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Clinical Trial Results:
Multizentrische Therapieoptimierungsstudie AML-BFM 2004 zur Behandlung der akuten myeloischen Leukämien bei Kindern und Jugendlichen Multicentric therapy optimizing study AML-BFM 2004 for the treatment of acute myeloic leukaemias for children and juveniles

Summary
EudraCT number
 2006-004710-41
Trial protocol
 AT  
Global end of trial date
25 Oct 2015

Results information
Results version number
 v1(current)
This version publication date
10 Nov 2016
First version publication date
10 Nov 2016
Other versions
Summary report(s)
 Synopsis AML-BFM 2004

Trial information

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Trial identification
Sponsor protocol code
AMLBFM0401
Additional study identifiers
ISRCTN number
 -
US NCT number
 -
WHO universal trial number (UTN)
 -
Sponsors
Sponsor organisation name
St. Anna Kinderkrebsforschung
Sponsor organisation address
Zimmermannplatz 10, Vienna, Austria, 1090
Public contact
Univ.Prof. Dr. Ruth Ladenstein, St. Anna Kinderkrebsforschung, +43 140470,
Scientific contact
Univ.Prof. Dr. Ruth Ladenstein, St. Anna Kinderkrebsforschung, +43 140470,
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)
No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Results analysis stage
Analysis stage
Final
Date of interim/final analysis
25 Oct 2015
Is this the analysis of the primary completion data?
Yes
Primary completion date
25 Oct 2015
Global end of trial reached?
Yes
Global end of trial date
25 Oct 2015
Was the trial ended prematurely?
No
General information about the trial
Main objective of the trial
1. improvement of prognosis of children and adolescents by intensification of cytostatic therapy by randomized implementation of liposomal daunorubicine in first induction 2. randomized implementation of 2-CDA as intensification in consolidation therapy for patients in high risk group with the aim of improvement of prognosis 3. randomized examination of efficacy of prophylactic CNS radiation 18 Gy vs. 12 Gy Notably, EudraCT number 2006-004710-41 had to be obtained only for the Austrian part of this much larger international academic Trial because the study was started on the national level in the month after a national legislative revision of the Austrian Medicinal Products Act in line with EU-Directive 2001/20/EC, whereas the trial was conducted in the main other countries under rules not yet falling under this Revision.
Protection of trial subjects
detailed supportive care measures were specified within the Trial protocol
Background therapy
 -
Evidence for comparator
 -
Actual start date of recruitment
01 Mar 2004
Long term follow-up planned
No
Independent data monitoring committee (IDMC) involvement?
No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled
Austria: 74
Worldwide total number of subjects
74
EEA total number of subjects
74
Number of subjects enrolled per age group
In utero
0
Preterm newborn - gestational age
0
Newborns (0-27 days)
0
Infants and toddlers (28 days-23 months)
12
Children (2-11 years)
27
Adolescents (12-17 years)
35
Adults (18-64 years)
0
From 65 to 84 years
0
85 years and over
0

Subject disposition

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Recruitment
Recruitment details
 recruitment in 8 Austrian participating hospitals from 01.03.2004 until 01.03.2011

Pre-assignment
Screening details
 Principal inclusion criteria: * age 0-18y * de novo AML, including Down Syndrome, primary myelosarcoma of acute mixed lineage leukemia * treatment in participating center

Period 1
Period 1 title
whole study period (overall period)
Is this the baseline period?
 Yes
Allocation method
Randomised - controlled
Blinding used
 Not blinded

Arms
Are arms mutually exclusive
No

Arm title
 ADxE
Arm description
 liposomal daunorubicin in first induction course
Arm type
 Experimental

Investigational medicinal product name
Daunoxome
Investigational medicinal product code
L01DB02
Other name
Pharmaceutical forms
Infusion
Routes of administration
Intravenous use
Dosage and administration details
240 mg/m2

Arm title
 AIE induction
Arm description
 standard induction therapy with cytarabine, idarubicin and etoposide
Arm type
 standard chemotherapy arm

