Clinical Trials Register

Summary
EudraCT Number:	2013-001276-38
Sponsor's Protocol Code Number:	ColoAd1-2001
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-07-31
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

2013-001276-38

A.3

Full title of the trial

A Clinical Study Of ColoAd1 Administered Intraperitoneally: Dose Finding and Proof of Concept in Platinum-Resistant Epithelial Ovarian Cancer

Estudio clínico de ColoAd1 (INN: EnAd) administrado por vía intraperitoneal: determinación de dosis y prueba de concepto en el cáncer de ovario epitelial resistente a platino.

A.3.1

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

Phase I/II Study of ColoAd1 Intraperitoneally in Ovarian Cancer Patients

Fase I/II estudio clínico de Colo Ad1 intraperitoneal en pacientes con cancer de ovario

A.4.1

Sponsor's protocol code number

ColoAd1-2001

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	PsiOxus Therapeutics Ltd
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	PsiOxus Therapeutics Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Chiltern International Ltd.
B.5.2	Functional name of contact point	Project Manager ColoAd1-2001
B.5.3	Address:
B.5.3.1	Street Address	Logan Building, Roslin Biocentre
B.5.3.2	Town/ city	Roslin, Midlothian
B.5.3.3	Post code	EH25 9TT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44131200 6320
B.5.5	Fax number	+44131200 6322
B.5.6	E-mail	regulatory.service@chiltern.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/15/1434
D.3 Description of the IMP
D.3.1	Product name	Enadenotucirev
D.3.2	Product code	EnAd
D.3.4	Pharmaceutical form	Concentrate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraperitoneal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	enadenotucirev
D.3.9.1	CAS number	1402042-02-7
D.3.9.2	Current sponsor code	EnAd
D.3.9.3	Other descriptive name	ColoAd1
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2000000000000
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

Epithelial ovarian cancer

Cáncer ovárico epitel

E.1.1.1

Medical condition in easily understood language

Ovarian Cancer

Cáncer ovárico

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10066697
E.1.2	Term	Ovarian cancer recurrent
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

Phase Ia:
- To determine the MTD and/or the dose of EnAd recommended for further studies when administered weekly by IP injection in patients with ovarian cancer
Phase Ib:
- To determine the MTD and/or the dose of EnAd recommended for further studies when administered by IP injection in combination with weekly IV paclitaxel in patients with ovarian cancer
Phase II and Phase Ib patients treated at the dose for Phase II:
- To evaluate the PFS of EnAd using RECIST v1.1, when administered by IP injection in combination with weekly IV paclitaxel in patients with recurrent platinum-resistant ovarian cancer

Fase Ia:
- Determinar la dosis máxima tolerada (DMT) y/o la dosis de EnAd recomendada para estudios posteriores cuando se administra semanalmente por inyección intraperitoneal (IP) en pacientes con cáncer de ovario
Fase Ib:
- Determinar la DMT y/o la dosis de EnAd recomendada para estudios posteriores cuando se administra por inyección IP combinada con paclitaxel intravenoso (IV) semanalmente en pacientes con cáncer de ovario
Pacientes de la Fase II y Fase Ib tratados con la dosis recomendada para la Fase II:
- Evaluar la supervivencia libre de progresión (PFS) de EnAd con RECIST v1.1, administrado por inyección IP junto con paclitaxel IV semanalmente en pacientes con cáncer de ovarios resistente al platino recurrente

E.2.2

Secondary objectives of the trial

Phase I only:
- Viral kinetics, distribution, clearance and shedding of EnAd
- Anti-tumour activity of EnAd in patients with ovarian cancer, as measured by response rate, duration of response, clinical benefit rate and PFS using RECIST v1.1, irRC criteria and GCIG CA-125 criteria
Phases I and II:
- Safety and tolerability of EnAd in patients with ovarian cancer
- Systemic and IP immune response to EnAd
Phase II and Phase Ib patients treated at the dose recommended for Phase II:
- PFS of EnAd in patients with recurrent, platinum-resistant ovarian cancer using irRC and GCIG CA-125 criteria
- Anti-tumour activity of EnAd in patients with recurrent, platinum-resistant ovarian cancer, as measured by response rate, duration of response, clinical benefit rate and PFS rate at 4 and 6 months using: RECIST v1.1; irRC criteria; GCIG CA-125 criteria
- IP cytological changes including the distribution of inflammatory cell infiltrates and EnAd viral particles in response to EnAd

