Clinical Trials Register

Summary
EudraCT Number:	2014-002476-92
Sponsor's Protocol Code Number:	20120215
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-07-10
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

Spain - AEMPS

A.2

EudraCT number

2014-002476-92

A.3

Full title of the trial

A Randomized, Open-label, Controlled Phase 3 Adaptive Trial to Investigate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab as Consolidation Therapy Versus Conventional Consolidation Chemotherapy in Pediatric Subjects with High-risk First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)

Ensayo adaptativo de fase 3 aleatorizado, abierto y controlado para investigar la eficacia, seguridad y tolerabilidad del anticuerpo BiTE® blinatumomab como tratamiento de consolidación frente a la quimioterapia de consolidación convencional en sujetos pediátricos con leucemia linfoblástica aguda (LLA) de precursores B en primera recaída de alto riesgo

A.3.1

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

Clinical Study to Investigate the Efficacy, Safety, and Tolerability of the bispecific antibody Blinatumomab as Consolidation Therapy Versus Conventional Consolidation Chemotherapy in Pediatric Subjects with High-risk First Relapse Acute Lymphoblastic Leukemia (ALL)

Ensayo clínico que investiga la eficacia, seguridad y tolerabilidad del anticuerpo específico, blinatumomab, como tratamiento de consolidación frente a la quimioterapia de consolidación convencional en pacientes pediátricos con leucemia linfoblástica aguda (LLA) en primera recaída de alto riesgo.

A.4.1

Sponsor's protocol code number

20120215

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/145/2014

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.5.4	Telephone number	+34900850153
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	Concentrate 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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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.2.5	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	dexamethasone
D.3.4	Pharmaceutical form
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	Dexamethasone
D.3.9.3	Other descriptive name	DEXAMETHASONE SODIUM PHOSPHATE
D.3.9.4	EV Substance Code	SUB01615MIG
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	4
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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.2.5	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	vincristine
D.3.4	Pharmaceutical form
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	vincristine
D.3.9.3	Other descriptive name	VINCRISTINE SULFATE
D.3.9.4	EV Substance Code	SUB05101MIG
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	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	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.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
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.2.5	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	Daunorubicin
D.3.4	Pharmaceutical form
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	daunorubicin
D.3.9.3	Other descriptive name	DAUNORUBICIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB01556MIG
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	20
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.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
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.2.5	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	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	methotrexate
D.3.9.3	Other descriptive name	METHOTREXATE
D.3.9.4	EV Substance Code	SUB08856MIG
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	25
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.IMP: 6
D.1.2 and D.1.3	IMP Role	Comparator
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.2.5	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	Ifosfamide
D.3.4	Pharmaceutical form
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	IFOSFAMIDE
D.3.9.1	CAS number	3778-73-2
D.3.9.4	EV Substance Code	SUB08125MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
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	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.IMP: 7
D.1.2 and D.1.3	IMP Role	Comparator
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.2.5	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	Erwinia L-asparaginase
D.3.4	Pharmaceutical form
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	Erwinia L-asparaginase
D.3.9.3	Other descriptive name	RECOMBINANT L-ASPARAGINASE
D.3.9.4	EV Substance Code	SUB130490
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000
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	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.IMP: 8
D.1.2 and D.1.3	IMP Role	Comparator
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.2.5	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	Pegaspargase
D.3.4	Pharmaceutical form
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	PEGASPARGASE
D.3.9.1	CAS number	130167-69-0
D.3.9.4	EV Substance Code	SUB03666MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3750
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	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

Patients with Philadelphia chromosome negative (Ph-) high-risk (HR) first relapse B-precursor ALL (as defined by I-BFM SG/IntReALL criteria)

Sujetos con LLA de precursores B en primera recaída de alto riesgo (AR) con cromosoma Filadelfia negativo (Ph-) (según la definición de los criterios del I-BFM SG/IntReALL)

E.1.1.1

Medical condition in easily understood language

Acute Lymphoblastic Leukemia ? a cancer of the blood and marrow

Leucemia Linfoblástica Aguda (LLA)- un cáncer de la sangre y de la médula ósea

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	18.0
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	18.0
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	18.0
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 evaluate event-free survival (EFS) after blinatumomab when compared to standard of care (SOC) chemotherapy.

Evaluar la supervivencia libre de acontecimientos (SLA) después de blinatumomab en comparación con el tratamiento estándar (SOC) de quimioterapia.

