Clinical Trials Register

Summary
EudraCT Number:	2012-000067-25
Sponsor's Protocol Code Number:	ALL11
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-07-13
Trial results	View 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

Netherlands - Competent Authority

A.2

EudraCT number

2012-000067-25

A.3

Full title of the trial

Protocol ALL-11: Treatment study protocol of the Dutch Childhood Oncology Group for children and adolescents (1-19 year) with newly diagnosed acute lymphoblastic leukemia

Protocol ALL-11: Protocol voor diagnostiek en behandeling van kinderen en adolescenten (1-19 jaar) met Acute Lymfatische Leukemie

A.3.1

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

Treatment with chemotherapy for children >1 and <19 years of age with acute lymphoblastic leukemia.

Behandeling met chemotherapie voor kinderen > 1 en <19 jaar met acute lymfatische leukemie.

A.3.2

Name or abbreviated title of the trial where available

DCOG Protocol ALL-11

SKION Protocol ALL-11

A.4.1

Sponsor's protocol code number

ALL11

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	Princess Máxima Center for pediatric oncology
B.1.3.4	Country	Netherlands
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	Princess Máxima Center
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Ministerie van OC&W
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	KIKA fonds
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Stichting Go4Children
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Princess Máxima Center for pediatric oncology
B.5.2	Functional name of contact point	Trial and Data Center
B.5.3	Address:
B.5.3.1	Street Address	Heidelberglaan 25
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3584 CS
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031889727272
B.5.5	Fax number	0031889725009
B.5.6	E-mail	trialsupport@prinsesmaximacentrum.nl

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	Nanogam 50 mg/ml opslossing voor infusie
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanquin
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	IVIG
D.3.2	Product code	RGV 31627
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	HUMAN NORMAL IMMUNOGLOBULIN
D.3.9.3	Other descriptive name	IVIG or Nanogam
D.3.9.4	EV Substance Code	SUB14196MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	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	Erwinase
D.2.1.1.2	Name of the Marketing Authorisation holder	EUSA Pharma SAS
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Erwinia L-asparaginase
D.3.2	Product code	RVG 16986
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
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	Erwinase
D.3.9.1	CAS number	9015-68-3
D.3.9.3	Other descriptive name	ASPARAGINASE
D.3.9.4	EV Substance Code	SUB12950MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000
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: 3
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	Oncaspar
D.2.1.1.2	Name of the Marketing Authorisation holder	MEDAC
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Oncaspar
D.3.2	Product code	30204.00.00
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for injection
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	Oncaspar
D.3.9.1	CAS number	70-47-3
D.3.9.3	Other descriptive name	ASPARAGINE
D.3.9.4	EV Substance Code	SUB12951MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3750
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

Acute lymphoblastic leukemia in children

Acute lymfatische leukemie bij kinderen

E.1.1.1

Medical condition in easily understood language

Bloodcancer

Bloedkanker

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10000845
E.1.2	Term	Acute lymphoblastic leukemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To treat children with ALL with the best available treatment as possible, based upon the risk factors of the patient at diagnosis.

Behandeling van kinderen met ALL volgens de best beschikbare therapie, rekening houdend met de aanwezigheid van risicofactoren bij diagnose.

E.2.2

Secondary objectives of the trial

Reduction of toxicity of treatment.
Reduction of allergic reactions on chemotherapy.
Reduction of infections during intensification of treatment.

Reductie van toxiciteit van behandeling.
Reductie van allergische reacties op chemotherapie.
Reductie van optreden van infecties tijdens intensieve fase van behandeling.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Two randomisations:
1) randomisation for treatment with asparaginase in order to reduce allergic reactions/silent inactivation of asparaginase.
2) randomisation for treatment with immunoglobulines in order to reduce infections during treatment.

Twee randomisaties:
1) Randomisaties voor behandeling met asparaginase om allergische reacties/silent inactivation te analyseren
2) Randomisatie voor behandeling met immuunglobulines om optreden infecties tijdens behandeling te reduceren.

E.3

Principal inclusion criteria

1. Newly diagnosed patients with T-lineage or precursor-B lineage ALL (patients with mature B-ALL are not eligible)
2. Age between ≥ 1 and < 19 years
3. Informed consent signed by parents/guardians and patient if 12 years or older
4. Diagnosis ALL confirmed by DCOG laboratory
5. Patient should be treated in a Dutch Childhood Oncology Centre
6. Patient should be >3 months settled in The Netherlands at diagnosis

1. Nieuwe diagnose patienten met T- of preB ALL (patienten met mature B-ALL zijn niet eligible)
2. Leeftijd ≥ 1 en < 19 jaar
3. Informed consent getekend door ouders/verzorgers en patient als patient ≥ 12 jaar
4. Diagnose bevestigd door SKION laboratorium
5. Patient wordt behandeld in kinderoncologisch centrum in NL
6. Patient is minimaal >3 maanden woonachtig in NL