Sólo Fase I:
-Cinética viral, distribución, depuración y excreción de EnAd administración IP
-Examinar acti. antitumoral de EnAd adm. IP, con paclitaxel IV pacientes con cáncer de ovarios, y PFS con RECIST v1.1, de respuesta sistema inmunológico (irRC) y criterios antígeno de cáncer 125 (CA-125) Intergrupo (GCIG)
Fases I y II:
-Seguridad y tolerabilidad de EnAd, inyección IP pacientes cáncer ovario
-Sistémica y sistema inmunológico IP a EnAd dministración inyección IP
Pacientes F II y F con dosis recomendada para Fase II:-Examinar PFS de EnAd administrado IP con paclitaxel IV pacientes cáncer ovarios resistente al platino con irRC y CA-125 GCIG
-Antitumoral de IP con paclitaxel IV pacientes cáncer de ovarios resistente al platino, beneficios clínicos y PFS a 4 y 6 meses, con:o RECIST v1.1o Criterios irRC o Criterios CA-125 GCIG
-Cambios citológicos IP, infiltraciones de células inflamatorias y partículas virales de EnAd respuesta a EnAd, después inyección IP con paclitaxel

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Able and willing to provide written informed consent and to comply with the study protocol
2. Age ? 18 years
3. Histologically confirmed non-resectable epithelial ovarian, fallopian tube or primary peritoneal cancer
4. Phase Ia and Phase Ib first 3 patients:
- Confirmed relapsed within the platinum-resistant time frame.
- Platinum-resistance is defined as progression within 6 months of receiving prior platinum-containing chemotherapy, with progression identified either by CT scanning (RECIST v1.1) or symptomatic CA125 progression (GCIG CA-125 criteria)
- The treatment immediately prior to study entry need not be platinum-based
OR
- Absence of other available treatment option
Phase Ib (after first 3 patients) and Phase II
- Confirmed relapsed within the platinum-resistant time frame
- Platinum-resistance is defined as progression within 6 months of receiving prior platinum-containing chemotherapy, with progression identified either by CT scanning (RECIST v1.1) or symptomatic CA125 progression (GCIG CA-125 criteria)
- The treatment immediately prior to study entry need not be platinum-based
Phase Ia and Phase Ib first 3 patients:
- Evaluable disease (by RECIST v1.1).
Phase Ib (after first 3 patients) and Phase II:
- Measurable disease (by RECIST v1.1)
5. Able to undergo IP injection, including all administration procedures e.g. placement of IP catheter, iatrogenic ascites and ascites drainage and comply with study procedures in the Investigator?s opinion
6. Recovered to at least grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancy at time of first administration of EnAd
7. ECOG Performance Status Score of 0 - 1
8. Adequate renal function
- Creatinine ? 1.8 mg/dl (159 µmol/l) or calculated creatinine clearance using the Cockcroft-Gault formula ? 45 ml/min, or measured creatinine clearance ? 45 ml/min
- Absence of clinically significant haematuria on urinalysis: dipstick ?2+
- Absence of clinically significant proteinuria on urinalysis: dipstick ? 2+
9. Adequate hepatic function
- Serum bilirubin <1.5 x upper limit of normal (ULN)
- Aspartate transaminase (AST) and alanine transaminase (ALT) ? 3 x ULN
10. Adequate bone marrow function:
- Absolute neutrophil count (ANC) ? 1.5 x 10e9/l
- Platelets ? 100 x 10e9/l
- Haemoglobin ? 90 g/l
11. Adequate coagulation tests: INR ? 1.5 x ULN;
12. Access to archival tumour samples
13. For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment
14. For women who are not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to use two adequate methods of contraception, including at least one method with a failure rate of < 1% per year (e.g. hormonal implants, combined oral contraceptives, vasectomised partner), during the treatment period and for at least 3 months after the last dose of study drug
15. For selected patients in the Phase Ia and Phase II part of the study participating in the exploratory assessment of tumour samples:
- Ovarian disease amenable to percutaneous image-guided biopsy.

