Clinical Trials Register

Summary
EudraCT Number:	2014-001700-21
Sponsor's Protocol Code Number:	20130320
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-09-25
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

2014-001700-21

A.3

Full title of the trial

An Open-Label, Multi-center, Expanded Access Protocol of Blinatumomab for the Treatment of Pediatric and Adolescent Subjects with Relapsed and/or Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Rialto Study)

Studio multicentrico, in aperto, ad accesso allargato con blinatumomab per il trattamento di soggetti pediatrici e adolescenti affetti da leucemia linfoblastica acuta (LLA) da precursori delle cellule B recidiva e/o refrattaria (studio Rialto)”

A.3.1

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

Clinical Study with the bispecific antibody Blinatumomab in pediatric and adolescent subjects with B-precursor Acute Lymphoblastic Leukemia (ALL) who did not respond to previous therapy or who relapsed after initial successful previous therapy

A.3.2

Name or abbreviated title of the trial where available

Rialto Study

Studio Rialto

A.4.1

Sponsor's protocol code number

20130320

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02187354

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	Amgen Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Amgen Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Amgen (EUROPE) GmbH
B.5.2	Functional name of contact point	IHQ medical Info-Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	Dammstrasse 23, P.O. Box 1557
B.5.3.2	Town/ city	Zug
B.5.3.3	Post code	CH-6300
B.5.3.4	Country	Switzerland
B.5.6	E-mail	MedinfoInternational@amgen.com

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	Yes
D.2.5.1	Orphan drug designation number	EU/3/09/650
D.3 Description of the IMP
D.3.1	Product name	Blinatumomab
D.3.2	Product code	AMG 103 , MT103
D.3.4	Pharmaceutical form	Powder 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	Blinatumomab
D.3.9.1	CAS number	853426-35-4
D.3.9.2	Current sponsor code	AMG 103
D.3.9.3	Other descriptive name	BLINATUMOMAB
D.3.9.4	EV Substance Code	SUB35403
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	30.3 to 38.5
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	Yes
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

Pediatric and Adolescent Subjects with Relapsed and/or Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

Soggetti pediatrici di eta’ >28 giorni e < 18 anni affetti da LLA da precursori delle cellule B recidiva/refrattaria

E.1.1.1

Medical condition in easily understood language

Acute Lymphoblastic Leukemia – a cancer of the blood and marrow

Leucemia linfoblastica acuta - tumore del sangue e del midollo osseo

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.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10063625
E.1.2	Term	Acute lymphoblastic leukemia recurrent
E.1.2	System Organ Class	100000004864

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	10066109
E.1.2	Term	Precursor B-lymphoblastic leukemia acute
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 estimate the incidence of treatment-emergent and treatment-related adverse events during treatment with blinatumomab in pediatric and adolescent subjects with B-precursor acute lymphoblastic leukemia (ALL) in second or later bone marrow relapse, in any marrow relapse after allogeneic HSCT (alloHSCT), or refractory to other treatments

Stimare l’incidenza di eventi avversi insorti durante il trattamento e correlati al trattamento durante il periodo di trattamento con blinatumomab in soggetti pediatrici e adolescenti affetti da LLA da precursori delle cellule B alla seconda o a una successiva recidiva midollare, a qualunque recidiva midollare dopo HSCT allogenico o in caso di refrattarietà ad altri trattamenti.

E.2.2

Secondary objectives of the trial

To describe key efficacy outcomes, including
1. incidence of complete response (CR) within 2 cycles of blinatumomab
2. minimal residual disease (MRD) remission within 2 cycles of blinatumomab
3. relapse free survival (RFS)
4. overall survival (OS)
5. incidence of alloHSCT
6. 100-day mortality after alloHSCT

Descrivere i principali outcome di efficacia, tra cui incidenza di una risposta completa (CR) entro 2 cicli di blinatumomab, remissione della malattia minima residua (MRD) entro 2 cicli di blinatumomab, sopravvivenza libera da recidiva (RFS), sopravvivenza globale (OS), incidenza di HSCT allogenico e mortalità a 100 giorni da HSCT allogenico