E.2.2

Secondary objectives of the trial

To evaluate the effect of blinatumomab on overall survival (OS) when compared to SOC chemotherapy
? To evaluate reduction in minimal residual disease (MRD) after blinatumomab when compared to SOC chemotherapy
? To evaluate the safety of blinatumomab when compared to SOC chemotherapy
? To evaluate the safety of allogeneic hematopoietic stem cell transplantation (alloHSCT) after blinatumomab when compared to alloHSCT after SOC chemotherapy

? Evaluar el efecto de blinatumomab en la supervivencia global (SG) en comparación con el SOC de quimioterapia.
? Evaluar la reducción de la enfermedad mínima residual (EMR) después de blinatumomab en comparación con el SOC de quimioterapia.
? Evaluar la seguridad de blinatumomab en comparación con el SOC de quimioterapia.
? Evaluar la seguridad del trasplante alogénico de células progenitoras hematopoyéticas (alo-TPH) después de blinatumomab en comparación con el alo-TPH tras el SOC de quimioterapia.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

* Subjects with Philadelphia (Ph-) chromosome negative high-risk (HR) first relapse B-precursor ALL (as defined by I-BFM SG/IntReALL criteria)
* Subjects with M1 or M2 marrow (< 25% leukemic cells by cytomorphology) at the time of randomization
* Age > 28 days and < 18 years at the time of informed consent/assent
* 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

* Sujetos con LLA de precursores B en primera recaída de alto riesgo (HR) con cromosoma Filadelfia negativo (Ph-) (según la definición de los criterios del I-BFM SG/IntReALL)
* Sujetos con médula M1 o M2 (< 25% de células leucémicas mediante citomorfología) en el momento de la aleatorización
* Edad > 28 días y < 18 años en el momento del asentimiento/consentimiento informado
* El representante legal autorizado del sujeto ha dado su consentimiento informado cuando el sujeto es legalmente demasiado joven para dar su consentimiento informado y el sujeto ha dado su asentimiento por escrito de acuerdo con las normativas y/o directrices locales antes de iniciar cualquier actividad/procedimiento específico del estudio

E.4

Principal exclusion criteria

* Clinically relevant CNS pathology requiring treatment (eg, unstable epilepsy) Evidence of current CNS (CNS 2, CNS 3) involvement by ALL. Subjects with CNS relapse at the time of relapse are eligible if CNS is successfully treated prior to enrollment.
* Abnormal renal or hepatic function prior to start of treatment (day 1) as defined in the 20120215 protocol
a. Serum creatinine levels above upper limit of normal, based on the normal ranges for age and gender of the local laboratories
b. Direct bilirubin > 1.5 mg/dl prior to start of treatment (unless related to Gilbert?s or Meulengracht disease)
* Peripheral neutrophils < 500/?l prior to start of treatment
* Peripheral platelets < 50,000/?l prior to start of treatment
* 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. Procedures required by IntReALL HR guidelines are allowed.
* Chemotherapy related toxicities that have not resolved to ? grade 2
* Symptoms and/or clinical signs and/or radiological and/or sonographic signs that indicate an acute or uncontrolled chronic infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol
* Known infection with HIV
* Known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing
* Post-menarchal subject who is pregnant or breastfeeding, or is planning to become pregnant or breastfeed while receiving protocol-required therapy and for at least 12 months thereafter
* Post-menarchal female subject who is not willing to practice true abstinence or use a highly effective form of contraception while receiving protocol-required therapy and for at least 12 months thereafter
* Sexually mature male subject who is not willing to practice true abstinence or use a condom while receiving protocol-required therapy and for at least 6 months thereafter
* Sexually mature male subject who is not willing to abstain from sperm donation while receiving protocol-required therapy and for at least 6 months thereafter
* Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject?s and investigator?s knowledge
* History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
* Placed into an institution due to juridical or regulatory ruling

* Patología del SNC clínicamente relevante que requiera tratamiento (p. ej., epilepsia inestable). Evidencia de afectación actual del SNC (SNC 2, SNC 3) por la LLA. Sujetos con recaída en el SNC que en el momento de la recaída sean elegibles si el SNC se trata satisfactoriamente antes de la inclusión.
* Función renal o hepática anormal antes del inicio del tratamiento (día 1) tal como se define en el protocolo 20120215:
a. Niveles de creatinina en suero por encima del límite superior de normalidad según límites de normalidad por edad y sexo de los laboratorios locales.
b. Bilirrubina directa > 1,5 mg/dL antes del inicio del tratamiento (salvo que esté relacionada con la enfermedad de Gilbert o Meulengracht)
* Neutrófilos periféricos < 500/µL antes del inicio del tratamiento
* Plaquetas periféricas < 50.000/µL antes del inicio del tratamiento
* Estar recibiendo actualmente tratamiento en otro estudio de un fármaco o dispositivo en investigación o haber transcurrido menos de 4 semanas desde el fin del tratamiento en otro estudio de un fármaco o dispositivo en investigación. Quedan excluidos otros procedimientos experimentales durante la participación en este estudio. Se permiten los procedimientos requeridos por las directrices de alto riesgo de IntReALL.
* Toxicidades relacionadas con la quimioterapia que no se hayan resuelto hasta un grado ? 2
* Síntomas y/o signos clínicos, radiológicos o ecográficos que indiquen una infección aguda o crónica incontrolada, o cualquier otra enfermedad o patología concurrente que pueda exacerbarse con el tratamiento o complicar seriamente el cumplimiento del protocolo
* Infección conocida por el virus de la inmunodeficiencia humana (VIH)
* Hipersensibilidad conocida a las inmunoglobulinas o a alguno de los productos o componentes que se administrarán durante la dosificación
* Mujer posmenárquica que esté embarazada o dando el pecho o que tenga previsto quedarse embarazada o dar el pecho mientras recibe el tratamiento requerido por el protocolo y durante al menos 12 meses más
* Mujer posmenárquica que no esté dispuesta a practicar una verdadera abstinencia sexual o a utilizar un método anticonceptivo altamente eficaz mientras recibe el tratamiento requerido por el protocolo y durante al menos 12 meses más
* Hombre sexualmente maduro que no esté dispuesto a practicar una verdadera abstinencia sexual o a utilizar un preservativo mientras recibe el tratamiento requerido por el protocolo y durante al menos 6 meses más
* Hombre sexualmente maduro que no esté dispuesto a abstenerse de donar esperma mientras recibe el tratamiento requerido por el protocolo y durante al menos 6 meses más
* Según informan el sujeto y el investigador, es posible que el sujeto no esté disponible para completar todas las visitas o procedimientos del estudio requeridos por el protocolo, incluidas las visitas de seguimiento, y/o cumplir todos los procedimientos del estudio
* Antecedentes o evidencia de cualquier otro trastorno, condición o enfermedad clínicamente significativo (excepto los indicados anteriormente) que, en opinión del investigador o del médico de Amgen, si se le consulta, pudieran suponer un riesgo para la seguridad del sujeto o interferir en la evaluación, los procedimientos o la realización del estudio.
* Estar internado en una institución por una decisión jurídica o normativa