1.Debe poder y desear facilitar un consentimiento informado y cumplir con el protocolo del estudio
2.? 18 años de edad
3.Confirmacion histológica de cancer epitelial de ovario no operable, de trompas de falopio o primario de peritoneo
4.Fase Ia y primeros 3 pacientes de la Fase Ib:
Recaída confirmada dentro del periodo de resistencia al platino.
- La resistencia al platino se define como una progresión dentro de los 6 meses posteriores a haber recibido una quimioterapia anterior que contuviera platino, con progresión identificada por tomografía computarizada (TC), escáner (RECIST v1.1) o progresión CA125 sintomática (criterios GCIG CA-125)
oEl tratamiento inmediatamente anterior a la entrada en el estudio no debe estar basado en platino
O
-Ausencia de otra opción de tratamiento disponible
Fase Ib (tras los primeros 3 pacientes) y Fase II
- Recaída confirmada dentro del periodo de resistencia al platino
- La resistencia al platino se define como una progresión dentro de los 6 meses posteriores a haber recibido una quimioterapia anterior que contuviera platino, con progresión identificada por TC, escáner (RECIST v1.1) o progresión CA125 sintomática (criterios GCIG CA-125)
- El tratamiento inmediatamente anterior a la entrada en el estudio no debe estar basado en platino
Fase Ia y primeros 3 pacientes de la Fase Ib:
- Enfermedad evaluable (por RECIST v1.1).
Fase Ib (tras los primeros 3 pacientes) y Fase II:
- Enfermedad medible (por RECIST v1.1).
5. Debe poder recibir una inyección IP, incluidos todos los procedimientos de administración, por ej. colocación de catéter IP, ascitis iatrogénicas y drenaje de ascitis, y cumplir con los procedimientos del estudio según la opinión del Investigador
6. Debe haberse recuperado al menos en grado 1 de los efectos (excluyendo la alopecia) de cualquier terapia anterior para su enfermedaden el momento de la primera administración de EnAd
7. Una puntuación de estado de rendimiento de ECOG de 0 - 1
8. Función renal adecuada
- Creatinina ? 1,8 mg/dl (159 ?mol/l) o aclaramiento de la creatinina calculada con la fórmula Cockcroft-Gault ? 45 ml/min., o aclaramiento de la creatinina medida ? 45 ml/min.
- Ausencia de hematuria clínicamente significativa en análisis de orina: tira reactiva ? 2+
- Ausencia de proteinuria clínicamente significativa en análisis de orina: tira reactiva ? 2+
9. Función hepática adecuada
- Bilirrubina sérica <1,5 x límite superior de la normalidad (ULN)
- Aspartato transaminasa (AST) y alanina transaminasa (ALT) ? 3 x ULN
10. unción de médula espinal adecuada:
- Recuento absoluto de neutrófilos (ANC) ? 1,5 x 109/l
- Plaquetas ? 100 x 109/l
- Hemoglobina ? 90 g/l
11. Pruebas de coagulación adecuadas: INR ? 1.5 x ULN
12.Acceso a muestras tumorales archivadas
13. En mujeres con potencial de embarazo, se debe presentar un test de embarazo negativo antes del reclutamiento
14. Para mujeres no postmenopáusicas (12 meses de amenorrea) o quirúrgicamente estériles (ausencia de ovarios y/o útero): acuerdo para usar dos métodos anticonceptivos adecuados, incluyendo, al menos, un método con una tasa de error de < 1% al año (por ej. implantes hormonales, anticonceptivos orales combinados, pareja vasectomizada), durante el periodo de tratamiento y al menos 3 meses después de la última dosis del fármaco del estudio
15. Para las pacientes seleccionadas en la Fase Ia y la Fase II del estudio que participan en la evaluación de la exploración de muestras tumorales:
-Enfermedad ovárica que responde a biopsia por imagen percutánea.

