Clinical Trials Register

Summary
EudraCT Number:	2016-003578-42
Sponsor's Protocol Code Number:	SANKOMA_2016
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:	2017-09-18
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

2016-003578-42

A.3

Full title of the trial

Phase I / II Clinical Trial, multicenter, open, of infusion of activated NK cells for the treatment of children, adolescents and young adults with sarcomas.

Ensayo Clínico Fase I/II, multicéntrico, abierto, de infusión de células NK activadas para el tratamiento de niños, adolescentes y adultos jóvenes con sarcomas.

A.3.1

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

Infusion of activated NK cells for the treatment of children, adolescents and young adults with sarcomas.

Infusión de células NK activadas para el tratamiento de niños, adolescentes y adultos jóvenes con sarcomas.

A.4.1

Sponsor's protocol code number

SANKOMA_2016

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 Pérez-Martínez
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	Servicio de Hemato-Oncología Infantil. Hospital Universitario La Paz.
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	Hospital Universitario La Paz
B.5.2	Functional name of contact point	UCICEC
B.5.3	Address:
B.5.3.1	Street Address	Paseo de la Castellana 261
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28046
B.5.3.4	Country	Spain
B.5.4	Telephone number	34912071876
B.5.5	Fax number	34912071466

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	NK CELLS
D.3.9.3	Other descriptive name	Natural Killer Cells
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	50000000
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)	No
	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	Yes
D.3.11.13.1	Other medicinal product type	NK cells from haploidentical donor
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 Farmaceutica 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	1000000
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

Sarcoma

E.1.1.1

Medical condition in easily understood language

Sarcoma

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10039491
E.1.2	Term	Sarcoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the safety of immunotherapy with haploidenic allogeneic NK cells and IL-2, following lymphoblative chemotherapy and / or radiotherapy (2Gy) in the tumor, in pediatric patients with refractory sarcoma.

Evaluar la seguridad de la inmunoterapia con células NK alogénicas haploidénticas e IL-2, tras quimioterapia linfoablativa y/o radioterapia (2Gy) en el tumor, en pacientes pediátricos con sarcoma refractario.

E.2.2

Secondary objectives of the trial

1. To analyze the incidence of episodes of febrile neutropenia, bacteremia, infections (viral, fungal), hematologic recovery and hospital admission associated with treatment with NK + IL-2 cells.

2. Evaluate the rate of disease progression five years after treatment with NK + IL-2 cells.

3. Determine the expression of NK cell ligands in both solid and serum tumor samples from patients with sarcoma. To correlate these results with the progression of the disease to identify new prognostic biomarkers.

1. Analizar la incidencia de episodios de neutropenia febril, bacteriemias, infecciones (víricas, fúngicas), recuperación hematológica e ingreso hospitalario asociado al tratamiento con las células NK + IL-2.

2. Evaluar la tasa de progresión de la enfermedad a cinco años tras el tratamiento con las células NK + IL-2.

3. Determinar la expresión de ligandos de las células NK, tanto en muestras de tumores sólidos como en suero de los pacientes con sarcoma. Correlacionar estos resultados con la progresión de la enfermedad para identificar nuevos biomarcadores pronósticos.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients aged between 0 and 30 years diagnosed with malignant sarcoma, who continue to present detectable residual disease (based on imaging techniques) at the end of conventional treatment.

2. Lansky / Karnofsky Index> 60%.

3. Functional alteration of organs (liver, renal, respiratory) mild-moderate (<4), according to National Cancer Institute criteria (NCI CTCAE v4).

4. Left ventricular ejection fraction> 39%.

5. Adult subjects who have voluntarily signed informed consent prior to the first study intervention.

6. Minors whose legal representative / guardian has voluntarily signed informed consent prior to the first study intervention.

7. In the case of mature minors (12-17 years of age), in addition to the consent signed by the legal guardian, the child's consent will be obtained.

8. Women with reproductive capacity should have a negative pregnancy test at the time of inclusion and should be given access to highly effective contraceptive methods (diaphragms plus spermicide or male condom plus spermicide, oral contraceptive combined with a second method of contraceptive implantation , Injectable contraceptive, permanent intrauterine device, sexual abstinence or partner with vasectomy) during their participation in the study and within 30 days after the last visit.

9. Presence of a compatible haploident donor (parent or sibling).

1. Pacientes de edad comprendida entre 0 y 30 años diagnosticados de sarcoma maligno, que al finalizar el tratamiento convencional siguen presentando enfermedad residual detectable (en base a técnicas de imagen).

2. Índice de Lansky/Karnofsky > 60%.

3. Alteración funcional de órganos (hepática, renal, respiratorio) leve-moderada (<4), según los criterios del National Cancer Institute (NCI CTCAE v4).

