Clinical Trials Register

Summary
EudraCT Number:	2012-005146-38
Sponsor's Protocol Code Number:	LANK-2
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-11-12
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

2012-005146-38

A.3

Full title of the trial

"LANK-2": activated and expanded NK cell immunotherapy together with salvage chemotherapy in children, adolescents and young adults with relapsed or refractary acute leukemia

"LANK-2": INMUNOTERAPIA CON CÉLULAS NATURAL KILLER ACTIVADAS Y EXPANDIDAS JUNTO CON QUIMIOTERAPIA DE RESCATE EN NIÑOS, ADOLESCENTES Y ADULTOS JÓVENES CON LEUCEMIA AGUDA EN RECAÍDA O REFRACTARIEDAD

A.3.1

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

"LANK-2": activated and expanded NK cell immunotherapy together with salvage chemotherapy in children, adolescents and young adults with relapsed or refractary acute leukemia

A.3.2

Name or abbreviated title of the trial where available

Activated and expanded NK cell immunotherapy in leukemia

INMUNOTERAPIA CON CÉLULAS NATURAL KILLER ACTIVADAS Y EXPANDIDAS EN LEUCEMIA

A.4.1

Sponsor's protocol code number

LANK-2

A.5.4

Other Identifiers

Name:

LYDIA

Number:

Sponsor

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	ANTONIO PEREZ MARTINEZ
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	AYUDAS MERK SERONO
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	APICES SOLUCIONES
B.5.2	Functional name of contact point	CLINICAL RESEARCH DEPARTMENT
B.5.3	Address:
B.5.3.1	Street Address	Salamanca, 7
B.5.3.2	Town/ city	Torrejón de la Calzada (Madrid)
B.5.3.3	Post code	28991
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34918166804103
B.5.5	Fax number	+34918169172
B.5.6	E-mail	juanluis.sanz@apices.es

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	NK cells
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Células NK diferenciadas adultas alogénicas haploidénticas de sangre periférica expandidas y activadas con IL-15
D.3.9.3	Other descriptive name	Mature peripheral blood haploidentical expanded and activated IL-15 stimulated NK cells
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1000000 to 10000000
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)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Proleukin
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Farmacéutica, S.A.
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.3.1	Product name	Proleukin
D.3.4	Pharmaceutical form	Powder for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INTERLEUKIN-2
D.3.9.1	CAS number	8000048-25-1
D.3.9.3	Other descriptive name	INTERLEUKIN-2
D.3.9.4	EV Substance Code	SUB14225MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	18000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	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

Relapsed/refractory acute leukaemia

LEUCEMIA AGUDA EN RECAÍDA O REFRACTARIEDAD

E.1.1.1

Medical condition in easily understood language

Relapsed/refractory paediatric acute leukaemia

LEUCEMIA AGUDA EN RECAÍDA O REFRACTARIEDAD

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	10000831
E.1.2	Term	Acute leukaemia NOS
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 safety of mature peripheral blood haploidentical expanded and activated IL-15 stimulated NK cells (NKAE) immunotherapy after salvage chemotherapy in patients with relapsed or refractary acute leukemia

Determinar la seguridad de la inmunoterapia con células NK diferenciadas adultas alogénicas haploidénticas de sangre periférica expandidas y activadas con IL-15 (NKAE) tras quimioterapia de rescate en pacientes con leucemia aguda en recaída o refractariedad.

E.2.2

Secondary objectives of the trial

Analyze incidence of episodes of febrile neutropenia, bacteremia, infections (viral and fungal), hematological recovery and days of hospitalization.
Evaluate complete remission rate (cytomorphological and by criteria of "minimal residual disease", flow cytometry and/or molecular biology) .
Assess immune reconstitution of lymphocytes and cytotoxic activity of NK cells pre and post NKAES infusion.

Analizar la incidencia de episodios de neutropenia febril, bacteriemias, infecciones (víricas, fúngicas), recuperación hematológica e ingreso hospitalario.
Evaluar la tasa de remisión completa (citomorfológica y por criterios de "enfermedad mínima residual", citometría de flujo y/o biología molecular).
Evaluar la reconstitución inmune de poblaciones linfocitarias y la actividad citotóxica de las células NK pre y post infusión de NKAE.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients betweem 0 and 23 years of age with diagnosis of acute lymphoblastic leukemia, in second relapse situation, postransplant relapse or refractary, or
2. Patients betweem 0 and 23 years of age with diagnosis of acute myeloblastic leukemia, relapsed or refractary. (Patient must meet inclusion critaria 1 or 2)
3. Lansky index > 60%
4. Mild (<2) functional organs alteration (hepatic, renal, respiratory)
according to National Cancer Institute criteria (NCI CTCAE v4).
5. Left ventricular ejection fraction > 39%
6. To grant informed consent in accordance with the current legal
regulations.
7. Presence of a compatible haploidentical donor (father or mother or brother).