E.4

Principal exclusion criteria

1. Tumours of malignant mixed mesodermal (MMMT) or mucinous subtypes, or non-epithelial ovarian cancers (e.g. Brenner tumours, Sex-cord tumours)
2. For Phases Ib and II only: Prior treatment with weekly paclitaxel monotherapy within 6 months prior to first dose of EnAd. Prior treatments with other schedules of paclitaxel or combination chemotherapy including weekly paclitaxel are accepted
3. Symptomatic sub-acute bowel obstruction, characterised by e.g. regular bloating, nausea, vomiting, constipation or diarrhoea
4. Pregnant or lactating (nursing) women
5. Known and/or a history or evidence of significant immunodeficiency due to underlying illness (e.g. human immunodeficiency virus [HIV]/acquired immunodeficiency syndrome [AIDS]) and/or medication (e.g. systemic corticosteroids at doses higher than dexamethasone 20 mg [or other corticosteroid equivalent to dexamethasone dose] for <= 14 days or prolonged administration [>14 days] of dexamethasone at doses higher than 10 mg but <=20 mg [or other corticosteroid equivalent to dexamethasone dose] or other immunosuppressive medications including cyclosporine, azathioprine, interferons, within the past 14 days)
6. Splenectomy
7. Prior allogeneic or autologous bone marrow or organ transplantation
8. Active infections requiring antibiotics, physician monitoring, or recurrent fevers >38.0degC associated with a clinical diagnosis of active infection
9. Active viral disease, positive serology for HIV, hepatitis B or hepatitis C
10. Use of the following anti-viral agents:
- Ribavirin, adefovir, lamivudine or cidofovir within 7 days prior to day 1
- or pegylated interferon (PEG-IFN) (within 14 days prior to day 1)
11. Administration of an investigational drug within 28 days
12. Concurrent administration of any cancer therapy other than planned study treatment
13. Major surgery within 2 weeks prior to first dose of EnAd
14. Phase Ib (after first 3 patients) and Phase II only: another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ or in situ stage 1 synchronous endometrial cancer)
15. Symptomatic central nervous system (CNS) metastasis
16. Inflammatory diseases of the bowel
17. Concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease
18. Any condition or illness that, in the opinion of the Investigator or the medical monitor, would compromise patient safety or interfere with the evaluation of the safety of the drug
19. Known allergy to treatment medication or its excipients
20. Any other medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent.

1. Tumores mesodérmicos malignos mixtos (MMMT) o de subtipos mucinoso, o cánceres de ovario no epiteliales (por ej. tumores de Brenner, tumores de los cordones sexuales)
2. Solo para las Fases Ib y II Tratamiento anterior con paclitaxel semanal monoterapia en los 6 meses anteriores a la primera dosis de EnAd. Se aceptan tratamientos anteriores con otros esquemas de paclitaxel o quimioterapia combinada, incluido paclitaxel semanal
3. Obstrucción intestinal subaguda sintomática, caracterizada por, por ej., hinchazón habitual, náuseas, vómitos, estreñimiento o diarrea
4. Mujeres embarazadas o en periodo de lactancia
5. Historial conocido o evidencias de inmunodeficiencia significativa debido a enfermedad subyacente (por ej. virus de inmunodeficiencia humana [VIH]/síndrome de inmunodeficiencia adquirida [SIDA]) y/o medicación (por ej. corticosteroides sistémicos a dosis más altas que la dexametasona de 20 mg (u otro corticosteroide equivalente a la dosis de dexametasona) durante 14 días o con administración prolongada (> 14 días) de dexametasona dosis superiores a los 10 mg, pero ? 20 mg (u otro corticosteroide equivalente a la dosis de dexametasona), u otras medicaciones inmunosupresoras, incluida la ciclosporina, azatioprina, interferonas, en los últimos 14 días)
6. Esplenectomía
7. Trasplante anterior de medula osea autologo o alogenico o trasplante de órganos
8. Infecciones activas que requieren antibióticos, control médico o fiebres recurrentes >38,0 ºC asociadas con un diagnóstico clínico de infección activa
9.Enfermedad viral activa, serología positiva para VIH, hepatitis B o hepatitis C
10. Uso de los siguientes agentes antivíricos:
- Ribavirina, adefovir, lamivudina o cidofovir en los 7 días anteriores al día 1
- o interferón pegilado (PEG-IFN) (en los 14 días anteriores al día 1)
11. Administración de un fármaco de investigación en 28 días
12. Administración concurrente de cualquier tratamiento de cáncer que no sea el planificado para el tratamiento del estudio
13. Cirugía mayor en las 2 semanas anteriores a la primera dosis de EnAd
14. Solo Fase Ib (tras los primeros 3 pacientes) y Fase II: Otra malignidad primaria en los 3 años anteriores (excepto cáncer de piel sin melanoma o cáncer cervical in situ o cáncer endometrial síncrono in situ en fase 1)
15. Metástasis sintomática del sistema nervioso central (SNC)
16. Enfermedades inflamatorias del intestino
17. Paro cardíaco congestivo concurrente o historial anterior de enfermedad cardíaca de clase III/IV por la New York Heart Association (NYHA)
18. Toda condición o enfermedad que, según la opinión del Investigador o del control médico, ponga en riesgo la seguridad de la paciente o interfiera con la evaluación de la seguridad del fármaco
19. Alergia conocida a la medicación del tratamiento o a sus excipientes
20. Cualquier otra condición médica o psicológica que impida la participación en el estudio o ponga en riesgo la capacidad de dar un consentimiento informado.

