Clinical Trials Register

Summary
EudraCT Number:	2009-018077-31
Sponsor's Protocol Code Number:	012010
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2012-03-20
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2009-018077-31

A.3

Full title of the trial

A PHASE I/II DOSE SCHEDULE FINDING STUDY OF CH14.18/CHO CONTINUOUS INFUSION COMBINED WITH SUBCUTANEOUS ALDESLEUKIN (IL-2) IN PATIENTS WITH PRIMARY REFRACTORY OR RELAPSED NEUROBLASTOMA A SIOPEN Study

Studio di fase I/II per dose e schedula dell'anticorpo monoclonale anti GD2 ch 14.18/CHO in infusione continua associato a Aldesleuchina (IL2) in pazienti con neuroblastoma refrattario o recidivato.

A.3.2

Name or abbreviated title of the trial where available

Long term continuous infusion ch.14.18/CHO plus s.c IL2

Infusione prolungata anticorpo ch.14.18/CHO e IL2

A.4.1

Sponsor's protocol code number

012010

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	St. Anna Kinderkrebsforchung Children's Cancer Research Institute
B.1.3.4	Country	Austria
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	St. Anna Kinderkrebsforchung Children's Cancer
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	St. Anna Kinderkrebsforchung Children's Cancer
B.5.2	Functional name of contact point	promotore sperimentazione
B.5.3	Address:
B.5.3.1	Street Address	Zimmermannplaz 10 A-1090
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	A-1090
B.5.3.4	Country	Italy
B.5.4	Telephone number	+43 (1) 40470-0
B.5.5	Fax number	+43 (1) 40470-7150
B.5.6	E-mail	ladenstein@ccri.at

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	No
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	ch.14.18/CHO
D.3.2	Product code	N.A.
D.3.4	Pharmaceutical form	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	Antineoplatics Agents
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	ch.14.18/CHO
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.3	Concentration number	4.6
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)	Yes
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	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	PROLEUKIN
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS FARMA SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Aldesleukin
D.3.10	Strength
D.3.10.1	Concentration unit	Munit million units
D.3.10.3	Concentration number	18
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	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	Yes
D.3.11.13.1	Other medicinal product type	prodotto ricombinante

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 refractory or relapsed neuroblatoma

Pazienti affetti da neuroblastoma refrattario o in ricaduta

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10066595
E.1.2	Term	Neuroblastoma recurrent
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	SOC
E.1.2	Classification code	10029205
E.1.2	Term	Nervous system disorders
E.1.2	System Organ Class	10029205 - Nervous system disorders

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

Primary :____ find a treatment plan that reduces the pain as tolerable profile tossicita'dell'anticorpo ch.14 18/CHO maintaining efficiency immunomodulation in patients (1 to 21 years) with refractory neuroblastoma (≥ 1 line of treatment conventional) or relapse using a 'prolonged and continuous infusion in combination with interleukin 2 (IL-2) sc

Primario:____ trovare un piano di cura tollerabile che riduca il dolore quale profilo di tossicita’dell’anticorpo ch.14 18/CHO mantenendo l’efficienza immunomodulatoria in pazienti (da 1 a 21 anni) con Neuroblastoma refrattario (≥ 1 linee di trattamenti convenzionali) o in ricaduta usando un’ infusione prolungata e continua in combinazione con Interleukina 2 (IL-2) s.c.

E.2.2

Secondary objectives of the trial

Assess pain intensity and relief with appropriate treatment with a validated instrument for self-documentation. • valid, during the first cycle of treatment, the correlations of activated NK cells and the level of ADCC using ch.14 18/CHO with MNC (mononucleoidi cell counts) and serum from patients on the fifteenth day. • Determine immune modulation resulting from the combined treatment of CH14. 18/CHO and sc Interleukin 2 (IL-2) by repeated analysis of NK cells, IL-2 soluble receptor, ADCC, CDC and antiidiotipo response (HAMA and HACA) • Obtain and increase the absolute count of lymphocytes and the absolute number of NK cells after each cycle as a measure of their response to IL-2 sc . • Determine the pharmacokinetics of ch.14 18/CHO. • Consider anti-tumor response resulting from this treatment plan using clinical findings in patients with measurable disease. • Confirm the results of the type of fixed-term infusion ch.14 18/CHO further 20 counts in patients.