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Morphologic and immunophenotypic evidence of CD19 positive B-precursor ALL (pro B-, pre B-, common ALL) with ≥ 5% blasts in bone marrow (M2 and M3) at study enrollment
2. Age > 28 days and < 18 years at the time of informed consent/assent
3. Relapsed/refractory disease, defined as one of the following:
• Second or later bone marrow relapse;
• Any marrow relapse after alloHSCT; or
• Refractory to other treatments:
o For patients in first relapse: failure to achieve a CR following a full standard reinduction chemotherapy regimen
o For patients who have not achieved a first remission: failure to achieve remission following a full standard induction regimen
• Subjects previously treated with blinatumomab may be eligible, if subject ended treatment for reason(s) other than disease progression or intolerability to blinatumomab
4. Subject’s legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/ procedures being initiated
5. Subject does not qualify for, or cannot access other comparable or satisfactory alternative therapy for CD19 positive B-precursor ALL
6. Adequate liver function defined as:
• ALT (SGPT) < 5 x upper limit of normal (ULN) for age at least once during screening

1. Prova morfologica ed immunofenotipica di CD19 positivo Bprecursor LLA (pro B , pre B- , comune ALL) con ≥ 5% di blasti nel midollo osseo (M2 e M3) al momento dell'arruolamento
2. Età >28 giorni e < 18 anni al momento del consenso informato
3. Malattia recidivante/refrattaria, definita come uno dei seguenti:
• Seconda o successiva ricaduta del midollo osseo;
• Qualsiasi ricaduta osseo dopo trapianto alloHSCT ( allogenic hematopoetic stem cell transplant); o
• refrattari ad altri trattamenti:
o Per i pazienti in prima recidiva: mancato raggiungimento di una completa remissione seguente ad un regime standard di reinduzione chemioterapica completo
• Soggetti trattati in precedenza con blinatumomab possono essere eleggibili. Se i soggetti hanno comcluso il trattamento per motivi diversi dal peggioramento della malattia o dall’intolleranza al blinatumomab
4. Rappresentante legalmente riconosciuto del soggetto ha fornito il consenso informato quando il soggetto era legalmente troppo giovane per fornire il consenso informato e il soggetto ha fornito consenso scritto sulla base di normative locali e / o linee guida prima di qualsiasi attività specifiche di studio o che venissero avviate le procedure
5. Soggetto che non puo' essere qualificato per, o non può accedere altra terapia alternativa comparabile o soddisfacente per CD19 positivo B-precursore LLA
6. Funzione epatica adeguata, definita come:
• ALT (SGPT) <5 volte il limite superiore della norma (ULN) per l'età, almeno una volta durante lo screening

E.4

Principal exclusion criteria

1. Any active acute Graft-versus-Host Disease (GvHD) grade 2 to grade 4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
2. Immunosuppressive agents to prevent or treat GvHD within 2 weeks prior to blinatumomab treatment (except for topical corticosteroids)
3. Active (overt) ALL in the CNS (confirmed by cerebrospinal fluid [CSF] analysis) or in testes
4. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis
- With the exception of CNS leukemia that is well controlled with intrathecal therapy
5. Current autoimmune disease or history of autoimmune disease with potential CNS involvement
6. Cancer chemotherapy within 2 weeks prior to start of blinatumomab (except for tyrosine kinase inhibitors (TKI) and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, glucocorticoids; intrathecal chemotherapy and dexamethasone are allowed until start of blinatumomab).
7. Radiotherapy within 2 weeks prior to blinatumomab treatment
8. Immunotherapy (eg, rituximab) within 4 weeks prior to blinatumomab treatment
9. Currently receiving treatment in another investigational device or drug study, or less than 4 weeks since ending treatment on another investigational device or drug study(s). Other investigational procedures while participating in this study are excluded.
10. Subject has known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing

1)Qualsiasi malattia Host Graft-versus-attiva acuta (GvHD) di grado 2 al grado 4 secondo i criteri Glucksberg o attiva GvHD cronica che richiede un trattamento sistemico
2)Agenti immunosoppressivi per prevenire o trattare la GvHD entro 2 settimane prima del trattamento con Blinatumomab (ad eccezione di corticosteroidi topici)
3)Attivo (palese) LLA nel sistema nervoso centrale (confermato dal liquido cerebrospinale [CSF] analisi) o nei testicoli
4)Storia o presenza di patologia clinicamente rilevante del sistema nervoso centrale come l'epilessia, convulsioni, paresi, afasia, ictus, gravi lesioni cerebrali, demenza, malattia cerebellare, sindrome cerebrale organica, psicosi – ad eccezione della leucemia del sistema nervoso centrale che è ben controllato con la terapia intratecale
5) Malattia autoimmune attuale o storia di malattia autoimmune con potenziale coinvolgimento del Sistema Nervoso centrale
6)Chemioterapia per il cancro entro 2 settimane prima dell'inizio del Blinatumomab (tranne che per gli inibitori della tirosin-chinasi (TKI) e / o una bassa dose di terapia di mantenimento, come vinca alcaloidi , mercaptopurina, metotrexate, glucocorticoidi, la chemioterapia intratecale e desametasone sono consentiti fino all'inizio di Blinatumomab).
7)Radioterapia entro 2 settimane prima del trattamento Blinatumomab
8)Immunoterapia (ad esempio, rituximab) entro 4 settimane prima del trattamento Blinatumomab
9)Soggetti con nota ipersensibilità alle immunoglobuline o uno qualsiasi dei prodotti o componenti da somministrare
10) Soggetti con nota infezione da'immunodeficienza umana (HIV) o infezione cronica da virus dell'epatite B (HBsAg positiva) o virus dell'epatite C (anti-HCV positivo)

E.5 End points

E.5.1

Primary end point(s)

Incidence of treatment-emergent and treatment-related adverse events

• Incidenza di eventi avversi insorti durante il trattamento e correlati al trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

Assessment throughout treatment period and 30 days after last dose (safety follow-up); primary analysis at the end of the second treatment cycle

Valutazione per tutto il periodo di trattamento e 30 giorni dopo l'ultima dose (di sicurezza follow-up); analisi primaria al termine del secondo ciclo di trattamento

E.5.2

Secondary end point(s)

1. Incidence of CR within 2 cycles of blinatumomab
2. MRD remission within 2 cycles of blinatumomab
3. Relapse-free survival
4. Overall survival
5. Incidence of alloHSCT
6. 100-day mortality after alloHSCT

Remissione della MRD entro 2 cicli di blinatumomab
• RFS
• OS
• Incidenza di HSCT allogenico
• Mortalità a 100 giorni in seguito a HSCT allogenico

E.5.2.1

Timepoint(s) of evaluation of this end point

1. + 2. Assessment at the end of the first and second treatment cycle
3.+4.+5. Assessment throughout entire study
6. Assessment 100 days after alloHSCT

1 +2: valutazione al termine del primo e secondo ciclo di trattamento
3+4 +5 Valutazione per tutta la durata dello studio
6.Valutazione 100 giorno dopo l’alloHSCT (allogenic hematopoetic stem cell transplant);

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

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)

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

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

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

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

Austria

France

Germany

Italy

Switzerland

United Kingdom

United States

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

the time when the last subject is assessed in the long-term survival portion of the study

La fine dello studio si verifica quando l'ultimo soggetto è valutato nella parte dello studio di sopravvivenza a lungo termine (long-term survival)

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

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

Babies and children who are too young to give assent. In this case merely the subject's legally acceptable representative will provide written informed consent.

Infanti e bambini che sono troppo giovani per dare il loro assenso. In questo caso solo il soggetto legalmente responsabile potra’ dare il consenso informato scritto

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)

none

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

2015-02-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-12

P. End of Trial
P.	End of Trial Status	Completed

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