Investigational medicinal product name
No investigational medicinal product assigned in this arm
Arm title
 AI/2-CDA
Arm description
 addition of 2-CDA to consolidation course
Arm type
 Experimental

Investigational medicinal product name
Cladribine
Investigational medicinal product code
L01BB04
Other name
Pharmaceutical forms
Infusion
Routes of administration
Intravenous use
Dosage and administration details
12 mg/m2

Arm title
 AI consolidation
Arm description
 standard consolidation course with cytarabine and idarubicine
Arm type
 standard chemotherapy arm

Investigational medicinal product name
No investigational medicinal product assigned in this arm
Arm title
 12 Gy
Arm description
 CNS irradiation reduced to 12 Gray
Arm type
 experimental arm: reduced irradiation

Investigational medicinal product name
No investigational medicinal product assigned in this arm
Arm title
 18 Gy
Arm description
 standard arm with CNS irradiation with 18 Gy
Arm type
 standard irradiaton arm

Investigational medicinal product name
No investigational medicinal product assigned in this arm
Number of subjects in period 1
ADxE AIE induction AI/2-CDA AI consolidation 12 Gy 18 Gy
Started
28
30
17
17
13
11
Completed
26
30
15
17
12
11
Not completed
2
0
2
0
1
0
     organisational reasons
2
-
-
-
-
-
     Lack of efficacy
-
-
1
-
-
-
     Adverse event, non-fatal
-
-
1
-
-
-
     Consent withdrawn by subject
-
-
-
-
1
-

Baseline characteristics

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Baseline characteristics reporting groups
Reporting group title
whole study period
Reporting group description
 -

Reporting group values
 whole study period Total
Number of subjects
 74 74
Age categorical
Units: Subjects
    In utero
 0 0
    Preterm newborn infants (gestational age < 37 wks)
 0 0
    Newborns (0-27 days)
 0 0
    Infants and toddlers (28 days-23 months)
 12 12
    Children (2-11 years)
 27 27
    Adolescents (12-17 years)
 35 35
    Adults (18-64 years)
 0 0
    From 65-84 years
 0 0
    85 years and over
 0 0
Gender categorical
Units: Subjects
    Female
 36 36
    Male
 38 38

End points

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End points reporting groups
Reporting group title
ADxE
Reporting group description
 liposomal daunorubicin in first induction course

Reporting group title
AIE induction
Reporting group description
 standard induction therapy with cytarabine, idarubicin and etoposide

Reporting group title
AI/2-CDA
Reporting group description
 addition of 2-CDA to consolidation course

Reporting group title
AI consolidation
Reporting group description
 standard consolidation course with cytarabine and idarubicine

Reporting group title
12 Gy
Reporting group description
 CNS irradiation reduced to 12 Gray

Reporting group title
18 Gy
Reporting group description
 standard arm with CNS irradiation with 18 Gy

Primary: survival

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End point title
 survival [1] [2]
End point description
End point type
Primary
End point timeframe
from diagnosis
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: Statistics is not meaningful for the small Austrian cohort - the full international data set is not available! Notably, EudraCT number 2006-004710-41 had to be obtained only for the Austrian part of this much larger international academic trial whereas the trial was conducted in the main other countries under rules not yet falling under EU-Directive 2001/20/EC.
[2] - 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: Statistics is not meaningful for the small Austrian cohort - the full international data set is not available! Notably, EudraCT number 2006-004710-41 had to be obtained only for the Austrian part of this much larger international academic trial whereas the trial was conducted in the main other countries under rules not yet falling under EU-Directive 2001/20/EC.
End point values
 ADxE AIE induction
Number of subjects analysed
26
30
Units: years
    event-free survival
5
5
    overall survival
5
5
No statistical analyses for this end point