•Valut. l’intensita' del dolore e il sollievo con l’opportuno trattamento con uno strumento di auto-documentazione validato.•Validare,durante il primo ciclo di trattamento,le correlazioni di cellule NK attivate e il livello di ch.14 18/CHO con ADCC usando MNC(conta cellule mononucleoidi)e siero dai paz al quindicesimo giorno.•Det. immuno modulazione risultante dal trattamento combinato di ch14.18/CHO and s.c.Interleukina 2(IL-2)mediante analisi ripetute di cellule NK,IL-2 recettore solubile,ADCC,CDC e risposta antiidiotipo(HAMA and HACA)•Ottenere e aumentare la conta assoluta di linfociti e il numero assoluto di cellule NK dopo ogni ciclo rispettivo come misura della risposta all’IL-2 s.c..•Det. la farmacocinetica di ch.14 18/CHO.•Valut. risposta anti-tumorale risultante da questo piano di trattamento usando accertamenti clinici in paz con malattia misurabile.•Confermare i risultati del tipo di durata di infusione determinato di ch.14 18/CHO in una conta ulteriore 20 paz.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Neuroblastoma patients with> 1 and ≤ 21 years, we have received at least one prior treatment with high doses followed by reinfusion of hematopoietic stem cells after conventional therapy to reduce tumor burden and meet any of the following criteria: • Refractory Neuroblastoma stage 4 with at least 2 lines of treatment before further doses resulting in an interval between diagnosis and transplantation of more than 9 months. Relapse res.in stage 4 • responsive metastatic recurrence after diagnosis of localized neuroblastoma

Pazienti con neuroblastoma con >1 e ≤ 21 anni , che abbiamo ricevuto almeno un precedente trattamento ad alte dosi seguito da reinfusione di cellule staminali emopoietiche dopo terapia convenzionale per ridurre il carico tumorale e che soddisfino uno dei seguenti criteri: • Neuroblastoma refrattario in stadio 4 con almeno 2 linee di trattamento prima di altre dosi causando un intervallo tra diagnosi e trapianto di piu' di 9 mesi. Ricaduta res.in stadio 4 • Recidiva metastatica responsiva dopo diagnosi di Neuroblastoma localizzato

E.4

Principal exclusion criteria

Progressive disease and / or previous treatment with ch.14.18/SP2/0 and / or ch14.18CHO

Malattia progressiva e/o trattamento precedente con ch.14.18/SP2/0 e/o ch14.18CHO

E.5 End points

E.5.1

Primary end point(s)

To find a tolerable treatment schedule which reduces the pain-toxicity profile of ch14.18/CHO whilst maintaining immunomodulatory efficacy in patients (1-21 years old) with either primary refractory (≥ 2 lines of conventional treatment) or relapsed neuroblastoma by using a prolonged continuous infusion in combination with s.c aldesleukin (IL-2).

riduzione del dolore quale tossicita' dell'anticorpo ch.14.18/CHO e IL2 s.c. mantenendone l' efficenza immunomodulatoria in pazienti con neuroblastoma refrattaria o in ricaduta.

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)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Information not present in EudraCT

E.8.1.3

Single blind

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Information not present in EudraCT

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

Australia

Israel

E.8.7

Trial has a data monitoring committee

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

18 months

È prevedibile che il reclutamento duri fino a 18 mesi.

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.1.1.5

Children (2-11years)

Yes

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.2

Adults (18-64 years)

Yes

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

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

minori

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

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

2011-04-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-03-29

P. End of Trial
P.	End of Trial Status	Ongoing

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