Clinical Trials Register

Summary
EudraCT Number:	2016-004877-42
Sponsor's Protocol Code Number:	PETHEMA-BLIN-01
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:	2018-02-28
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

Spain - AEMPS

A.2

EudraCT number

2016-004877-42

A.3

Full title of the trial

A phase II, open-label study to evaluate the effect of blinatumomab administered during consolidation to reduce the level of minimal residual disease (MRD) assessed through flow cytometry in adult patients up to 55 years of age with high-risk Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukaemia (ALL) with good response (MRD < 0.1%) after induction therapy

Estudio de fase II, abierto, para evaluar el efecto del blinatumomab administrado durante la consolidación para reducir el nivel de enfermedad residual (ER) evaluada mediante citofluorometría en pacientes adultos hasta 55 años con leucemia linfoblástica aguda (LLA) de alto riesgo (AR) sin cromosoma Filadelfia (Ph-) con buena respuesta (ER<0.1%) después del tratamiento de inducción

A.3.1

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

Effect of Blinatumomab in adult patients up to 55 years with acute lymphoblastic leukemia

Estudio para evaluar el efecto del Blinatumomab en pacientes adultos hasta 55 años con leucemia linfoblástica aguda

A.4.1

Sponsor's protocol code number

PETHEMA-BLIN-01

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	FUNDACIÓN PETHEMA
B.1.3.4	Country	Spain
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	AMGEN
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FUNDACIÓN PETHEMA
B.5.2	Functional name of contact point	Juan José Lahuerta Palacios
B.5.3	Address:
B.5.3.1	Street Address	Profesor Martín Lagos s/n
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28040
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034913303011
B.5.6	E-mail	jjlahuerta@telefonica.net

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	BLINCYTO
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Powder for 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.3.9.2	Current sponsor code	BLINATUMOMAB
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	equal
D.3.10.3	Concentration number	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)	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

Acute lymphoblastic leukaemia

Leucemia Linfoblástica Aguda

E.1.1.1

Medical condition in easily understood language

Acute lymphoblastic leukaemia

Leucemia Linfoblástica Aguda

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10000844
E.1.2	Term	Acute lymphoblastic leukaemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the MRD reduction rate, determined by flow cytometry, after early consolidation following the inclusion of blinatumomab administered during the early consolidation phase in patients ≤ 55 years with high-risk Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukaemia (ALL) with MRD < 0.1% (< 1×10–3) after induction therapy

Evaluar la frecuencia de la reducción de la ER, determinada por citometría de flujo, después de la consolidación precoz tras la inclusión de blinatumomab administrado durante la fase de consolidación precoz en pacientes ≤ 55 años con leucemia linfoblástica aguda (LLA) de alto riesgo (AR) sin cromosoma Filadelfia (Ph-) con ER<0,1% (<1x10-3) tras el tratamiento de inducción

E.2.2

Secondary objectives of the trial

• To assess the MRD reduction rate, determined by flow cytometry, after late consolidation phase.
• To assess 5-year disease-free survival.
• To assess 5-year overall survival.
• To assess the extent of MRD reduction.
• To compare these efficacy results with those of similar patients treated with standard consolidation therapy without blinatumomab (Protocol ALL-AR-11), measured as a comparison of the percentages of patients reaching a MRD level of < 0.01% (< 1×10–4) at the end of the consolidation in this trial and in the ALL-AR-11 study.
• To assess the MRD kinetics during maintenance therapy and during the follow-up period once the ALL treatment has been completed.
• To assess the safety of treatment with blinatumomab administered during early and late consolidation

• Evaluar la frecuencia de la reducción de la ER, determinada por citometría de flujo, después de la consolidación tardía
• Evaluar la supervivencia libre de enfermedad a 5 años
• Evaluar la supervivencia global a 5 años
• Evaluar la profundidad de la reducción de la ER.
• Comparar estos resultados de eficacia con los de pacientes similares tratados con terapia de consolidación estándar sin blinatumomab (Protocolo ALL-AR-11), medida como comparación de los porcentajes de pacientes que alcancen un nivel de ER<0,01% (<1x10-4) al final de la consolidación en el presente ensayo y en el estudio ALL-HR-11.
• Evaluar la cinética de la ER durante el tratamiento de mantenimiento y durante el periodo de seguimiento una vez finalizado el tratamiento de la LLA.
• Evaluar la seguridad del tratamiento con blinatumomab administrado durante la consolidación precoz y la tardía.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Men and women between 18 to 55 years of age, both inclusive.
2. Patients with Philadelphia chromosome-negative or BCR-ABL-negative, CD19-positive ALL, with high-risk characteristics. The definition of high-risk ALL implies the presence of one or more of the following factors:
- Aged 30–55 years.
- Leukocytes > 30×109/l in B-precursor ALL.
- Any of the following cytogenetic or molecular abnormalities:
o 11q23 abnormalities, or proven MLL rearrangement.
o Complex karyotype (more than 5 chromosome abnormalities).
- Pro-B ALL, regardless of the number of leukocytes.
3. Previous treatment according to routine clinical practice in Spanish centres, in accordance with the PETHEMA protocol for patients with high-risk ALL (ALL-AR-11), in complete remission (MRD < 0.1%) (< 1×10–3) centralised assessment through flow cytometry) after induction therapy.
4. ECOG < 2.
5. Ability to understand the study and willingness to sign the written informed consent form