1. Pacientes de edad comprendida entre 0 y 23 años diagnosticados de leucemia aguda linfoblástica en situación clínica de segunda recaída, de recaída postrasplante o en situación de refractariedad, o
2. Pacientes de edad comprendida entre 0 y 23 años diagnosticados de leucemia aguda mieloblástica en situación clínica de recaída o de refractariedad. (El paciente debe cumplir el criterio 1 o el criterio 2).
3. Índice de Lansky > 60%.
4. Alteración funcional de órganos (hepática, renal, respiratorio) leve
(<2), según los criterios del National Cancer Institute (NCI CTCAE v4).
5. Fracción de eyección del ventrículo izquierdo >39%.
6. Otorgar consentimiento informado de acuerdo con la normativa legal
vigente.
7. Presencia de un donante haploidéntico compatible (padre o madre o hermano).

E.4

Principal exclusion criteria

1. Patients with a history of poor treatment compliance.
2. Patients following a psycho-social assessment are censored as unfit for the procedure.
3. Functional impairment of organs (liver, kidney, respiratory) severe (4), according to the criteria of the National Cancer Institute (NCI CTCAE 4.3).
4. Positive HIV serology.
5. Should be considered contraindications, interactions, precautions for use and dose reductions indicated in the respective data sheets.

1. Pacientes con antecedentes de mal cumplimiento terapéutico.
2. Pacientes que tras una evaluación psico-social se censuran como no aptos para el procedimiento.
3. Alteración funcional de órganos (hepática, renal, respiratorio) grave (4), según los criterios del National Cáncer Institute (NCI CTCAE 4.3).
4. Serología HIV positiva.
5. Se deben considerar las contraindicaciones, interacciones, precauciones de uso y reducciones de dosis indicadas en las fichas técnicas correspondientes.

E.5 End points

E.5.1

Primary end point(s)

Safety of mature peripheral blood haploidentical expanded and activated IL-15 stimulated NK cells infusion after chemotherapy

Seguridad de la infusión de células NK diferenciadas adultas alogénicas haploidénticas de sangre periférica expandidas y activadas con IL-15 tras quimioterapia.

E.5.1.1

Timepoint(s) of evaluation of this end point

2 months after infusion

2 meses tras la infusión

E.5.2

Secondary end point(s)

1. Incidence of episodes of febrile neutropenia, bacteriemia or viral or fungal infections
2. Days of hematological recovery (neutrophils >500/microL, lymphocytes >250/microL and platelets >50.000/microL), days of hospitalization, in each cycle
3. Immune reconstitution: Median of T-cell , B, NK, NKT and dendritic cells count and subpopulations of T and NK lymphocytes (cel/microL) during post-treatment follow-up period
4. In vitro cytotoxic activity of NK cells of the patient measured by real-time fluorescence-TDA Eur compared with that of the donor (Blomberg et al. J Immunol Methods 1986)
5. Objective response rate according to cytomorphologic and by "minimal residual disease" criteria (cytometry and/or real time PCR) at the end of the treatment

1. Incidencia de episodios de neutropenia febril, bacteriemia o infecciones víricas o fúngicas.
2. Días hasta recuperación hematológica (neutrófilos >500/microL, linfocitos >250/microL y plaquetas >50.000/microL, días de ingreso hospitalario, en cada ciclo.
3. Reconstitución inmune: Mediana de recuento de células T, B, NK, NKT, dendríticas y subpoblaciones de linfocitos T y NK (cel/microL) durante el periodo de seguimiento post-tratamiento.
4. Actividad citotóxica in vitro de las células NK del paciente comparándola con su donante medida con fluorescencia a tiempo real Eur-TDA (Blomberg et al. J Immunol Methods 1986)
5. Tasa de respuesta objetiva según los criterios citomorfológicos y por enfermedad mínima residual (citometría y/o PCR tiempo real) al final del tratamiento.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. after each cycle
2. after each cycle
3. weekly
4. weekly
5. after treatment

1. después de cada ciclo
2. después de cada ciclo
3. cada semana
4. cada semana
5. después del tratamiento

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

End of follow-up

Final 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

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

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)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children under 12

Niños menores de 12 años

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

Expected normal treatment of the disease

Tratamiento normal esperado de esta enfermedad

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

2013-03-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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