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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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AMLBFM0401

ISRCTN number

US NCT number

WHO universal trial number (UTN)

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,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

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?

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

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 74

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

recruitment in 8 Austrian participating hospitals from 01.03.2004 until 01.03.2011

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 title

whole study period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

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

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

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

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

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

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
Consent withdrawn by subject	-	-	-	-	1	-
Adverse event, non-fatal	-	-	1	-	-	-
organisational reasons	2	-	-	-	-	-
Lack of efficacy	-	-	1	-	-	-

Baseline characteristics

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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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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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Timeframe for reporting adverse events

from start of treatment up to 5 years after treatment

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

2.0

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
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
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
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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Were there any global substantial amendments to the protocol? Yes

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

Were there any global interruptions to the trial? No

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.

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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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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: survival

Primary: survival

Primary: survival

Primary: survival

Primary: survival

Primary: survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: survival

Primary: survival

Primary: survival

Primary: survival

Primary: survival

Primary: survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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