Primary: survival

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End point title
 survival [3] [4]
End point description
End point type
Primary
End point timeframe
from 2nd randomisation
Notes
[3] - 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: Statistics is not meaningful for the small Austrian cohort - the full international data set is not available! Notably, EudraCT number 2006-004710-41 had to be obtained only for the Austrian part of this much larger international academic trial whereas the trial was conducted in the main other countries under rules not yet falling under EU-Directive 2001/20/EC.
[4] - 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: Statistics is not meaningful for the small Austrian cohort - the full international data set is not available! Notably, EudraCT number 2006-004710-41 had to be obtained only for the Austrian part of this much larger international academic trial whereas the trial was conducted in the main other countries under rules not yet falling under EU-Directive 2001/20/EC.
End point values
 AI/2-CDA AI consolidation
Number of subjects analysed
15
17
Units: years
    event-free survival
5
5
    overall survival
5
5
No statistical analyses for this end point

Primary: survival

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End point title
 survival [5] [6]
End point description
End point type
Primary
End point timeframe
from 3rd randomisation
Notes
[5] - 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: Statistics is not meaningful for the small Austrian cohort - the full international data set is not available! Notably, EudraCT number 2006-004710-41 had to be obtained only for the Austrian part of this much larger international academic trial whereas the trial was conducted in the main other countries under rules not yet falling under EU-Directive 2001/20/EC.
[6] - 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: Statistics is not meaningful for the small Austrian cohort - the full international data set is not available! Notably, EudraCT number 2006-004710-41 had to be obtained only for the Austrian part of this much larger international academic trial whereas the trial was conducted in the main other countries under rules not yet falling under EU-Directive 2001/20/EC.
End point values
 12 Gy 18 Gy
Number of subjects analysed
12
11
Units: years
    disease-free survival
5
5
No statistical analyses for this end point

Adverse events

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Adverse events information [1]
Timeframe for reporting adverse events
from start of treatment up to 5 years after treatment
Assessment type
 Systematic
Dictionary used for adverse event reporting
Dictionary name
 CTCAE
Dictionary version
2.0
Reporting groups
Reporting group title
ADxE
Reporting group description
 liposomal daunorubicin in first induction course

Reporting group title
AIE induction
Reporting group description
 standard induction therapy with cytarabine, idarubicin and etoposide

Reporting group title
AI/2-CDA
Reporting group description
 addition of 2-CDA to consolidation course

Reporting group title
AI consolidation
Reporting group description
 standard consolidation course with cytarabine and idarubicine

Reporting group title
12 Gy
Reporting group description
 CNS irradiation reduced to 12 Gray

Reporting group title
18 Gy
Reporting group description
 standard arm with CNS irradiation with 18 Gy

