Clinical Trials Register

Summary
EudraCT Number:	2016-001600-40
Sponsor's Protocol Code Number:	D2401GBM2
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:	2016-07-04
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

2016-001600-40

A.3

Full title of the trial

Phase II randomized trial of DNX-2401 oncolytic adenovirus added to standard of care for newly diagnosed glioblastoma

Estudio randomizado Fase II del adenovirus oncolítico DNX-2401 añadido al tratamiento estándar de primera línea en glioblastoma

A.3.1

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

Phase II randomized trial of DNX-2401 oncolytic adenovirus added to standard of care for newly diagnosed glioblastoma

Estudio randomizado Fase II del adenovirus oncolítico DNX-2401 añadido al tratamiento estándar de primera línea en glioblastoma

A.4.1

Sponsor's protocol code number

D2401GBM2

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	Clínica Universidad de Navarra
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	DNAtrix, 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	Clínica Universidad de Navarra
B.5.2	Functional name of contact point	UCEC
B.5.3	Address:
B.5.3.1	Street Address	Avenida de Pío XII, 36
B.5.3.2	Town/ city	Pamplona
B.5.3.3	Post code	31008
B.5.3.4	Country	Spain
B.5.4	Telephone number	349482554002725
B.5.5	Fax number	34948296667
B.5.6	E-mail	ucicec@unav.es

D. IMP Identification
D.IMP: 1
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	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	adenovirus DNX-2401
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intracerebral use Intratumoral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ad-DNX-2401
D.3.9.3	Other descriptive name	Adenovirus DNX-2401
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	50000000000
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	No
D.3.11.3.2	Gene therapy medical product	Yes
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for injection
D.8.4	Route of administration of the placebo	Intratumoral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Multiforme Glioblastom (MGB) is the more common malignant brain tumor, with an incidence around 4 cases per 100.000 hab/year.

Glioblastoma multiforme (GBM) es el más común de los tumores cerebrales malignos, con una incidencia de alrededor de 4 casos por cada 100.000 hab/año.

E.1.1.1

Medical condition in easily understood language

Multiforme Glioblastom (MGB)

Glioblastoma multiforme (GBM)

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10029110
E.1.2	Term	Neoplasms of unspecified nature
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

Overall Survival.

Supervivencia global

E.2.2

Secondary objectives of the trial

1. To evaluate changes in quality of life (QoL) based on results of the European Organization for Research and Treatment of Cancer (EORTC)-QLQ-BN20, and EORTC-QLQ-C30.
2. Volumetric change in tumor
2.1 Volumetric change of the contrast-enhancing tumor volume
2. 2 Volumetric changes of FLAIR abnormal volume
3. Progression Free survival based on iRANO

1. Evaluar cambios en la calidad de vida (Qol) basados en resultados de European Organization for Research and Treatment of Cancer (EORTC)-QLQ-BN20, y EORTC-QLQ-C30.
2. Cambios volumétricos en el tumor
2.1 Cambio volumétrico del contraste-mejora en el volumen del tumor
2. 2 cambios volumétrico en el estilo del tumor
3. Supervivencia libre de progresión basado en iRANO

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients willing and able to give informed consent.
2. Patient must be, in the investigator opinion, able to comply with all the protocol procedures.
3. Age over 18
4. Negative pregnant test in case of fertile women*
5. Patients with suspected diagnosis of Glioblastoma based on MRI,
5. The tumor should be considered candidate to resection surgery by the investigator criteria or being less than 4cm in bigger diameter if the tumor is considered unresectable or the patient is unwilling to have resection surgery.
6. A diagnosis of High Grade Glioma should be confirmed during surgical procedure.
7. Karnofsky Performance Status ≥ 60 before inclusion Or could use "candidate to resection surgery" in number 5 to select cases with good enough situation and eliminate this criterium, preoperative situation in newly diagnosed can be tricky as sometimes a deficit at presentation of the disease can improve.
8. Must have adequate renal, bone marrow and liver function.

