessment methods of PCR or flow cytometry.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Up to End of Treatment (Cycle 1, Day 29)
|
||||||||||||||||||
|
|||||||||||||||||||
Statistical analysis title |
MRD response by flow cytometry | ||||||||||||||||||
Comparison groups |
HC3 Chemotherapy v Blinatumomab
|
||||||||||||||||||
Number of subjects included in analysis |
110
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
< 0.001 [10] | ||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||
Confidence interval |
|||||||||||||||||||
Notes [10] - Cochran-Mantel-Haenszel test adjusting for the stratification factors: age (1 to 9 years vs other [< 1 year and > 9 years]), and marrow/MRD status (M1 with MRD level < 10-3 vs M1 with MRD level ≥ 10-3 vs M2). |
|||||||||||||||||||
Statistical analysis title |
MRD response by PCR | ||||||||||||||||||
Comparison groups |
HC3 Chemotherapy v Blinatumomab
|
||||||||||||||||||
Number of subjects included in analysis |
110
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
< 0.001 [11] | ||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||
Confidence interval |
|||||||||||||||||||
Notes [11] - Cochran-Mantel-Haenszel test adjusting for the stratification factors: age (1 to 9 years vs other [< 1 year and > 9 years]), and marrow/MRD status (M1 with MRD level < 10^-3 vs M1 with MRD level ≥ 10^-3 vs M2). |
|
|||||||||||||
End point title |
Cumulative Incidence of Relapse (CIR) | ||||||||||||
End point description |
CIR estimate, presented as median months to relapse, calculated from date of achievement of first CR, using the cumulative incidence method (Fine JP, Gray RJ:1999). Deaths prior to relapse not considered related to an otherwise undocumented relapse were treated as a competing risk. Participants still alive without a date of relapse were censored at the time of last follow-up. Relapse=presence of ≥1 of the following: isolated bone marrow relapse (M3 marrow [representative bone marrow aspirate or biopsy with ≥25% blasts] in the absence of extramedullary involvement), combined bone marrow relapse (M2 or M3 marrow and ≥1 extramedullary manifestation of acute lymphoblastic leukemia), central nervous system extramedullary relapse, testicular extramedullary relapse, extramedullary relapse at other sites. FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received. 99999 = data was not estimable.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At final analysis, the overall maximum follow-up time was 82.0 months.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
HR | ||||||||||||
Statistical analysis description |
The subdistribution HR estimates are obtained from the subdistribution Cox model. (HR < 1.0 indicates a lower average event rate and a longer relapse-free time for blinatumomab relative to HC3.)
|
||||||||||||
Comparison groups |
HC3 Chemotherapy v Blinatumomab
|
||||||||||||
Number of subjects included in analysis |
111
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.29
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.16 | ||||||||||||
upper limit |
0.52 | ||||||||||||
Statistical analysis title |
Stratified HR | ||||||||||||
Statistical analysis description |
The subdistribution HR estimates are obtained from the subdistribution Cox model. (HR < 1.0 indicates a lower average event rate and a longer relapse-free time for blinatumomab relative to HC3.) Stratification factors are age and marrow/MRD status.
|
||||||||||||
Comparison groups |
HC3 Chemotherapy v Blinatumomab
|
||||||||||||
Number of subjects included in analysis |
111
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
Stratified HR | ||||||||||||
Point estimate |
0.27
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.15 | ||||||||||||
upper limit |
0.48 |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Adverse event (AE): any untoward medical occurrence. Serious AE: an AE meeting at least 1 of the following serious criteria: fatal; life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Severity was graded according to the Common Terminology Criteria for AEs (CTCAE) version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Investigational product (IP) in the HC3 arm refers to dexamethasone, methotrexate, daunorubicin, erwinase, ifosfamide, asparaginase, and vincristine, and in the blinatumomab arm refers to blinatumomab. Treatment-related refers to the assessment of a relationship between IP and the event.
