Clinical Trials Register

Summary
EudraCT Number:	2015-002185-23
Sponsor's Protocol Code Number:	DIPG
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:	2020-11-04
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

2015-002185-23

A.3

Full title of the trial

Phase 2 open label randomized study of radiotherapy, concomitant nimotuzumab and vinorelbine and re-irradiation at relapse versus radiotherapy and multiple elective radiotherapy courses with concomitant vinorelbine and nimotuzumab for newly diagnosed childhood and adolescence diffuse intrinsic pontine glioma (DIPG)

Studio randomizzato di radioterapia, nimotuzumab e vinorelbina concomitanti e re-irradiazione alla recidiva rispetto a radioterapia a più cicli elettiva con vinorelbina e nimotuzumab concomitanti, in bambini e adolescenti con nuova diagnosi glioma diffuso intrinseco del ponte (DIPG)

A.3.1

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

The study is designed for patients diagnosed with a brain tumor (diffuse intrinsic pontine glioma) aged from 2 to 21 years old.

Lo studio è pensato per pazienti affetti da un tumore cerebrale (glioma diffuso intrinseco del ponte) che abbiano età compresa tra 2 e 21 anni.

A.3.2

Name or abbreviated title of the trial where available

INT - DIPG 2015

A.4.1

Sponsor's protocol code number

DIPG

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	FONDAZIONE IRCCS "ISTITUTO NAZIONALE DEI TUMORI"
B.1.3.4	Country	Italy
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	donazioni modali
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione IRCCS Istituto Nazionale dei Tumori
B.5.2	Functional name of contact point	S.C. Pediatria Oncologica
B.5.3	Address:
B.5.3.1	Street Address	via Giacomo Venezian, 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	0223902590
B.5.5	Fax number	0223902648
B.5.6	E-mail	luna.boschetti@istitutotumori.mi.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	NAVELBINE - 10 MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONE 1 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	PIERRE FABRE PHARMA S.R.L.
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.3.1	Product name	Vinorelbina
D.3.2	Product code	[vinorelbina]
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.3.9.1	CAS number	71486-22-1
D.3.9.2	Current sponsor code	Vinorelbina
D.3.9.3	Other descriptive name	Vinorelbine
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	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	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	CIMAher
D.2.1.1.2	Name of the Marketing Authorisation holder	CECMED
D.2.1.2	Country which granted the Marketing Authorisation	Cuba
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	ORPHA82913
D.3 Description of the IMP
D.3.1	Product name	Cimaher
D.3.2	Product code	[Cimaher]
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	0828933-51-3
D.3.9.2	Current sponsor code	Nimotuzumab
D.3.9.3	Other descriptive name	Nimotuzumab
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	200 to 400
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	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.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

diffuse intrinsic pontine glioma

glioma diffuso intrinseco del ponte

E.1.1.1

Medical condition in easily understood language

children and adolescent affected by malignant glioma of the brain stem

bambini e adolescenti di età superiore a 2 anni affetti da glioma maligno del tronco encefalico

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10006143
E.1.2	Term	Brain stem glioma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 aim of this study will be to compare the best response up to 36 weeks (CR+PR) between conventional and experimental irradiation. Such an end point was chosen since tumor reduction has been demonstrated to be correlated with better PFS and OS. The response will be evaluated according to radiological and clinical criteria

Esaminare la fattibilità, il tasso di risposta e i risultati di progressione libera da malattia (PFS) e sopravvivenza globale (OS) in uno studio randomizzato che confronta due diversi schemi di irradiazione per DIPG durante la somministrazione dello stesso trattamento sistemico

E.2.2

Secondary objectives of the trial

To compare the disease stabilization rate (considering SD only) up to week 36 between the two arms. The evaluation will be done according to radiological and clinical criteria; to compare PFS and OS between the two arms; to assess safety of radiotherapy; to assess the quality of life and life situation. • To assess PFS and OS of diffuse midline glioma with K27 mutation using the standard arm of the main protocol

