Clinical Trials Register

Summary
EudraCT Number:	2010-022235-10
Sponsor's Protocol Code Number:	ITCC-015/EWOG-MDS-Azacytidine-2010
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-02-06
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2010-022235-10

A.3

Full title of the trial

A Phase I/II study of Azacitidine (Vidaza®) in pediatric patients with newly diagnosed or relapsed high-grade pediatric MDS or JMML

Studio di fase I/II per il trattamento con Azacitidina (Vidaza®) in pazienti pediatrici con sindrome mielodisplastica avanzata, o con leucemia mielomonocitica giovanile (JMML), di nuova diagnosi o recidivata

A.3.1

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

Azacitidine in children with MDS or JMML

Azacitidina in pazienti pediatrici MDS of JMML

A.3.2

Name or abbreviated title of the trial where available

Azacitidine in high grade MDS and JMML pediatric patients

Azacitidina in pazienti pediatrici MDS of JMML

A.4.1

Sponsor's protocol code number

ITCC-015/EWOG-MDS-Azacytidine-2010

A.5.4

Other Identifiers

Name:

NTR 2578

Number:

Nederlands Trial Register

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	Erasmus MC
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	Go4Children Foundation
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Celgene
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione IRCCS Policlinico San Matte
B.5.2	Functional name of contact point	Oncoematologia pediatrica
B.5.3	Address:
B.5.3.1	Street Address	P.le Golgi 19
B.5.3.2	Town/ city	Pavia
B.5.3.3	Post code	27100
B.5.3.4	Country	Italy
B.5.4	Telephone number	390382502607
B.5.5	Fax number	390382501251
B.5.6	E-mail	m.zecca@smatteo.pv.it

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	vidaza
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	ORPHA86359
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AZACITIDINE
D.3.9.1	CAS number	320672
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	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

Advanced Myelodysplastic Syndromes (MDS) and Juvenile Myelomonocytic Leukemia (JMML)

sindrome mielodisplastica avanzata (MDS) e con leucemia mielomonocitica giovanile (JMML)

E.1.1.1

Medical condition in easily understood language

MDS and JMML

MDS eJMML

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	15.1
E.1.2	Level	LLT
E.1.2	Classification code	10054439
E.1.2	Term	Juvenile chronic myelomonocytic leukemia
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.1
E.1.2	Level	LLT
E.1.2	Classification code	10068361
E.1.2	Term	MDS
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 establish the recommended dose and preliminary efficacy of azacitidine in children with newly diagnosed and relapsed advanced MDS or JMML.

Stabilire il dosaggio pediatrico e l’efficacia preliminare del farmaco azacitidina in pazienti pediatrici con MDS avanzate o JMML, di nuova diagnosi o ricadute.

E.2.2

Secondary objectives of the trial

-To determine the safety and tolerability of azacitidine in newly diagnosed and relapsed advanced MDS and JMML
-To determine (preliminary) the hematological remission rate in these patients
-To describe the durability of response and long-term follow-up, including that of patients undergoing stem-cell transplant after treatment with azacitidine
-To determine the plasma pharmacokinetic parameters of azacitidine
-To study the pharmacodynamic effects of azacitidine in pediatric advanced MDS or JMML

- Stabilire la sicurezza del farmaco azacitidina in pazienti pediatrici con MDS avanzate (RAEB, RAEB-t) o JMML, di nuova diagnosi o ricadute
- Stabilire l’incidenza di risposta ematologica nei pazienti arruolati (preliminare)
- Descrivere la durata di risposta ed il follow-up a lungo termine incluso quello di pazienti avviati al trapianto di cellule staminali emopoietiche dopo trattamento con azacitidina
- Determinare il profilo farmacocinetico di azacitidina nel paziente pediatrico
- Studiare gli effetti farmacodinamici di azacitidina nelle MDS avanzate o JMML

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

In this study 4 subgroups of patients are eligible, which will be enrolled in 4 different strata:

