Clinical Trials Register

Summary
EudraCT Number:	2016-001060-11
Sponsor's Protocol Code Number:	FSJD-RTB-2015
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:	2017-05-23
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

2016-001060-11

A.3

Full title of the trial

A Phase I, unicentric, open and dose escalation clinical trial to evaluate the safety and the activity of the oncolytic adenovirus VCN-01 in patients with refractory retinoblastoma

Ensayo clínico fase I, unicéntrico, abierto y de escalado de dosis, para evaluar la seguridad y la actividad del adenovirus oncolítico VCN-01 en pacientes con retinoblastoma refractario

A.3.1

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

A Phase I clinical trial to evaluate the safety and the activity of the oncolytic adenovirus VCN-01 in patients with refractory retinoblastoma

Ensayo clínico fase I para evaluar la seguridad y la actividad del adenovirus oncolítico VCN-01 en pacientes con retinoblastoma refractario

A.4.1

Sponsor's protocol code number

FSJD-RTB-2015

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	Fundació Sant Joan de Déu
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	Fondo del Ministerio de Sanidad y Política Social.
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	SERMES PLANIFICACION S.L
B.5.2	Functional name of contact point	Unidad de Puesta en Marcha
B.5.3	Address:
B.5.3.1	Street Address	Rufino González 14, Esc.1ª-2ºD
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28037
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34913756930
B.5.5	Fax number	+34917542721
B.5.6	E-mail	start-up@sermescro.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	VCN-01
D.3.2	Product code	VCN-01
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VCN-01
D.3.9.2	Current sponsor code	VCN-01
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1800000000000
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	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	Yes
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

Refractory Retinoblastoma

Retinoblastoma refractario.

E.1.1.1

Medical condition in easily understood language

Retinoblastoma

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	10038916
E.1.2	Term	Retinoblastoma
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 determinate safety and tolerability of two intravitreal injections of VCN-01 through the evaluation of the adverse events and the laboratory tests to set the maximum tolerated dose (MTD) of the VCN-01 virus.

Determinar seguridad y tolerabilidad de dos inyecciones intravítreas de VCN-01 a través de la evaluación de los acontecimientos adversos y los análisis de laboratorio, para establecer la dosis máxima tolerada (MTD) del virus VCN-01.

E.2.2

Secondary objectives of the trial

- To evaluate the anti-tumor response of VCN-01 in patients with advanced intraocular retinoblastoma with vitreous seeding massive within the limitations imposed by the phase I design of the study.
- To evaluate the excretion profile of VCN-01.
- To evaluate the immune response by the presence of neutralizing antibodies in the patients of the study.

-Evaluar la respuesta antitumoral de VCN-01 en pacientes con retinoblastoma intraocular avanzado con siembras vítreas masivas dentro de las limitaciones que impone el diseño de fase I del estudio.
-Evaluar el perfil de excreción de VCN-01.
-Evaluar la respuesta inmune mediante la presencia de anticuerpos neutralizantes en los pacientes del estudio.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients with retinoblastoma both with somatic mutation of the RB1gen with active tumor in a single eye, as with germinal mutation of the RB1gen with active tumor in a single eye and the not affected fellow eye or with active tumor in a single eye and the fellow eye already enucleated relapsed or refractories with the use of systemic chemotherapy, intra-arterial or intravitreal or radiotherapy in whom enucleation is the only advisable treatment.
2. Normal renal function: serum creatinine: <45µmol/L (0-2 years); <57µmol/L (3-6 years); <60µmol/L (7-10 years); <80µmol/L (11-13 years).
3. Normal liver function: serum ALT: <0,52µkat/L (from 9 months to 12 years); serum AST: 61-80 g/L (from 8 months to 5 years); 63-83 g/L (5-9 years); 63-82 g/L (9-12 years).
4. Adequate bone-marrow reserve expressed in an absolute neutrophil count > 1000/mm3, platelets >100.000/mm3 and hemoglobin >8 g/dl, without transfusional support.
5. Older than one year and youger than 12 years at the time of inclusion in the study.
6. Signed informed consent form.

1.Pacientes con retinoblastoma tanto con mutación somática del genRB1 con tumor activo en un solo ojo, como con mutación germinal del RB1 con tumor activo en un solo ojo y el ojo contralateral no afectado o con tumor activo en un solo ojo y el ojo contralateral ya enucleado recaídos o refractarios con el uso de quimioterapia sistémica, intra-arterial o intravítrea o radioterapia en quienes la enucleación sea el único tratamiento recomendable.
2.Función renal normal: creatinina en suero: <45µmol/L (0-2 años); <57µmol/L (3-6 años); <60µmol/L (7-10 años); <80µmol/L (11-13 años).
3.Función hepática normal: ALT en suero: <0,52µkat/L (de 9 meses a 12 años); AST en suero: 61-80 g/L (de 8 meses a 5 años); 63-83 g/L (5-9años); 63-82 g/L (9-12 años)
4.Adecuada reserva medular manifestada en un recuento absoluto de neutrófilos > 1000/mm3, plaquetas >100.000/mm3 y hemoglobina >8 g/dl, sin apoyo transfusional ni de citoquinas por lo menos un mes antes del ingreso al estudio.
5.Edad mayor de un año y menor de 12 años en el momento de la inclusión en el estudio.
6.Formulario de consentimiento informado firmado.

