Clinical Trials Register

Summary
EudraCT Number:	2013-000018-39
Sponsor's Protocol Code Number:	AMLBFM2012
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-09-09
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2013-000018-39

A.3

Full title of the trial

Clinical trial for the treatment of acute myeloid leukemia in children and adolescents

Klinische Prüfung zur Behandlung der akuten myeloischen Leukämien bei Kindern und Jugendlichen

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Clinical trials for the treatment of acute myeloid leukemia in children and adolescents

Klinische Prüfung zur Behandlung der akuten myeloischen Leukämien bei Kindern und Jugendlichen

A.3.2

Name or abbreviated title of the trial where available

AML-BFM 2012

A.4.1

Sponsor's protocol code number

AMLBFM2012

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH gGmbH)
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Deutsche Krebshilfe e. V.
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinikum Essen, Kinderheilkunde III
B.5.2	Functional name of contact point	AML-BFM
B.5.3	Address:
B.5.3.1	Street Address	Hufelandstraße 55
B.5.3.2	Town/ city	Essen
B.5.3.3	Post code	45122
B.5.3.4	Country	Germany
B.5.4	Telephone number	00492017233755
B.5.5	Fax number	00492017235386
B.5.6	E-mail	aml-bfm@uk-essen.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Evoltra
D.2.1.1.2	Name of the Marketing Authorisation holder	Genzyme
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	ORPHA72855
D.3 Description of the IMP
D.3.1	Product name	Evoltra
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLOFARABIN
D.3.9.1	CAS number	123318-82-1
D.3.9.4	EV Substance Code	SUB21902
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Etopophos
D.2.1.1.2	Name of the Marketing Authorisation holder	Bistol-Myers Squibb
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Etopophos
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Etoposid
D.3.9.3	Other descriptive name	ETOPOSIDE PHOSPHATE
D.3.9.4	EV Substance Code	SUB13772MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

AML

E.1.1.1

Medical condition in easily understood language

acute myeloid leukemia

Akute Myeloische Leukämie

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. improvement of event-free survival of children and adolescents with AML by clofarabine in combination with cytarabine and liposomal daunorubicin in the induction therapy.
2. reduction of therapy toxicity and improve quality of life by a shortened maintenance therapy without worsening the prognosis.

1. Verbesserung des ereignisfreien Überlebens von Kindern und Jugendlichen mit AML durch Clofarabin in Kombination mit Cytarabin und liposomalem Daunorubicin in der Induktionstherapie.
2. Verringerung der Therapietoxizität und Verbesserung der Lebensqualität durch eine verkürzte Erhaltungstherapie, ohne die Prognose zu verschlechtern.

E.2.2

Secondary objectives of the trial

3. improvement of event-free survival by a zyto-/molekulargenetisch and MRD-based risk classification. Comprehensive biological characterization to improve treatment stratification and as a basis of molecular therapeutic options.
4. Measurement of the side effects of the combined therapy of molecular active substances in combination with conventional chemotherapy.
5. detection of molecular relapse after completion of intensive chemotherapy followed by MRD monitoring in peripheral blood (up to 18 months from diagnosis)

3. Verbesserung des ereignisfreien Überlebens durch eine zyto-/molekulargenetisch und MRD basierte Risikoklassifikation. Umfassende biologische Charakterisierung zur Verbesserung der Therapiestratifizierung und als Grundlage molekularer Therapieoptionen.
4. Erfassung der Nebenwirkungen der kombinierten Therapie molekular-wirksamer Substanzen in Kombination mit konventioneller Chemotherapie.
5. Erfassung eines molekularen Rezidivs nach Abschluss der intensiven Chemotherapie durch MRD-Monitoring im peripheren Blut (bis Monat 18 ab Diagnose)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• diagnosis of AML (according to WHO classification 2008)
• Acute leukemia with mixed line assignment and myeloid dominance (MPAL; according to WHO classification 2008: included dominant myeloid biphenotypic leukemia, and acute undifferentiated leukemia (AUL))
• Age 0 to 18 years old
• Consent for study participation and for data processing and data dissemination

• Diagnose einer AML (lt. WHO Klassifikation 2008)
• Akute Leukämie mit gemischter Linienzuordnung und myeloischer Dominanz (MPAL; lt. WHO-Klassifikation 2008: eingeschlossen dominant myeloisch biphänotypische Leukämien und akute undifferenzierte Leukämien (AUL))
• Alter 0 bis 18 Jahre
• Einwilligungserklärung zur Studienteilnahme und zur Datenverarbeitung und Datenweitergabe