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: Non-serious events have not been reported in detail
Serious adverse events
 ADxE AIE induction AI/2-CDA AI consolidation 12 Gy 18 Gy
Total subjects affected by serious adverse events
     subjects affected / exposed
5 / 26 (19.23%)
11 / 30 (36.67%)
6 / 15 (40.00%)
4 / 17 (23.53%)
0 / 12 (0.00%)
0 / 11 (0.00%)
     number of deaths (all causes)
8
8
7
7
3
2
     number of deaths resulting from adverse events
2
2
2
1
0
0
Vascular disorders
major bleeding or DIC
     subjects affected / exposed
0 / 26 (0.00%)
2 / 30 (6.67%)
0 / 15 (0.00%)
0 / 17 (0.00%)
0 / 12 (0.00%)
0 / 11 (0.00%)
     occurrences causally related to treatment / all
0 / 0
3 / 3
0 / 0
0 / 0
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 8
0 / 8
0 / 7
0 / 7
0 / 3
0 / 2
Cardiac disorders
Cardiomyopathy
     subjects affected / exposed
0 / 26 (0.00%)
1 / 30 (3.33%)
1 / 15 (6.67%)
0 / 17 (0.00%)
0 / 12 (0.00%)
0 / 11 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
1 / 1
0 / 0
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 8
0 / 8
0 / 7
0 / 7
0 / 3
0 / 2
Blood and lymphatic system disorders
Aplasia
Additional description: non-regeneration
     subjects affected / exposed
0 / 26 (0.00%)
1 / 30 (3.33%)
0 / 15 (0.00%)
0 / 17 (0.00%)
0 / 12 (0.00%)
0 / 11 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
0 / 0
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 8
0 / 8
0 / 7
0 / 7
0 / 3
0 / 2
Immune system disorders
HLH
     subjects affected / exposed
2 / 26 (7.69%)
0 / 30 (0.00%)
1 / 15 (6.67%)
1 / 17 (5.88%)
0 / 12 (0.00%)
0 / 11 (0.00%)
     occurrences causally related to treatment / all
2 / 2
0 / 0
1 / 1
1 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
1 / 8
1 / 8
0 / 7
0 / 7
0 / 3
0 / 2
Nervous system disorders
Encephalopathy
     subjects affected / exposed
1 / 26 (3.85%)
1 / 30 (3.33%)
1 / 15 (6.67%)
1 / 17 (5.88%)
0 / 12 (0.00%)
0 / 11 (0.00%)
     occurrences causally related to treatment / all
1 / 1
1 / 1
1 / 1
1 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
1 / 8
0 / 8
1 / 7
0 / 7
0 / 3
0 / 2
Infections and infestations
severe bacterial infections
     subjects affected / exposed
1 / 26 (3.85%)
6 / 30 (20.00%)
1 / 15 (6.67%)
1 / 17 (5.88%)
0 / 12 (0.00%)
0 / 11 (0.00%)
     occurrences causally related to treatment / all
1 / 1
6 / 6
1 / 1
1 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 8
1 / 8
0 / 7
0 / 7
0 / 3
0 / 2
invasive fungal infection
     subjects affected / exposed
2 / 26 (7.69%)
2 / 30 (6.67%)
2 / 15 (13.33%)
1 / 17 (5.88%)
0 / 12 (0.00%)
0 / 11 (0.00%)
     occurrences causally related to treatment / all
2 / 2
2 / 2
2 / 2
1 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
1 / 8
1 / 8
2 / 7
0 / 7
0 / 3
0 / 2
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events
 ADxE AIE induction AI/2-CDA AI consolidation 12 Gy 18 Gy
Total subjects affected by non serious adverse events
     subjects affected / exposed
0 / 26 (0.00%)
0 / 30 (0.00%)
0 / 15 (0.00%)
0 / 17 (0.00%)
0 / 12 (0.00%)
0 / 11 (0.00%)

More information

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Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date
Amendment
31 May 2010
Amendment 05-2010 for Austria study AML-BFM 2004: - all randomisations closed - continuation with best therapy, i.e.: - 1st induction with liposomal daunorubicine 80 mg/m²/d/3x (ADxE) - consolidation for high risk patients: 2-CDA 2x6mg/m² as intensification in AI - extension of study duration - prophylactic CNS irradiation with 12 Gy - re-introduction of HAM for AML with t(8;21) ML-DS (Down Syndrom) amendment for Austria in AML-BFM 2004: - all ML-DS-Patienten receive AIE induction (idarubicine 8 mg/m2) - reduction of number of prophylactic intrathecal cytarabine injections from 7 to 4 - dosage of cytostatic therapy according to kg body weight until body weight of 12 kg (up to date 10 kg) - no more etoposide in intensification ==> high dose cytarabine; HA) - maintenance therapy is dispensed

Interruptions (globally)
Were there any global interruptions to the trial? No

Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
Statistics is not meaningful for the small Austrian cohort - the full international data set is not available because the trial was in the main other countries not conducted under rules depending on EU-Directive 2001/20/EC.

Online references
http://www.ncbi.nlm.nih.gov/pubmed/21480469
http://www.ncbi.nlm.nih.gov/pubmed/23700063
http://www.ncbi.nlm.nih.gov/pubmed/23704089
http://www.ncbi.nlm.nih.gov/pubmed/25985446
http://www.ncbi.nlm.nih.gov/pubmed/25869725
http://www.ncbi.nlm.nih.gov/pubmed/26771808
http://www.ncbi.nlm.nih.gov/pubmed/26814618

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