E.5 End points

E.5.1

Primary end point(s)

EFS

SLA

E.5.1.1

Timepoint(s) of evaluation of this end point

from the time of randomization until the date of relapse or M2 marrow after having achieved a CR, failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first.

desde el momento de la aleatorización hasta la fecha de la recaída o médula M2 después de alcanzar una RC, la imposibilidad de alcanzar una RC al final del tratamiento, la aparición de una neoplasia secundaria o la muerte por cualquier causa, lo que ocurra antes.

E.5.2

Secondary end point(s)

*OS
*MRD response
*Incidence of adverse events (both serious and non-serious), treatment-related adverse events, adverse events of interest, clinically significant changes in laboratory values
*Survival status at 100 days following HSCT
*Incidence of anti-blinatumomab antibody formation (blinatumomab arm only)

* SG
* Respuesta de la EMR
* Incidencia de acontecimientos adversos (graves y no graves), acontecimientos adversos relacionados con el tratamiento, acontecimientos adversos de interés y cambios clínicamente significativos en los valores analíticos
* Estado de la supervivencia 100 días después del alo-TPH
* Incidencia de la formación de anticuerpos anti-blinatumomab (solo en el grupo de blinatumomab)

E.5.2.1

Timepoint(s) of evaluation of this end point

*OS: from time of randomization until the end of the study, or death, whatever comes first .
*MRD response: at the end of treatment with investigational product(s)
*Incidence of adverse events (both serious and non-serious), treatment-related adverse events, adverse events of interest, clinically significant changes in laboratory values : during the treatment period
*Survival status: at 100 days following alloHSCT
* Incidence of anti-blinatumomab antibody formation (blinatumomab arm only): during the whole study

* SG: desde el momento de la aleatorización hasta el final del estudio o la muerte, lo que ocurra primero
* Respuesta de la EMR: al final del tratamiento con el producto en investigación
* Incidencia de acontecimientos adversos (graves y no graves), acontecimientos adversos relacionados con el tratamiento, acontecimientos adversos de interés y cambios clínicamente significativos en los valores analíticos: durante el período de tratamiento
* Estado de la supervivencia: 100 días después del alo-TPH
* Incidencia de la formación de anticuerpos anti-blinatumomab (solo en el grupo de blinatumomab): durante todo el estudio

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

Yes

E.6.13.1

Other scope of the trial description

Incidence of anti-blinatumomab antibody formation (blinatumomab arm only)

Incidencia de la formación de anticuerpos anti-blinatumomab (solo en el grupo de blinatumomab)

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

Yes

E.8.1.1

Randomised

Yes

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)

Yes

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

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

Austria

Belgium

Czech Republic

Denmark

France

Germany

Israel

Italy

Netherlands

Poland

Portugal

Spain

Sweden

Switzerland

United Kingdom

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

End of study (primary completion): when the last subject is assessed or receives an intervention for the purposes of final collection of data for the primary endpoint
End of Trial: when the last subject is assessed or receives an intervention for evaluation in the study; including follow-up assessments

Fin del estudio (finalización principal): el momento en que el último sujeto se evalúa o recibe una intervención con la intención de recopilar los últimos datos para la variable principal
Fin del Ensayo: el momento en que el último sujeto se evalúa o recibe una intervención para la evaluación en el estudio, incluidas las evaluaciones de seguimiento

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:

320

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:

128

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

160

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 from 28 days to 17 years old

Edad > 28 días y < 18 años

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

270

F.4.2.2

In the whole clinical trial

320

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

Ninguno

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	International Berlin-Frankfurt-Muenster Study Group / IntReALL
G.4.3.4	Network Country	United Kingdom

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-07-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-05

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

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