Confrontare il tasso di stabilizzazione della malattia (considerando solo SD) fino a 36 settimane nei due bracci. La valutazione sarà fatta in accordo con criteri radiologici e clinici; confrontare PFS e OS nei due bracci; valutare la sicurezza della radioterapia; valutare la qualità di vita. Valutare PFS e OS dei gliomi diffusi della linea mediana con mutazione k27 usando come confronto il braccio standard dello studio principale.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients from 2 to 21 years old will be eligible
- No previous treatment consented apart from steroids
- Strict eligibility criteria will radiologically-verified DIPG (an intrinsic, pontine-based infiltrative lesion hypointense on T1- and hyperintense on T2-weighted sequences, involving at least 2/3 of the pons)
- Symptoms lasting less than 6 months
- Life expectancy =4 weeks
- Karnowski/Lansky performance status > or = 40 %
- No organ dysfunction
- No pregnancy or breast-feeding
- Patients undergo baseline cranial MRI with gadolinium, to be repeated if treatment begins more than 2 weeks; spinal MRI due to the occurrence of metastatic cases at diagnosis will also be mandatory
- Written and signed informed consent from parents or legal guardians will be obtained before starting the treatment-
- For diffuse midline glioma observational arm, central reviewed pathology of the disease according to standard Italian procedure, i.e. referral to the Neuropathology at Sapienza University in Rome.

- pazienti di età compresa tra 2 e 21 anni
- pazienti che non abbiano ricevuto alcun trattamento pregresso a parte l’assunzione di steroidi
- verifica radiologica di DIPG (una lesione intrinseca, pontina infiltrante ipointensa in T1 ed iperintensa in T2 in sequenze pesate, che coinvolgono almeno 2/3 del ponte)
- pazienti con sintomatologia da meno di 6 mesi
- aspettativa di vita di almeno 4 settimane
- Karnowski/Lansky > o = 40 %
- nessuna disfunzione d’organo
- pazienti non in gravidanza o allattamento
- risonanza magnetica (RM) basale dell’encefalo con gadolinio, che va ripetuta nel caso in cui il trattamento non cominci entro due settimane; sarà inoltre obbligatoria una risonanza del midollo per casi metastatici alla diagnosi
- ottenimento della firma sul consenso informato scritto da parte dei genitori/tutori legali prima dell’inizio dello studio.
- per i pazienti con glioma diffuso del braccio osservazionale verrà fatta una revisione istologica in accordo alle procedure italiane standard facendo riferimento al reparto di Neuropatologia dell’Università la Sapienza di Roma.

E.4

Principal exclusion criteria

- Patients below 2 years or over 21
- Pre-treatment with radio or chemotherapy
- Neurofibromatosis 1
- Non-typical imaging
- Symptoms duration over 6 months, Lansky/Karnowski scores below 40
- Metastatic disease as shown by MRI
- Organ disfunction, pregnancy or breast-feeding
- Absence of parents, patient or tutor consent
- Not central review diagnosis of diffuse midline glioma histone H3, K27 mutated

- Pazienti di età inferiore ai 2 anni e superiore ai 21
- Pazienti pre-trattati con radio o chemioterapia
- Pazienti affetti da Neurofibromatosi 1
- Immagini radiologiche non tipiche per la malattia
- Durata dei sintomi superiore ai 6 mesi, Lansky/Karnowski inferiore al 40%
- Malattia metastatica dimostrata dalla RM
- Disfunzione d’organo, gravidanza o allattamento
- Mancanza del consenso da parte dei genitori, del paziente o dei tutori legali
- Nessuna revisione centrale alla diagnosi di glioma diffuso della linea mediana con mutazione di K27

E.5 End points

E.5.1

Primary end point(s)

number of best responses (complete and partial responses) up to week 36 will be calculated in the conventional and experimental irradiation arms, and the comparison between the response rates will be performed

numero di risposte (complete e parziali) entro la 36esima settimana calcolato nei due bracci di trattamento. Verrà eseguito il confronto tra i tassi di risposta

E.5.1.1

Timepoint(s) of evaluation of this end point

36 months

36 mesi

E.5.2

Secondary end point(s)

first progression of disease, first recurrence, secondary malignancy, death

prima progressione di malattia, prima recidiva, diagnosi di secondo tumore, morte

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

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

Yes

E.6.13.1

Other scope of the trial description

assessment of quality of life and life situation

valutazione della qualità della vita

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

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.8.2.4

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

Information not present in EudraCT

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

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.1.1.1

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)

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)

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

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

in children and adolescents who are too young to give consent, according to local law, will be required to sign an informed consent to parents / guardians. The consent of the patient may be required or not according to the local legislation.

a bambini e adolescenti che sono troppo piccoli per dare il proprio consenso, in base alla legislazione locale, verrà richiesta la sottoscrizione di un consenso informato da parte dei genitori/tutori. L’assenso dei pazienti può essere richiesto o men

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)

patients will be kept in follow-up

i pazienti vengono mantenuti in follow-up

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

2015-07-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-25

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

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