E.4

Principal exclusion criteria

1. Presence of factors that require immediate enucleation of the affected eye as can be glaucoma, rubeosis iridis, commitment on the anterior chamber.
2. Comorbidity situations: uncontrolled epilepsy with anticonvulsant treatment, no compensated cardiological disease with the treatment.
3. Active infections.
4. Other chronic or acute active diseases that would be an exclusion criteria under the criterion of the investigator.
5. Having received attenuated or live vaccines background in the 30 days prior to the inclusion in the study.
6. Immunosuppression of any cause.
7. Trilateral retinoblastoma.
8. Extraocular extension.
9. Antecedent of having received treatment for retinoblastoma with chemotherapy or radiotherapy by any route in the 30 days before the inclusion in the study.
10. Patients who cannot complete the study procedures for psychological or social reasons.
11. Pregnancy. Female potential of childbearing patients should agree with doing a blood or urine pregnancy test and the result shall be negative to enter into the study.

1.Presencia de factores que requieran enucleación inmediata de ojo afectado como pueden ser glaucoma, rubeosis iridis, compromiso de la cámara anterior.
2.Situaciones de comorbilidad: Epilepsia no controlada con el tratamiento anticonvulsivante, enfermedad cardiológica no compensada con el tratamiento.
3.Infecciones activas.
4.Otras enfermedades crónicas o agudas activas que bajo criterio del investigador fuera un criterio de exclusión.
5.Antecedente de haber recibido vacunas atenuadas o vivas en los 30 días previos a la inclusión en el estudio.
6.Inmunosupresión de cualquier causa.
7.Retinoblastoma trilateral.
8.Diseminación extraocular.
9.Antecedente de haber recibido tratamiento para el retinoblastoma con quimioterapia o radioterapia por cualquier vía en los 30 días previos a la inclusión en el estudio.
10.Pacientes que no puedan completar los procedimientos del estudio por razones psicológicas o sociales.
11.Embarazo. Las pacientes de sexo femenino con potencial de procrear deben estar de acuerdo en someterse a una prueba de embarazo en sangre u orina y el resultado debe ser negativo para entrar en el estudio.

E.5 End points

E.5.1

Primary end point(s)

Safety and tolerability: Safety and tolerability of two intravitreal injections of VCN-01.

Seguridad y tolerabilidad: La seguridad y tolerabilidad de dos inyecciones intravítreas de VCN-01

E.5.1.1

Timepoint(s) of evaluation of this end point

Throughout all study

A lo largo de todo el estudio

E.5.2

Secondary end point(s)

*Tumor response rate (TRT) to VCN-01 28 days after administration. For this purpose it shall be defined as:
- Response to treatment: do not meet progressive disease (PD) criteria and notes inactivation, calcification or reduction volume in at least a vitreous seeding or retinal tumor
- Progressive disease (PD): clear progression of the disease, marked by an increase of tumor volume, of retinal detachment, of vitreous seeding or commitment on the anterior chamber
- Stable disease: no changes to the current situation for inclusion in the study

* Presence of the virus in blood samples, aqueous humor, swab of ocular or nasal surface and its difference between viral particles before and after the treatment to evaluate the excretion profile of the VCN-01

* Presence of neutralizing antibodies in blood samples in the patients of the study to evaluate the immune response

* Tasa de respuesta tumoral (ORR) al VCN-01 a los 28 días post-administración. Para tal fin se definirá como;
- Respuesta al tratamiento: no cumple criterios de enfermedad progresiva (EP) y se observa inactivación, calcificación o reducción del volumen de al menos una siembra vítrea o tumor retiniano
- Enfermedad progresiva (EP): Evidente progresión de enfermedad, manifestada por aumento del volumen tumoral, del desprendimiento de retina, de las siembras vítreas o subretinianas. Presencia de glaucoma o compromiso de la cámara anterior
- Enfermedad estable: Sin cambios con respecto a la situación a la inclusión en el estudio

* Presencia del virus en muestras de sangre, humor acuoso, hisopo de superficie ocular y nasal, y su diferencia entre la partículas virales antes y después del tratamiento para evaluar el perfil de excreción del VCN-01

* La presencia de anticuerpos neutralizantes en muestras de sangre en los pacientes del estudio para evaluar la respuesta inmune

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 0, 1, 2, 7, 15, 16, 21, 28, 42 y 180

Día 0, 1, 2, 7, 15, 16, 21, 28, 42 y 180

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

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Establish safety and tolerability in pediatric population by means of dose escalation

Establecer seguridad y tolerabilidad en población pediátrica mediante escalado de dosis

E.7.2

Therapeutic exploratory (Phase II)

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

Yes

E.8.4

The trial involves multiple sites in the 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

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)

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

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

pediatric patients

Pacientes pediátricos

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)

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

2017-08-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-02

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

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