•stratum 1: newly diagnosed patients with advanced MDS (RAEB or RAEB-t) in a ‘pre stem cell transplantation window’.
•stratum 2: relapsed patients with advanced MDS in a ‘re-transplantation window’. At relapse azacitidine may also be continued when a 2nd transplant is not feasible, as long as the patient benefits from treatment.
•stratum 3: newly diagnosed patients with JMML in a ‘pre-stem cell transplantation window’.
•stratum 4: relapsed patients with JMML in a ‘re-transplantation window’. Azacitidine may also be continued when a 2nd transplant is not feasible and as long as the patient benefits from treatment.
•straum 5:newly diagnosed or relapsed patients with secondary advanced MDS, occurring after
chemotherapy, radiotherapy and or stem-cell transplantation, or secondary cases after
prior treatment for aplastic anemia. Note: secondary MDS cases after bone-marrow failures or familial cases are not eligible

General conditions:
•Advanced primary or secondary MDS or JMML confirmed by the diagnostic criteria as specified in the EWOG-MDS 2006 protocol (see appendix 1)
•1 month to ≤ 18 years old
•Lansky play score ≥ 60; or Karnofsky performance status ≥ 60 (appendix 2)
•Life expectancy ≥ 3 months
•Normal renal function defined as less than or equal to NCI-CTCAE grade 1 (max 1.5 x ULN).
•Normal liver function defined as less than or equal to NCI-CTCAE grade 1 (max 2.5 x ULN for transaminases and bilirubin)
•No chemotherapy within 3 weeks of start of study medication. For 6-MP or low-dose cytarabine in JMML patients 1 week wash-out time is sufficient.
•For JMML patients: saturation >92% without additional supply of oxygen
•For JMML patients: peripheral blood monocyte count > 1.0x109/l
•For relapsed patients following HSCT: recovery of all acute toxic effects of prior chemotherapy/stem-cell transplantation.
•Able to comply with scheduled follow-up and with management of toxicity.
•For patients with childbearing potential, a negative test for pregnancy is to be considered before entry on study. If applicable, use of an effective contraceptive method.
•Written informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations.

- MDS avanzate primarie o secondarie o JMML, diagnosticate secondo i criteri specificati nel protocollo EWOG-MDS 2006
- età > 1 mese e ≤ 18 anni
- Lansky play score ≥ 60; o Karnofsky performance status ≥ 60 -aspettativa di vita almeno 3 mesi
-Funzione renale normale definita come inferiore o uguale a NCI-CTCAE
grado 1 (max 1.5 x ULN).
- Funzione epatica normale definita come inferiore o uguale a NCI-CTCAE
grado 1 (max 2.5 x ULN per transaminasi e bilirubina)
- Non chemiotherapia entro 3 settimane dall’inizio dell’assunzione di azacitidina. Per la 6-MP o citarabina a basse dosi in pazienti con JMML 1 settimana di wash-out time è sufficiente.
- per pazienti con JMML: saturazione >92% senza supporto di ossigeno
- per pazienti con JMML: conte monocitarie periferiche maggiori di 1.0x109/l
- per pazienti ricaduti dopo TCSE: assenza di tossicità acuta da chemioterapia /TCSE.
- capacità di seguire il follow-up stabilito dal protocollo, e di gestire eventuale tossicità
- non evidenza di gravidanza o periodo di allattamento
- consenso informato firmato

E.4

Principal exclusion criteria

Prior or current history:
•Other serious illnesses or medical conditions
•Genetic abnormalities indicative of AML
•JMML patients in whom a diagnosis of Noonan syndrome is suspected based on clinical history and/or presenting symptoms
•Patients with secondary MDS with underlying bone-marrow failure syndromes or with familial MDS
•Isolated extramedullary disease
•Symptomatic CNS-involvement
•Current uncontrolled infection
•Cardiac toxicity (shortening fraction below 28%)
•Concurrent treatment with any other anti-cancer therapy is not allowed
•Pregnant or lactating patients
•Patients who cannot be regularly followed up for psychological, social, familial or geographic reasons
•Patient with expected non compliance to toxicity management guidelines
•Prior treatment with a demethylating agent
•Allergy to azicitidine or mannitol.