4. Fracción de eyección del ventrículo izquierdo >39%.

5. Sujetos adultos que hayan firmado voluntariamente el consentimiento informado antes de la primera intervención del estudio.

6. Sujetos menores cuyo representante/tutor legal hayan firmado voluntariamente el consentimiento informado antes de la primera intervención del estudio.

7. En el caso de menores maduros (12 - 17 años de edad), además del consentimiento firmado por el tutor legal, se obtendrá el asentimiento del menor.

8. Las mujeres con capacidad de procrear deben tener una prueba de embarazo negativa en el momento de la inclusión y deben acceder a usar métodos anticonceptivos altamente eficaces (diafragmas más espermicida o preservativo masculino más espermicida, anticonceptivo oral combinado con un segundo método de implante anticonceptivo, anticonceptivo inyectable, dispositivo intrauterino permanente, abstinencia sexual o pareja con vasectomía) durante su participación en el estudio y en los 30 días siguientes a la última visita.

9. Presencia de un donante haploidéntico compatible (padre o madre o hermano).

E.4

Principal exclusion criteria

1. Patients with a history of poor therapeutic compliance.

2. Patients who, after a psycho-social evaluation, are censored as unfit for the procedure:
• Socio-familial situation that makes it impossible to participate correctly in the study.
• Patients with emotional or psychological problems secondary to the disease such as posttraumatic stress disorder, phobias, delusions, psychosis, requiring specialist support.
• Evaluation of family involvement in the patient's health.
• Inability to understand test information.

3. Functional alteration of organs (severe hepatic, renal, respiratory) (4), according to the criteria of the National Cancer Institute (NCI CTCAE 4.3).

4. The contraindications, interactions, precautions for use and dose reductions indicated in the relevant technical data sheets should be considered.

5. Subjects who have been given other investigational drugs within 90 days prior to inclusion.

1. Pacientes con antecedentes de mal cumplimiento terapéutico.

2. Pacientes que tras una evaluación psico-social se censuran como no aptos para el procedimiento.
• Situación socio-familiar que imposibilite la correcta participación en el estudio.
• Pacientes con problemas emocionales o psicológicos secundarios a la enfermedad como trastorno de estrés postraumático, fobias, delirios, psicosis, con requerimiento de soporte por especialistas.
• Evaluación de la implicación de los familiares en la salud del paciente.
• Imposibilidad de comprender la información sobre el ensayo.

3. Alteración funcional de órganos (hepática, renal, respiratorio) grave (4), según los criterios del National Cáncer Institute (NCI CTCAE 4.3).

4. Se deben considerar las contraindicaciones, interacciones, precauciones de uso y reducciones de dosis indicadas en las fichas técnicas correspondientes.

5. Sujetos a quienes se les haya administrado otros medicamentos en investigación en los 90 días anteriores a la inclusión.

E.5 End points

E.5.1

Primary end point(s)

Safety of infusion of haploidenic allogeneic adult differentiated NK cells in combination with IL-2 after chemotherapy and radiotherapy

Seguridad de la infusión de las células NK diferenciadas adultas alogénicas haploidénticas en combinación con IL-2 tras quimioterapia y radioterapia

E.5.1.1

Timepoint(s) of evaluation of this end point

36 months

36 meses

E.5.2

Secondary end point(s)

1. Incidence of episodes of febrile neutropenia, bacteremia, infections (viral, fungal), hematological recovery and hospital admission associated with treatment.

2. Five-year progression rate of disease following treatment with NK + IL-2 cells. This will be determined by imaging techniques.

3. Expression levels of inhibitory / activating ligands of NK cells in samples from solid and serum tumors of patients. These will be determined by immunohistochemistry and PCR techniques

1. Incidencia de episodios de neutropenia febril, bacteriemias, infecciones (víricas, fúngicas), recuperación hematológica e ingreso hospitalario asociado al tratamiento.

2. Tasa de progresión a cinco años de la enfermedad tras el tratamiento con las células NK + IL-2. Ésta se determinará mediante técnicas de diagnóstico por imagen.

3. Niveles de expresión de ligandos inhibidores / activadores de las células NK en muestras de los tumores sólidos y en suero de los pacientes. Éstos se determinarán mediante técnicas de inmunohistoquímica y de PCR

E.5.2.1

Timepoint(s) of evaluation of this end point

36 months

36 meses

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

Levels of expression of inhibitory / activating ligands of NK cells in samples from solid tumors and serum of patients.

Niveles de expresión de ligandos inhibidores / activadores de las células NK en muestras de los tumores sólidos y en suero de los pacientes.

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

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

Yes

E.8.1.7.1

Other trial design description

Brazo unico

Single arm

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 (LVLS)

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)

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.1.3.1

Number of subjects for this age range:

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.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

2018-04-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-22

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

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