E.5 End points

E.5.1

Primary end point(s)

Phase Ia
- The maximally-tolerated dose (MTD) and/or the dose of EnAd recommended for further studies of EnAd when administered as monotherapy by IP injection in patients with ovarian cancer
Phase Ib
The dose of EnAd recommended for further studies of EnAd, when administered by weekly IP injection, in combination with weekly IV paclitaxel in patients with ovarian cancer.
Phase II and Phase Ib patients treated at the dose for Phase II:
- The PFS as measured by RECIST v1.1 criteria, of EnAd administered by IP injection, in combination with weekly IV paclitaxel in patients with ovarian cancer

Fase Ia
- La dosis máxima tolerada MTD y/o la dosis de EnAd recomendada para estudios de EnAd cuando es administrada como monoterapia por inyección vía IP en pacientes con cáncer ovárico.
Fase Ib
- La dosis de EnAd recomendada para estudios futuros de EnAd, cuando se administra por vía IP de inyección semanal, en combinación con paclitaxel semanal vía IV en pacientes con cáncer ovárico.
Fase II y Fase Ib para pacientes tratados con la dosis de Fase II:
-El PFS se ha medido por el criterio de RECIST v1.1 el EnAd administrado vía IP en inyección, en combinación con paclitaxel en pacientes con cáncer de ovario resistente al platino recurrente.

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase 1a - 28 (±3) days post last EnAd administration
Phase 1b - 28 (±3) days post last EnAd administration
Phase II - 28 (±3) days post last EnAd administration

Fase 1a - 28 (±3) días posteriores a la última administración de EnAd
Fase 1b - 28 (±3) días posteriores a la última administración de EnAd
Fase II - 28 (±3) días posteriores a la última administración de EnAd

E.5.2

Secondary end point(s)

Safety and tolerability:
- Incidence, nature, severity and seriousness of AEs as characterised using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03)
- Incidence, nature, and severity of changes in laboratory values, vital signs, and physical exam
Efficacy:
- Response rate, duration of response, clinical benefit rate measured by RECIST v1.1, irRC and CICG criteria, progression free survival measured by RECIST v1.1 irRC, and GCIG CA-125 criteria, PFS rate at 4 and 6 months measured by RECIST v1.1 criteria and irRC
Kinetics and immunity:
- Describe the kinetics and clearance of EnAd following administration by IP injection:
- Blood kinetics of EnAd according to qPCR measurement of serial blood samples for EnAd genome copies and where relevant by plaque assay to determine the presence of viable replicating virus
- Viral shedding of EnAd according to qPCR measurement of buccal and rectal swabs for EnAd genome copies
- Persistence of EnAd in the peritoneal cavity according to qPCR measurement of serial peritoneal samples for EnAd genome copies and where relevant by plaque assay to determine the presence of viable replicating virus
- Describe the adaptive and innate immune response to EnAd following administration by IP injection:
- EnAd specific antibody response in blood by enzyme-linked immunosorbent (ELISA) and neutralising assays
- EnAd specific antibody response in peritoneal fluid by ELISA and neutralising assays
- Describe the cytokine response in peripheral blood to EnAd following administration by IP injection by multiplex assay
- Describe the pathological changes including cancer cell burden, inflammatory infiltrates and viral particles in biopsies from 2 patients in Phase Ia (treated at the dose to be recommended for Phase II studies as a monotherapy) and 6 patients treated in Phase II. Specific immunohistochemistry (IHC) staining of the tissues will be for, but not limited to:
- CD11b (Dendritic cells / macrophages)
- CD8+ (Cytotoxic T Lymphocytes)
- NKp46 (Natural killer cells)
- CD25 (Regulatory T cells)
- EnAd hexon (EnAd viral particles)
- Describe the IP cytological changes including the ovarian cancer cell burden, inflammatory cell infiltrates and EnAd viral particles in response to EnAd following administration by IP injection in combination with paclitaxel in patients treated in Phase II and in patients treated at the dose to be recommended for studies with EnAd administered as monotherapy IP
- Evaluate the criteria used to assess the onset, extent and duration of tumour responses and recommend a set of criteria for the assessment of efficacy of EnAd in further clinical trial protocols of EnAd in ovarian cancer

