Clinical Trials Register

Summary
EudraCT Number:	2008-003235-20
Sponsor's Protocol Code Number:	ALL-NOPHO-2008
National Competent Authority:	Lithuania - SMCA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2008-12-17
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

Lithuania - SMCA

A.2

EudraCT number

2008-003235-20

A.3

Full title of the trial

NOPHO-ALL-2008 Treatment Protocol for Children (1.0 - 17.9 years of age) with Acute Lymphoblastic Leukemia

NOPHO-ALL-2008 gydymo protokolas vaikų (1-17.9 metų amžiaus) ūmiai
limfoblastinei leukemijai gydyti

A.3.1

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

Protocol for Treatment of Children (1.0 - 17.9 years of age) with Acute
Lymphoblastic Leukemia

Gydymo protokolas vaikų (1-17.9 metų amžiaus) ūmiai limfoblastinei
leukemijai gydyti

A.4.1

Sponsor's protocol code number

ALL-NOPHO-2008

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Rigshospitalet
B.1.3.4	Country	Denmark
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Information not present in EudraCT
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	Methotrexate
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Methotrexate
D.3.9.1	CAS number	59-05-2
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	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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Information not present in EudraCT
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	Mercaptopurine
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Mercaptopurine
D.3.9.1	CAS number	6112-76-1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Information not present in EudraCT
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	Asparaginase
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Asparaginase pegylated
D.3.9.1	CAS number	9015-68-3
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	750
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)	Information not present in EudraCT
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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

ūminė limfoblastinė leukemija

E.1.1.1

Medical condition in easily understood language

acute lymphoblastic leukemia

ūminė limfoblastinė leukemija

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	17.0
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

1. To increase the fraction of patients, who become MRD-negative during consolidation for the non-HR ALL group through individualised intensification of the 6MP-dosage days 30-85. We will additionally measure EFS and toxicity as secondary end points of effect.
2. To test if intramuscular PEG-asparaginase administered either at six or two week intervals from day 92 until 8 months from diagnosis for patients with non-HR ALL will result in equal probability of EFS. As secondary endpoints asparaginase antibody production and toxicity including allergic reactions in the treatment-arms will be analysed.
3. To test if replacing six doses of conventional triple i.t. therapy with DepoCyte® during maintenance therapy for HR-ALL will yield an equal or reduced rate of serious toxicity (SAEs and SUSARs) with a similar or decreased CNS- and overall relapse rate

1. Padidinti ne DR ŪLL ligonių skaičių, kuriems konsolidacijos metu
minimali liktinė liga taptų neigiama 30-85 protokolo dienomis
individualiai didinant 6 MP dozę. Papildomai bus vertinamas
išgyvenamumas be įvykio ri toksiškumas.
2. Ištirti, ar ne DR ligoniams nuo 92 protokolo dienos iki 8 protokolo
mėnesio skiriant PEG-asparaginazę į raumenis šešių arba dviejų savaičių
intervalais, bus pasiektas vienodas išgyvenamumas be įvykių.
Papildomai bus tiriamas antikūnų prieš asparaginazę susidarymas ir
toksiškumas, įskaitant alergines reakcijas skirtingų šakų ligoniams.
3. Ištirti, ar DR ligoniams palaikomojo gydymo metu pakeičiant įprastą
intratekalinį gydymą trimis preparatais preparatu DepoCyte išsivystys
toks pats arba mažesnis toksiškumas tuo pačiu išsivytant tokiam pačiam
skaičiu arba mažiau CNS ir bendrai visų ligos recidyvų.

E.2.2

Secondary objectives of the trial

Not applicable

Netaikoma

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Non B-ALL
2. Non Ph+ ALL
3. Age 1.0 - 17.9 years of age.