Anamnesi di:
- altre malattie gravi
- anomalie genetiche caratterisitche di leucemia mieloide acuta
- pazienti con JMML nei quail sia sospettata una diagnosi di Sindrome di Noonan basata su storia clinica o sintomatologia clinica
- pazienti con MDS secondarie associate a bone-marrow failure syndromes o con MDS familiari
- malattia isolata extramidollare
- interessamento SNC sintomatico
- infezione non controllata in corso
- tossicità cardiaca (frazione eiezione < 28%)
- trattamento concomitante con altri farmaci citostatici
- pazienti in gravidanza o allattamento
- pazienti che non possono essere seguiti regolarmente per cause psicologiche, sociali, familiari o geografiche
- pazienti con attesa non compliance alle linee guida sulla gestione della tossicità
- trattamento precedente con agenti demetilanti
- allergia ad azicitidina o mannitolo.

E.5 End points

E.5.1

Primary end point(s)

The primary objective of this study is to establish a recommended dose and preliminary efficacy of azacitidine in children with newly diagnosed or relapsed advanced MDS or JMML.

L'obiettivo primario dello studio è stabilire il dosaggio pediatrico e l’efficacia preliminare del farmaco azacitidina in pazienti pediatrici con MDS avanzate o JMML, di nuova diagnosi o ricadute

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary endpoint may be limited by Dose Limiting toxicities in cycle 1 but otherwise full evaluation of the primary endpoint is possible after of treatment and after end of study.

Alla fine del trattamento

E.5.2

Secondary end point(s)

Other objectives concern:
•To determine the safety and tolerability of azacitidine in newly diagnosed and relapsed MDS and/or JMML.
•To determine (preliminary) the hematological remission rate in these patients.
•To describe the durability of response and long-term follow-up (at least 1 year after end of treatment), including that of patients undergoing stem-cell transplant after treatment with azacitidine.
•To determine the plasma pharmacokinetic parameters of azacitidine.
•To study the pharmacodynamic effects of azacitidine in pediatric MDS or JMML.

Obiettivi secondari:
- Stabilire la sicurezza del farmaco azacitidina in pazienti pediatrici con MDS avanzate (RAEB, RAEB-t) o JMML, di nuova diagnosi o ricadute
- Stabilire l’incidenza di risposta ematologica nei pazienti arruolati (preliminare)
- Descrivere la durata di risposta ed il follow-up a lungo termine,
incluso quello di pazienti avviati al trapianto di cellule staminali emopoietiche dopo trattamento con azacitidina
- Determinare il profilo farmacocinetico di azacitidina nel paziente pediatrico
- Studiare gli effetti farmacodinamici di azacitidina nelle MDS avanzate o JMML

E.5.2.1

Timepoint(s) of evaluation of this end point

For most endpoints after 3 cycles, and others after 1 year after HSCT or 1 year after last treatment with azacitidine when no HSCT is given

Per la maggior parte degli endpoints, dopo 3 cicli; per altri 1 anno dopo HSCT o dopo 1 anno dall'ultimo trattamento con azacitidina in caso in cui non venga effettuato HSCT

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

Yes

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

Yes

E.7.1.3.1

Other trial type description

Phase I-II

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

dati storici relativi al periodo in cui il paziente non veniva trattato con chemioterapia in attesa

historical data when time to transplant was not bridged with chemotherapy

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

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

Last patient last visit

Ultima visita dell'ultimo paziente

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:

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:

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

children 1 month of age until children 12 years of age

bambini di età > 1 mese fino a 12 anni

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

follow up (safety, survival, and new therapy) until 1 year after HSCT or last treatment in case HSCT did not take place.

Follow-up (sicurezza, sopravvivenza e nuova terapia) fino a 1 anno dal HSCT o dall'aultimo trattamento in caso non sia stato effettuato HSCT

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	ITCC
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	DCOG-ECTC
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	EWOG-MDS
G.4.3.4	Network Country	Netherlands

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-06-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-17

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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