Seguridad y tolerabilidad:
- Incidencia, naturaleza, gravedad y seriedad de los AA caracterizados utilizando el Criterio y terminología común de acontecimientos adversos del Instituto nacional de cáncer (NCI CTCAE v4.03)
- Incidencia, naturaleza y severidad de cambios en los valores de laboratorio, signos vitales y examen físico
Eficacia:
- Tasa de respuesta, duración de la respuesta, tasa beneficios clínicos medidos por los criterios de RECIST v1.1, irRC y CICG progresión de sobrevivencia libre medida bajo el criterio de RECIST v1.1, irRC, y GCIG CA-125, Tasa PFS a 4 y 6 meses medido por el criterio de RECIST v1.1 y RECIST v1.1.
Cinética e inmunidad:
- Describe la cinética y la eliminación del EnAd seguida de la administración de la inyección vía IP
- Cinética en la sangre de EnAd conforme a la medida de qPCR de una serie de pruebas de sangre para determinar copia del genoma EnAd y donde sea relevante por valoración de placas para determinar la presencia de réplicas de virus viables
- Diseminación viral de EnAd conforme a las mediciones de qPCR por medio de hisopos bucales y rectales para copias del genoma EnAd
- Persistencia en la cavidad peritoneal de EnAd conforme a la medida de qPCR de una serie de muestras peritoneas para determinar copia del genoma EnAd y donde sea relevante por valoración de placas para determinar la presencia de réplicas de virus viables
- Describir la respuesta adaptativa y e innata al EnAd tras la administración de vía
Inyección IP:
- La respuesta anticuerpo especifica de EnAd en sangre por Ensayo de inmunoabsorción ligado a enzimas (ELISA) y ensayos neutralizantes
- La respuesta anticuerpo especifica de EnAd en fluido peritoneo por (ELISA) y ensayos neutralizantes
- Describir la respuesta cinética en sangre periferica al EnAd trasla administración vía inyección IP por ensayo multiplex

E.5.2.1

Timepoint(s) of evaluation of this end point

Safety and tolerability:
Performed at each visit up to 28 (±3) days post last EnAd administration
Efficacy:
Response rate, duration of response, clinical benefit rate - 28 (±3) days post last EnAd administration; PFS at 4 and 6 months; CA-125 will be performed at baseline, days 29 and 50 and then at 2 monthly intervals
Kinetics and Immunity:
ColoAd1 shedding - Days 1, 2, 8, 15, 29, 36, 50 and 28 (±3) days post last EnAd administration
Blood kinetics - Days 1, 8, 15 and 50
Cytokine profile - Days 1, 8 and 15
ColoAd1 blood antibody status - Days 1, 29 and 50
Peritoneal fluid kinetics - Days 1, 8, 15, 29, and 28 (±3) days post last EnAd administration
Antibody status in peritoneal fluid - Days 1, 29, 50 and 28 (±3) days post last EnAd administration

Seguridad y tolerabilidad: Se realiza en cada visita hasta la 28 (±3) tras la última administración EnAd
Eficacia: Ratio de respuesta, duración de respuesta, ratio de beneficio clínico - 28 (±3) tras la última administración EnAd; PFS en mes4 y 6; CA-125 se realizará en la línea de base, días29 y 50 y después en intervalos de 2meses.
Cinéticos e Inmunidad: Desprendimiento de ColoAd1- Días1, 2, 8, 15, 29, 36, 50 y 28(±3) tras última administración EnAd/Cínetica de sangre - Días 1, 8, 15 y 50/ Perfil cinético - Días 1, 8 y 15/ Estado del anticuerpo en sangre ColoAd1 - Días 1, 29 y 50/ Cinéticas de fluido peritoneal - Días 1, 8, 15, 29, y 28 (±3) tras la última administración EnAd/ Estado del anticuerpo en el fluido peritoneal - Días 1, 29, 50 y 28 (±3) tras la última administración EnAd

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

Yes

E.6.7

Pharmacodynamic

Yes

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

Dose escalation/dose finding

Escalado de dosis/busqueda de dosis

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

Dose escalation

Escalado de dosis

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Última visita último paciente

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)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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)

Patients will receive standard of care as determined by the treating physician.

Los pacientes recibirán los cuidados estándar determinados por el médico que le atiende.

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

2015-10-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-08

P. End of Trial
P.	End of Trial Status	Completed

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Orphan Designation Number:
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