1. Mujeres o varones entre 18 y 55 años de edad, ambos incluidos
2. Pacientes con LLA sin cromosoma Filadelfia o BCR-ABL negativo, CD19 positivo, con características de alto riesgo. La definición de LLA de alto riesgo implica la presencia de uno o más de los siguientes factores:
- Edad 30-55 años.
- Leucocitos > 30x109/L en LLA de precursores B
- Alguna de las siguientes alteraciones citogenéticas o moleculares:
o Alteraciones en 11q23, o demostración del reordenamiento MLL.
o Cariotipo complejo (más de 5 alteraciones cromosómicas)
- LLA Pro-B, independientemente de la cifra de leucocitos.
3. Tratamiento previo según la práctica clínica habitual en centros españoles, de acuerdo al protocolo de PETHEMA para pacientes con LLA de alto riesgo (LAL-AR-11), en remisión completa (ER <0,1% (<1x10-3) evaluación centralizada por citometría de flujo) después del tratamiento de inducción.
4. ECOG <2.
5. Capacidad para entender el estudio y voluntad de firmar el consentimiento informado por escrito

E.4

Principal exclusion criteria

1. ALL with Philadelphia chromosome (Ph +).
2. Burkitt's leukemia (mature B phenotype) according to the WHO classification.
3. T cell ALL
4. ALL of precursors B with high risk characteristics with ER ≥0.1% (≥1x10-3) after receiving
induction chemotherapy.
5. Previous history or presence of clinically significant disease of the central nervous system
(CNS): epilepsy, seizures, paresis, aphasia, stroke, brain injuries
severe, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome,
psychosis.
6. Presence or history of autoimmune disease with potential CNS involvement.
7. Radiotherapy in the 2 weeks prior to the start of treatment with blinatumomab.
8. Immunotherapy (eg, rituximab) in the 4 weeks prior to the start of treatment with
blinatumomab.
9. Any product under investigation for leukemia in the 4 weeks prior to the start of the
treatment with blinatumomab.

10. Treatment with any investigational medication after signing the consent
informed.
11. Candidate candidate for allogeneic transplantation of hematopoietic progenitors (TPH) in the
moment of inclusion.
12. Known hypersensitivity to immunoglobulins or to any component of the product in
investigation.
13. Abnormal laboratory values:
to. AST (SGOT) and / or ALT (SGPT) and / or alkaline phosphatase ≥5  LSN.
b. Total bilirubin ≥1.5  ULN (except if it is related to Gilbert's disease or
Meulengracht).
c. Creatinine ≥1.5  LSN.
d. Creatinine clearance calculated <50 ml / min.
and. Hemoglobin ≥9 g / dl (transfusion allowed).
14. History of malignant disease different from ALL in the 5 years prior to the start of treatment
with blinatumomab, with the exception of basal or squamous cell carcinoma of the skin or
carcinoma in situ of the cervix
15. Non-controlled active infection, or any other concurrent medical condition or disease that
it is considered that it interferes with the performance of the study according to the researcher's criteria.
16. HIV infection or chronic infection with hepatitis B virus (HBs Ag positive) or virus of the
Hepatitis C (anti-HCV positive).
17. Pregnant or lactating women.
18. Women of childbearing age who are not willing to use effective contraception during
Participation in the study and until at least 3 months later. Men who are not willing to
take measures to avoid pregnancy of the couple during participation in the study and
less until 3 months later.
19. Previous treatment with blinatumomab.
20. Patients who do not want or can not comply with the protocol.