1. Ne B-ŪLL.
2. ŪLL be nustatytos Filadelfijos chromosomos.
3. Amžius nuo 1,0 iki 17,9 metų.

E.4

Principal exclusion criteria

1. Bilineage ALL.
2. Pre-treatment with glucocorticosteroids or other antileukemic agents. Patients, who have been treated with systemic glucocorticosteroids or other anticancer agents (e.g. methotrexate or thiopurines) for more than a week prior to the diagnosis of ALL and initiation of antileukemic therapy, can be treated by the NOPHO ALL-2008 protocol and will be registered, but they cannot be included in the randomised trials.
3. Incomplete exploration for the risk group stratifying cytogenetic aberrations.
4. ALL predisposition syndromes. Patients with certain ALL-predisposing disorders (e.g. Down syndrome, Ataxia Telangiectasia) can be entered into the protocol with the amendments outlined in section 16, but can not be included in the randomised trials.
5. Previous cancer. Patients who have previously been treated for a malignant neoplasm can be treated by the NOPHO ALL-2008 protocol and will be registered, but they cannot be included in the randomised trials (see section 16). They will be treated according to the control arms of the protocol.
6. Intolerance to one or more anticancer agent.
7. Administration of additional chemotherapy during induction therapy for non-HR ALL. Patients with non-HR ALL, who at day 15 have a M3 bone marrow should not be given additional chemotherapy. If given, the patients will not be eligible for the SR-ALL treatment arm and the patient will not be eligible for randomisation.
8. Sexually active females not using contraception.
9. TPMT-deficiency (6MP-randomisation only).
10. DepoCyte during induction therapy (DepoCyte randomisation only)

1. Dviejų eilių ŪLL.
2. Gydymas gliukokortikosteroidais ar kitais priešleukeminiais
preparatais iki diagnozuojant ŪLL. Ligoniai, kurie iki diagnozuojant ir
pradedant gydyti ŪLL daugiau nei savaitę buvo gydyti
gliukokortikosteroidais ar kitais priešleukeminiais preparatais (pvz.,
metotreksatu arba tiopurinais) gali būti gydyomi pagal NOPHO ALL-2008
protokolą ir registuojami, bet negali būti įtraukti į randomizuojamuosius
tyrimus.
3. Nepakankamas citogenetinis ištyrimas pagal klasifikavimo į rizikos
grupes kriterijus.
4. ŪLL predisponuojantys sindromai. Ligoniai, sergantys kai kuriais
sindromais (pvz., Dauno sindromu ar ataksija telangiektazija) gali būti
gydomi pagal NOPHO ALL-2008 protokolą pritaikius 16 skyriuje surašytas pastabas, bet negali būti įtraukiami į randomizuojamuosius
tyrimus.
5. Anksčiau buvusi vėžinė liga. Ligoniai, anskčiau gydyti dėl onkologinės
ligos gal būti gydomi pagal NOPHO ALL-2008 protokolą ir registruojami
(žr. 16 skyrių), bet negali būti įtraukiami į randomizuojamuosius
tyrimus. Jie turi būti gydomi pagal kontrolinę chemoterapijos šaką.
6. Vieno ar daugiau priešleukeminio preparato netoleravimas.
7. Ne DR ŪLL ligoniai, kuriems skirtas papildomas gydymas indukcijos
metu. Ne DR ŪLL ligoniams, kuriems 15 protokolo dieną kaulų čiulpuose
nustatoma M3, negali būti skiriama papildoma chemoterapija. Jeigu toks
gydymas skiriamas, toks ligonis negali būti klasifikuojamas kaip SR
ligonis, ir negali būti randomizuojamas.
8. Lytiškai aktyvų gyvenimą gyvenančios moterys, nenaudojandčios
kontracepcijos.
9. TPMT-deficitas (tik 6MP randomizacijai).
10. DepoCyte skyrimas indukcijos metu (tik DepoCyte randomizacijos
tyrimui).

E.5 End points

E.5.1

Primary end point(s)

A. Reduction of relapse rate and/or level of residual disease without an unacceptable increase in toxicitý.
OR
B. Equal rate of relapse with a reduction of rate of significant toxicities

A. Recidyvų skaičiaus ir/arba liktinės ligos lygio sumažinimas
nepadidinant nepriimtino toksiškumo lygio.
ARBA
B. Toks patsa recidyvų skaičius sumažinant reikšmingo toksiškumo lygį.

E.5.1.1

Timepoint(s) of evaluation of this end point

Not applicable

Netaikoma

E.5.2

Secondary end point(s)

Not applicable

Netaikoma

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable

Netaikoma

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

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)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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

LVLS

Paskutinis paskutinio paciento vizitas

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:

160

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:

118

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

Young children.

maži vaikai

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

160

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1000

F.4.2.2

In the whole clinical trial

1000

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)

None

Nėra

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

2009-04-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-03-05

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2016-04-03

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