Safety Analysis Set: participants who received protocol-specified therapy analyzed according to the treatment they received.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Participants With TEAEs of Interest | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
TEAEs of interest included capillary leak syndrome (CLS), cytokine release syndrome (CRS), decreased immunoglobulins (DI), elevated liver enzymes (ELE), embolic and thrombotic events (ETE), infections (INF), infusion reactions without considering duration (IRWCD), medication errors (ME), neurologic events (NE), neutropenia and febrile neutropenia (NFN), pancreatitis (PNC), tumor lysis syndrome, leukoencephalopathy, immunogenicity. Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death.
Safety Analysis Set: participants who received protocol-specified therapy analyzed according to the treatment they received.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Increases (↑) or decreases (↓) in laboratory value grades (Gr) from baseline (BL) to worst postbaseline (→ PB) grade are presented. NA=not available.
Safety Analysis Set: who received protocol-specified therapy analyzed according to the treatment they received.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Up to Day 29 (± 2 days)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) | ||||||||||||
End point description |
The analysis of 100-day mortality after alloHSCT was assessed for participants who received an alloHSCT while in remission and did not receive any additional anti-leukemic treatment. 100-day mortality after alloHSCT was calculated relative to the date of alloHSCT. The 100-day mortality rate after alloHSCT was defined as the percentage of participants having died up to 100 days after alloHSCT, estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants still alive were censored at the date they were last known to be alive.
HSCT Analysis Set: participants who underwent an HSCT while in remission without any other anti-leukemic therapy.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From the date of alloHSCT until death/censor date; median follow up time was 1742.0 days for blinatumomab and 1619.0 days for HC3.
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||
End point title |
Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only) [12] | ||||||||||
End point description |
Participants receiving blinatumomab had blood samples analyzed for binding antibodies. Samples testing positive for binding antibodies were also tested for neutralizing antibodies. Participants who were binding antibody-positive or neutralizing antibody-positive post-baseline with a negative or no result at baseline are presented.
Safety Analysis Set: participants who received protocol-specified therapy analyzed according to the treatment they received. Participants in the blinatumumab arm with a post-baseline result.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Day 1 to Day 29
|
||||||||||
Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The secondary endpoint assessed anti-blinatumomab antibodies in participants assigned to the blinatumomab arm only. |
|||||||||||
|
|||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Pharmacokinetics: Concentration of Blinatumomab at Steady State (Css) (Blinatumomab arm only) [13] | ||||||||
End point description |
Pharmacokinetic (PK) Analysis Set: participants who received any infusion of blinatumomab and had at least one PK sample collected.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15
|
||||||||
Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The secondary endpoint assessed blinatumomab pharmacokinetics in participants assigned to the blinatumomab arm only. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Pharmacokinetics: Clearance (CL) of Blinatumomab (Blinatumomab arm only) [14] | ||||||||
End point description |
PK Analysis Set: participants who received any infusion of blinatumomab and had at least one PK sample collected
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15
|
||||||||
Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The secondary endpoint assessed blinatumomab pharmacokinetics in participants assigned to the blinatumomab arm only. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
All-cause mortality is reported from randomization through the end of study; the median overall follow-up time was 55.2 months. Treatment-emergent adverse events are reported from first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
All-cause mortality is reported for all participants enrolled/randomized in the study. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
One 4-week cycle of blinatumomab 15 μg/m^2/day as a continuous intravenous infusion (CIVI). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
HC3 Chemotherapy
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Reporting group description |
One week of treatment with HC3 followed by 3 weeks of no 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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15 Apr 2015 |
- modified exclusion criteria to clarify that participants with abnormal serum creatinine were to be excluded from the study
- added measures to prevent and/or minimize pain and discomfort during blood draws
- added measures to minimize the blood volumes drawn during the study |
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29 Sep 2015 |
- added prophylactic intrathecal hydrocortisone as an alternative to prednisolone to allow the United Kingdom and Australia to participate in the study
- changed distribution of sites participating in the study (New Zealand was removed)
- changed the time period for administration of intrathecal prophylaxis to align with best medical practice for the standard of care arm
- added "cumulative incidence of relapse" to secondary endpoints