1. LLA con cromosoma Filadelfia (Ph+).
2. Leucemia de Burkitt (fenotipo B maduro) según la clasificación de la OMS.
3. LLA de células T.
4. LLA de precursores B con características de alto riesgo con ER ≥0.1% (≥1x10-3) después de recibir quimioterapia de inducción.
5. Historia previa o presencia de enfermedad clínicamente significativa del sistema nervioso central (SNC): epilepsia, convulsiones, paresia, afasia, accidente cerebrovascular, lesiones cerebrales graves, demencia, enfermedad de Parkinson, enfermedad cerebelosa, síndrome orgánico cerebral, psicosis.
6. Presencia o antecedentes de enfermedad autoinmune con afectación potencial del SNC.
7. Radioterapia en las 2 semanas previas al inicio del tratamiento con blinatumomab.
8. Inmunoterapia (p. ej., rituximab) en las 4 semanas previas al inicio del tratamiento con blinatumomab.
9. Cualquier producto en investigación para la leucemia en las 4 semanas previas al inicio del tratamiento con blinatumomab.
10. Tratamiento con cualquier medicamento en investigación después de la firma del consentimiento informado.
11. Paciente candidato para trasplante alogénico de progenitores hematopoyéticos (TPH) en el momento de la inclusión.
12. Hipersensibilidad conocida a las inmunoglobulinas o a cualquier componente del producto en investigación.
13. Valores anormales de laboratorio:
a. AST (SGOT) y/o ALT (SGPT) y/o fosfatasa alcalina ≥5 × LSN.
b. Bilirrubina total ≥1.5 × LSN (excepto si está relacionada con la enfermedad de Gilbert o Meulengracht).
c. Creatinina ≥1,5 × LSN.
d. Aclaramiento de creatinina calculado <50 ml/min.
e. Hemoglobina ≥9 g/dl (transfusión permitida).
14. Historial de enfermedad maligna diferente a la LLA en los 5 años previos al inicio del tratamiento con blinatumomab, con la excepción de carcinoma basocelular o escamoso de la piel o de carcinoma in situ del cuello uterino
15. Infección activa no controlada, o cualquier otra enfermedad o condición médica concurrente que se considere que interfiere con la realización del estudio según criterio del investigador.
16. Infección por VIH o infección crónica por el virus de la hepatitis B (HBs Ag positivo) o virus de la hepatitis C (anti-VHC positivo).
17. Mujeres embarazadas o en periodo de lactancia.
18. Mujeres en edad fértil que no estén dispuestas a utilizar un método anticonceptivo eficaz durante la participación en el estudio y hasta al menos 3 meses después. Varones que no estén dispuestos a tomar medidas para evitar el embarazo de la pareja durante la participación en el estudio y al menos hasta 3 meses después.
19. Tratamiento previo con blinatumomab.
20. Pacientes que no quieran o no puedan cumplir con el protocolo

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study will be the percentage of patients achieving MRD < 0.01% (< 1×10–4).

La variable principal del estudio será el porcentaje de pacientes que alcanzan un nivel de ER <0,01% (<1x10-4).

E.5.1.1

Timepoint(s) of evaluation of this end point

Percentage of patients achieving MRD < 0.01% (< 1×10–4) at the end of early consolidation.

Porcentaje de pacientes que alcanzan un nivel de ER <0,01% (<1x10-4) al final de la consolidación precoz

E.5.2

Secondary end point(s)

• Percentage of patients achieving MRD < 0.01% (< 1×10–4).
• Disease-free survival.
• Overall survival.
• Levels of minimal residual disease.
• Toxicity profile of the treatment with blinatumomab.

• Porcentaje de pacientes con ER<0,01% (<1x10-4).
• Supervivencia libre de enfermedad.
• Supervivencia global.
• Niveles de enfermedad residual.
• Perfil de toxicidad del tratamiento con blinatumomab.

E.5.2.1

Timepoint(s) of evaluation of this end point

• MRD < 0.01% (< 1×10–4) at the end of late consolidation.
• 5-year disease-free survival.
• 5-year overall survival.
• Levels of minimal residual disease: after treatment with blinatumomab , during the maintenance period (every 3 months) and during follow-up after discontinuing treatment (every 3 months for the first 2 years after completing CT, every 6 months during year 3 and at the end of the follow-up)
• Toxicity profile of the treatment with blinatumomab administered after two consolidation cycles.

• ER<0,01% (<1x10-4) al final de la consolidación tardía
• Supervivencia libre de enfermedad a 5 años
• Supervivencia global a 5 años
• Niveles de enfermedad residual: tras el tratamiento con blinatumomab, durante el período de mantenimiento y durante el seguimiento tras el cese del tratamiento (cada 3 meses durante los 2 primeros años después de finalizar la QT), cada 6 meses durante el tercer año y hasta finalizar el seguimiento, anualmente).
• Perfil de toxicidad del tratamiento con blinatumomab administrado tras dos ciclos de consolidación.

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

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

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

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

UVUP

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

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)

F.1.1.6

Adolescents (12-17 years)

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

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

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

Ninguno

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

2018-04-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-13

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

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