1. Los pacientes que deseen y puedan dar su consentimiento informado.
2. El paciente debe ser, en opinión del investigador, capaz de cumplir con todos los procedimientos de protocolo.
3. Edad más de 18
4. Prueba de embarazo negativa en el caso de las mujeres fértiles *
5. Los pacientes con sospecha de diagnóstico de glioblastoma basada en la RM,
5. El tumor debe ser considerado candidato para la cirugía de resección por los criterios del investigador o sea inferior a 4 cm de diámetro más grande si el tumor se considera resecable o el paciente no está dispuesto a someterse a una operación de resección.
6. Un diagnóstico de glioma de alto grado debe confirmarse durante el procedimiento quirúrgico.
7. Karnofsky Performance Status ≥ 60 antes de su inclusión o podría utilizar "candidato a la cirugía de resección" en el número 5 para seleccionar los casos con buena situación lo suficiente y eliminar este criterio, la situación preoperatoria en recién diagnosticada puede ser complicado ya que a veces un déficit en la presentación de la enfermedad puede mejorar.
8. Debe tener renal adecuada, la médula ósea y la función hepática.

E.4

Principal exclusion criteria

1. Severe infections or intercurrent medical conditions including, but not limited to, severe renal, hepatic, heart or bone marrow failure, that, on investigator´s criteria, do not allow the inclusion. Patients must be afebrile at baseline [i.e., < 38 degrees (C )].
2. Previous treatment for the suspected glioblastoma with radiotherapy, chemotherapy, or immunotherapy. Previous partial resection is not an exclusion criterium.
3. Subjects with immunodeficiency, autoimmune conditions or active hepatitis.
4. Any medical or psychological condition that might interfere with the subject's ability to participate or give informed consent or would compromise the patient’s ability to tolerate therapy or any disease that will obscure toxicity or dangerously alter drug metabolism.
5. Current diagnosis of other cancer except in situ cervical cancer, basal or squamous cell carcinoma of the skin. Patients with a history of another cancer remain eligible if they are cancer free for at least three years.
6. Pregnant or breast-feeding females will be excluded, due to the risk for the fetal development of a recombinant virus containing genes related to cellular growth and differentiation.
7. Severe bone marrow hypoplasia.
8. AST and/or ALT > 4 times over upper normal laboratory level.
9. Neutrophils < 1.5 x 109/L
10. Thrombocytes ≤ 100 x 109/L
11. Hemoglobin < 9g/dl
12. If final pathology diagnose of a patient would fail to confirm the suspected diagnosis of glioblastoma or any of its variants (like gliosarcoma, giant-cell glioblastoma, or any other), that patient would follow the procedures of the trial and would be counted for toxicity analysis, but not for survival analysis.
13. Patients with Li-Fraumini Syndrome or with a known germ line deficit in the retinoblastoma gene or its related pathways.
14. Biologic/immunotherapy (e.g., IL-2, IL-12, interferon) within 4 weeks of DNX-2401 administration.
15. Vaccination of any kind within 30 days prior to DNX-2401 administration.
16. Inability to undergo MRI examination for any reason.

1. Las infecciones graves o condiciones médicas intercurrentes incluyendo, pero no limitado a, renal grave, insuficiencia hepática, insuficiencia cardíaca o la médula ósea, que, en los criterios del investigador, no permite la inserción. Los pacientes deben estar afebril al inicio del estudio [es decir, <38 grados (C)].
2. El tratamiento previo para el glioblastoma sospecha con radioterapia, quimioterapia o inmunoterapia. resección parcial anterior no es un criterio de exclusión.
3. Los sujetos con inmunodeficiencia, enfermedades autoinmunes o hepatitis activa.
4. Cualquier condición médica o psicológica que pueda interferir con la capacidad del sujeto para participar o dar su consentimiento informado o comprometería la capacidad del paciente para tolerar la terapia o cualquier enfermedad que va a oscurecer la toxicidad o peligrosamente alterar el metabolismo de fármacos.
5. diagnóstico actual de otro tipo de cáncer, excepto en el cáncer de cuello uterino in situ, basal o carcinoma de células escamosas de la piel. Los pacientes con una historia de otro cáncer siguen siendo elegibles si están libres de cáncer durante al menos tres años.
serán excluidos 6. Las mujeres embarazadas o en periodo de lactancia, debido al riesgo para el desarrollo fetal de un virus recombinante que contiene los genes relacionados con el crecimiento y la diferenciación celular.
7. severa hipoplasia de la médula ósea.
8. AST y / o ALT> 4 veces sobre el nivel normal de laboratorio superior.
9. Los neutrófilos <1,5 x 109 / L
10. Los trombocitos ≤ 100 x 109 / l
11. La hemoglobina <9 g / dl
12. Si definitiva diagnóstico de patología de un paciente sería un fracaso para confirmar el diagnóstico de sospecha de glioblastoma o cualquiera de sus variantes (como Gliosarcoma, glioblastoma de células gigantes, o cualquier otro), que sería paciente siga los procedimientos de la prueba y se contaría para el análisis de la toxicidad, pero no para el análisis de supervivencia.
13. Los pacientes con el síndrome de Li-Fraumini o con un déficit línea germinal conocido en el gen del retinoblastoma o sus vías relacionadas.
14. biológica / inmunoterapia (por ejemplo, IL-2, IL-12, interferón) dentro de las 4 semanas de la administración DNX-2401.
15. La vacunación de cualquier tipo dentro de los 30 días anteriores a la administración DNX-2401.
16. Incapacidad para someterse a un examen de resonancia magnética por cualquier motivo.