- clarified that MRD aliquots for PCR and/or flow cytometry that were to be collected at screening, Day 15 (blinatumomab arm only), and at Day 29 were to be analyzed at a central lab defined by the sponsor
- updated pregnancy, contraception, and lactation requirements to align with current risk and discomforts language |
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19 Apr 2016 |
- added "population PK analysis" as a secondary endpoint
- corrected the time frame for administration of intrathecal prophylaxis as premedication in the HC3 arm
- changed treatment-free interval from 2 weeks to 1 week when defining a cycle in the adaptive design
- updated the number of sites from 60 to 75
- in inclusion criteria, added a requirement for historical samples for central analysis of MRD
- updated exclusion criteria to clarify that for participants with total bilirubin < 1.5 mg/dL, measurement of direct bilirubin was not required, and to remove exclusion of other investigational procedures during study contact
- clarified that maximum daily dose of blinatumomab was not to exceed 28 µg/day
- clarified criteria for discontinuation of blinatumomab
- updated laboratory analyte listing
- updated language for pregnancy and lactation reporting |
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11 Jul 2017 |
- added text to "evaluate PK of blinatumomab" to the secondary objectives. Previously, this was an endpoint that was not listed as an objective
- secondary endpoints for population PK analysis were clarified
- clarified that not all participants were to proceed to transplant if M1 marrow occurred after consolidation (reasons not to proceed to transplant may include issues such as donor not available, infection, organ function issues)
- updated number of study centers from 75 to 82
- updated the definition of primary completion to include the premature conclusion of the study
- updated inclusion criteria to remove definition of M2 marrow and to exclude central nervous system relapse participants from having to supply material requested for central lab MRD analysis
- updated exclusion criteria to change direct bilirubin values to total bilirubin and increased the acceptable level of total bilirubin for study entry, to indicate that other exclusion criteria do not have to resolve to ≤ grade 2 for study participation and to clarify that asparaginase reactions were not an exclusion criterion
- clarified that the screening period could be extended by up to 7 days for bone marrow count recovery and/or scheduling of bone marrow collection only
- clarified that anticonvulsant treatment needed to be started before resumption of the cycle after a seizure had interrupted the blinatumomab infusion
- clarified that blinatumomab should only be discontinued in case of blinatumomab-related relevant neurologic events
- added allergic reactions as a complication that occurs with asparaginase
- clarified the concomitant medications that needed to be collected
- clarified the timing of intrathecal chemotherapy and that it could have been administered before signing consent as long as it was administered within 7 days prior to treatment start |
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05 Dec 2017 |
- adaptation was removed from the protocol to align with the Pediatric Investigation Plan amendment
- inclusion criterion updated to clarify what cases were exempt from supplying material from relapse for PCR central lab analysis
- the section on excluded treatments and/or procedures during the study period was updated to exclude participants who received additional cycles of the study drugs (HC3 or blinatumomab) after the treatment cycle was completed until an event occurred
- long-term follow-up for participants was changed from 36 months after alloHSCT to until the last participant enrolled on the study was 36 months after alloHSCT to allow longer follow-up data on the participants to be collected while the study was open
- primary completion and end of study language was updated |
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01 Nov 2019 |
- added an exploratory endpoint
- updated the number of study centers from 82 to 113
- updated adverse event guidance |
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23 Dec 2021 |
- clarified that adverse events associated with key safety parameter should be reported for the duration of the study with the exception of those related to other anti-cancer therapies occurring post blinatumomab treatment could be excluded
- updated language to clarify that serious adverse events suspected to be related to blinatumomab that the investigator became aware of were to be reported to Amgen within 24 hours of awareness during the long-term follow-up phase
- changed the contraception period, avoidance of pregnancy, breast feeding, and sperm donation period from 6 months to 48 hours
- updated the language for reporting procedures for adverse events and serious adverse events
- clarified that only adverse events and serious adverse events were to be reported if there was harm from overdose
- updated the serious adverse event reporting, pregnancy, and lactation form in the appendices |
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01 Aug 2022 |
- updated contraception duration
- clarified that where there was a potential overlap of contraceptive duration requirements due to different treatments, the most conservative contraceptive duration requirement was to be followed
- overdose language was updated to inform that for HC3 chemotherapy or concomitant medications, overdose was not to be reported as an adverse event/serious adverse event unless it was an intentional overdose |
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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 |