E.4

Principal exclusion criteria

• Patients with acute promyelocytic leukemia / AML with t (15, 17); PML / RARA
• pre-existing conditions / syndromes which preclude treatment
• Patients with trisomy 21 and ML-DS and / or transient myeloproliferative syndrome (reference to the TMD-prevention study or the ML-DS 2006 Study)
• Acute leukemias bilineäre
• Secondary acute myeloid leukemia observation patients
• refusal of treatment
• Participation in another clinical trial, the Invention could affect the questions of this study
• Pregnancy
• Lactation
• Hypersensitivity to clofarabine
• patients of reproductive age who reject an effective pregnancy prevention
• previous treatment with cytostatic drugs for more than 14 days

• Patienten mit einer akuten Promyelozytenleukämie / AML mit t(15;17); PML/RARA
• Vorerkrankung/Syndrome, die eine Behandlung ausschließen
• Patienten mit Trisomie 21 und ML-DS und/oder transientem myeloproliferativem Syndrom (Verweis an die TMD-Präventionsstudie oder die ML-DS 2006 Studie)
• Akute bilineäre Leukämien
• Sekundäre akute myeloische Leukämien, Beobachtungspatienten
• Ablehnung der Therapie
• Teilnahme an einer anderen klinischen Prüfung, deren Invention die Fragestellungen dieser Studie beeinträchtigen könnten
• Schwangerschaft
• Stillzeit
• Überempfindlichkeit gegen Clofarabin
• Patienten im fortpflanzungsfähigen Alter, die eine effektive Schwangerschaftsverhütung ablehnen
• Vortherapie mit zytostatischen Medikamenten von mehr als 14 Tagen

E.5 End points

E.5.1

Primary end point(s)

1: Event-free survival of patients randomized
2: Disease-free survival from randomization 2

1: Ereignisfreies Überleben der randomisierten Patienten
2: Erkrankungsfreies Überleben ab Randomisierung 2

E.5.1.1

Timepoint(s) of evaluation of this end point

After 33% have occurred or 66% of the expected under the null hypothesis events, an interim analysis of randomization 1 is performed. Four years after the end of the patients receiving the final evaluation (including final report and publication) is provided.

Nachdem 33% bzw 66% der unter der Nullhypothese erwarteten Ereignisse aufgetreten sind, wird eine Zwischenauswertung der Randomisierung 1 durchgeführt. Vier Jahre nach dem Ende der Patientenaufnahme ist die endgültige Auswertung (einschließlich Abschlußbericht und Publikation) vorgesehen.

E.5.2

Secondary end point(s)

Leukemia-free survival and overall survival
Disease-free survival correlated to minimal residual disease
Detection of molecular relapse
Ansprechkinetik of minimal residual disease: AML t (8, 21); inv (16), MLL rearrangement, Flt3-ITD/TDK, c-KIT mutation, NPM1, WT1 mutation
relapse incidence
Measure quality of life through toxicity monitoring

Leukämiefreies Überleben und Gesamtüberleben
Erkrankungsfreies Überleben in Korrelation zur minimalen Resterkrankung
Erfassung des molekularen Rezidivs
Ansprechkinetik der minimalen Resterkrankung: AML t(8;21); inv(16), MLL-Rearrangement, Flt3-ITD/TDK, c-kit-Mutation, NPM1-, WT1-Mutation
Rezidivinzidenz
Erfassung der Lebensqualität durch Toxizitätsmonitoring

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Czech Republic

Slovakia

Switzerland

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

625

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Yes

F.1.1.2.1

Number of subjects for this age range:

625

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

625

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

625

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

625

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

625

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Subjects are under aged.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

450

F.4.2

For a multinational trial

F.4.2.1

In the EEA

150

F.4.2.2

In the whole clinical trial

625

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Depending on the disease, the study participants are to participate in the clinical trial, healed the corresponding relapse therapy are supplied as part of recurrence in accordance with or died. If further treatment is required, this is carried out regularly by the treating physician according to the specifications of the current guidelines.

Abhängig vom Krankheitsverlauf sind die Studienteilnehmer nach Teilnahme an der klinischen Prüfung, geheilt, werden im Rahmen eines Rezidivs nach Maßgabe der entsprechenden Rezidivtherapie versorgt oder sind verstorben. Sollte eine Weiterbehandlung erforderlich sein, erfolgt sie regulär durch den behandelnden Arzt nach Vorgaben der aktuellen Leitlinien.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	AML-BFM Study Group

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-11-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2019-03-01

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