E.4

Principal exclusion criteria

1. Age ≥ 19 years at diagnosis
2. Age < 366 days at diagnosis (infant ALL); these patients are eligible for the Interfant protocol
3. Patients with secondary ALL
4. Patients with mature B-ALL (immunophenotypical or documented presence of karyotype t(8;14), t(2;8), t(8;22) and breakpoint as in B-ALL)
5. Patients with relapsed ALL
6. Pre-existing contra-indications for treatment according to (parts of) protocol ALL-11.
7. Essential data missing (in consultation with the protocol chairman)
8. Treatment with systemic corticosteroids and/or cytostatics in a 4-week interval prior to diagnosis. One exception is the use of corticosteroids as emergency treatment.
9. Patients with Ph-positive ALL (documented presence of t(9;22)(q34;q11) and/or of the BCR/ABL fusion transcript). These patients will be transferred to the EsPhALL protocol in induction according to the guidelines of the EsPhALL protocol.

1. Leeftijd ≥ 19 jaar bij diagnose
2. Leeftijd < 366 dagen bij diagnose (infant ALL), deze kinderen worden behandeld volgens Interfant protocol
3. secundaire ALL
4. Mature B-ALL (vastgesteld door immunophenotypering, danwel door karyotpye t(8;14), t(2;8), t(8;22) en breekpunt als bij B-ALL)
5. recidief ALL
6. pre-existente contra-indicaties voor behandeling met (delen) van protocol ALL-11
7.essentiele data missen
8. behandeling met systemische corticosteroiden en/of chemotherapie in de 4 weken voorafgaande aan diagnose. Uitzondering is het gebruik van corticosteroiden als ‘noodbehandeling’.
9. Ph-positieve ALL (aanwezigheid van t(9;22)(q34;q11) en/of aanw van de BCR-ABL fusieproduct) Deze patienten worden behandeld volgens EsPhALL-protocol.

E.5 End points

E.5.1

Primary end point(s)

1. Primary endpoint is survival.
2. Primary endpoint is the number of allergic reactions/silent inactivation of asparaginase.
3. Primary endpoint is the number of infectious episodes for which patients are admitted to the hospital and receive therapeutic antibiotics or antifungals.
4. Primary endpoint is the number of patients with allergic reaction or silent inactivation to PEGasparaginase and who are therefore switched to Erwinase.

1. Primaire eindpunt is survival.
2. primaire eindpunt is aantal allergische reacties/silent inactivation bij asparaginase.
3. Primaire eindpunt is het aantal infectieuze episodes voor patienten die opgenomen zijn in het ziekenhuis en therapeutisch antibiotica of antifungale therapie krijgen.
4. Primaire eindpunt is het aantal patienten met allergische reactie/silent inactivatie op PEG-asparaginase en om deze reden switch naar behandeling met Erwinase.

E.5.1.1

Timepoint(s) of evaluation of this end point

During interim analyses and also at the end of this protocol, expected in 2018.

Gedurende interim analyses en aan het eind van dit protocol, verwachting 2018.

E.5.2

Secondary end point(s)

1. Secondary endpoints are EFS, CIR, death in induction, death in remission and toxicity.
2. Secondary endpoints are toxicity, EFS and survival.
3. Secondary endpoint is the average cumulative dose of PEGasparaginase administered to patients in the MR arm A compared to the historical control of the ALL-10 MR study.

1. Secondaire eindpunten zijn EFS, CIR, overlijden in inductie, overlijden in remissie and toxiciteit.
2. Secondaire eindpunten zijn toxiciteit, EFS en overleving.
3. Secondaire eindpunt is de gemiddelde cummulatieve dosis van PEGasparaginase toegediend aan patienten in de MR arm A vergeleken met de historische controle van de ALL-10 MR studie.

E.5.2.1

Timepoint(s) of evaluation of this end point

During interim analyses and also at the end of this protocol, expected in 2018.

Gedurende interim analyses en aan het eind van dit protocol, verwachting 2018.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

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)

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

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

Individual follow-up for 5 years after study entry is required for this protocol. Long-term follow-up is strongly recommended and will be organised according to Dutch guideline

Iedere patient wordt 5 jaar lang gezien door de behandelend arts, hierna zal hij/zij via de lange termijn effecten poli (LATER) gevolgd worden.

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

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:

818

F.1.1.1

In Utero

F.1.1.2

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

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

600

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

163

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

819

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

819

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)

no plans for treatment at the end of study.

geen behandeling na einde studie.

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-07-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-10-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-05-30

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