E.5 End points

E.5.1

Primary end point(s)

Overall Survival.
The mean comparative groups for survival would be Group A versus B1 and B1 versus B2, so the number would be similar.
Survival will be also compared to survival expected from a published calculator of GBM survival which takes into account age, KPS, EOR and intention to treat with radiotherapy plus temozolomide (Marko et al J Clin. Onc. 2014). This calculator provides the OS expected for each patient considering his prognostic factors (Age, KPS, EOR), so for each case it will be calculated if he has lived longer or shorter than expected.

Supervivencia global
Se realizará comparación de la supervivencia global del grupo A frente al B1 y del B1 frente al B2, el número de sujetos será similar en los tres grupos.
Se comparará la supervivencia también frente a una calculadora de supervivencia de GBM publicada que tiene en consideración los principales factores de riesgo, edad, KPS, grado de resección y la intención de tratar con radioterapia más temozolomida (Marko et al. J Clin Oncol)

E.5.1.1

Timepoint(s) of evaluation of this end point

Overall Survival between groups will be compared through Kaplan-Meier curve, so comparison will use the full follow-up. a comparison will also be made with OS at two year.

La supervivencia entre los grupos se comparará mediante curva de Kaplan-Meier, en todo el intervalo de seguimiento. Se comparará también la supervivencia a 2 años

E.5.2

Secondary end point(s)

1. Cambios en calidad de vida según los resultados de los cuestionarios de la European Organization for Research and Treatment of Cancer (EORTC) QLQ-BN20, y EORTC-QLQ-C30
2. Evolución volumétrica del tumor
2.1 Cambios volumétricos de la porción tumoral que capta contraste
2.2 Cambios volumétricos en el volumen anormal en FLAIR
3. Supervivencia libre de progresión según los criterios iRANO

E.5.2.1

Timepoint(s) of evaluation of this end point

- QOL will be determined in clinical visits at 12, 18 and 24 months, using (EORTC QLQ-BN20 and EORTC-QLQ-C30)
- Tumor volume changes:
Tumor volumes will be manually drawn in each slice in software Brainlab iplannet, however different software could be used later if, at the criteria of the PI, provides similar results.
After the measurements done, The following volumes will be quantified at all the scheduled MRIs on the calendar visit, preoperartively, later afrter surgery at 1-3 days, 4, 14, 22 weeks, 9, 12, 15, 18, 21, 24 and 30 months:
These volumes will be collected and analized as an spider plot.
- Progression free survival. PFS will be determined by iRANO criteria and compared through Kaplan Meier curve in all the follow-up.

- La calidad de vida se determinará en las visitas clínicas a 12, 18 y 24 meses, mediante las escalas EORTC QLQ-BN20 ay EORTC-QLQ-C30.
- Cambios en el volumen tumoral:
Los volúmenes se cuantificaran mediante dibujo manual sobre software Brainlab en cada una de las Resonancias realizadas. Los volúmenes se recogerán en las RM pautadas en las RM previstas en el calendario de seguimiento, en el día 1-3 a 4, 14 y 22 semanas, y a 9, 12, 15, 18, 21, 24 y 30 meses:
Los volúmenes se recogerán y analizarán como "spider plot"
- La supervivencia libre de progresión (SLP) se determinará utilizando los criterios iRANO.

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

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

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

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

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)

Yes

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)

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

2016-09-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-27

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-03-04

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