Clinical Trials Register

Summary
EudraCT Number:	2015-002782-32
Sponsor's Protocol Code Number:	MK-3475-181
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:	2015-11-25
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

2015-002782-32

A.3

Full title of the trial

A Phase III Randomized Open-label Study of Single Agent Pembrolizumab vs Physicians' Choice of Single Agent Docetaxel, Paclitaxel, or Irinotecan in Subjects with Advanced/Metastatic Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus that have Progressed after First-Line Standard Therapy (KEYNOTE-181)

Estudio de fase III, abierto y aleatorizado de pembrolizumab en monoterapia frente a la elección del médico entre docetaxel, paclitaxel o irinotecán en monoterapia en sujetos con adenocarcinoma y carcinoma epidermoide del esófago avanzados o metastásicos que han presentado progresión después de recibir un tratamiento de primera línea convencional (KEYNOTE-181)

A.3.1

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

A Phase III study of Pembrolizumab compared to Physicians? choice of Docetaxel, Paclitaxel, or Irinotecan in Previously Treated Subjects with Advanced/Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus

Estudio de fase III de pembrolizumab frente a la elección del médico entre docetaxel, paclitaxel o irinotecán en sujetos con adenocarcinoma y carcinoma epidermoide del esófago avanzados o metastásicos

A.3.2

Name or abbreviated title of the trial where available

Study of Pembrolizumab vs Docetaxel, Paclitaxel or Irinotecan in Subjects with Esophagus Carcinoma

Estudio pembrolizumab vs docetaxel, paclitaxel o irinotecán en sujetos con carcinoma del esófago

A.4.1

Sponsor's protocol code number

MK-3475-181

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02564263

A.5.4

Other Identifiers

Name:

KEYNOTE

Number:

181

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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
B.1.3.4	Country	United States
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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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	Merck Sharp & Dohme de España S.A.
B.5.2	Functional name of contact point	Investigación Clínica
B.5.3	Address:
B.5.3.1	Street Address	C/ Josefa Valcárcel, 38
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28027
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34913210600
B.5.5	Fax number	+34913210590
B.5.6	E-mail	ensayos_clinicos@merck.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	Yes
D.2.1.1.1	Trade name	Keytruda
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp and Dohme, Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Pembrolizumab
D.3.2	Product code	MK-3475
D.3.4	Pharmaceutical form	Solution for infusion
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	Pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.3	Other descriptive name	Anti-PD-1 monoclonal antibody
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	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	Yes
D.2.1.1.1	Trade name	Docetaxel-Actavis 20 mg/ml concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group PTC ehf
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Docetaxel
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
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	Docetaxel
D.3.9.1	CAS number	114977-28-5
D.3.9.3	Other descriptive name	docetaxel
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	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.IMP: 3
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	Yes
D.2.1.1.1	Trade name	Paclitaxel-Actavis 6mg/ml concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group PTC ehf
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Paclitaxel
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
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	Paclitaxel
D.3.9.1	CAS number	33069-62-4
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	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.IMP: 4
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	Yes
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	Irinotecan
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
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	Irinotecan
D.3.9.1	CAS number	97682-44-5
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	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

Esophageal Carcinoma

Carcinoma del esófago

E.1.1.1

Medical condition in easily understood language

Esophageal Carcinoma

Carcinoma del esófago

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	18.1
E.1.2	Level	PT
E.1.2	Classification code	10030155
E.1.2	Term	Oesophageal carcinoma
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 compare Progression Free Survival (PFS) and Overall Survival (OS) per RECIST 1.1 assessed by blinded central imaging vendor in all subjects and in Gene Expression Profile (GEP) high subjects.

Comparar la SSP y la SG según los criterios RECIST 1.1 evaluados por un laboratorio central de diagnóstico por imagen en todos los sujetos con PEG alto.

E.2.2

Secondary objectives of the trial

To evaluate safety and tolerability of study drugs in all subjects, as well as PFS, by investigator assessment, and Overall Response Rate (ORR), by blinded central vendor review, per RECIST 1.1 among GEP high subjects and all subjects, when treated with pembrolizumab compared to investigators choice of paclitaxel, docetaxel, or irinotecan.

Evaluar el perfil de seguridad y tolerabilidad de los medicamentos del estudio en todos los sujetos, así como la SSP según la evaluación del Investigador y la TRG según los criterios RECIST 1.1 evaluada mediante una revisión realizada por un laboratorio central en sujetos con PEG alto en comparación con todos los sujetos cuando reciben pembrolizumab en comparación con paclitaxel, docetaxel o irinotecán a elección del investigador.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.

Merck llevará a cabo investigaciones biomédicas futuras con las muestras obtenidas específicamente con estos fines durante este ensayo clínico. Estas investigaciones tendrán por objeto el análisis de biomarcadores para abordar aspectos nuevos que no se describen en otras partes del protocolo (como parte del ensayo principal) y solo se llevarán a cabo en muestras de los sujetos que hayan otorgado el consentimiento correspondiente. El objetivo de la obtención de muestras para investigaciones biomédicas futuras consiste en estudiar e
identificar biomarcadores que proporcionen información a los científicos
sobre las enfermedades y sus tratamientos. El objetivo último es utilizar tal información para desarrollar fármacos más seguros y eficaces y/o para garantizar que los pacientes reciban la dosis correcta del fármaco adecuado en el momento preciso.

E.3

Principal inclusion criteria

Subjects must:
- Be > or = to 18 years of age on the day of signing the informed consent.
- Have histologically or cytologically confirmed diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ.
- Have metastatic disease or locally advanced, unresectable disease.
- Have a life expectancy greater than 3 months.
- Have measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment.
- Have an ECOG performance status of 0 or 1.
- Have experienced documented objective radiographic or clinical disease progression during or after first-line locally or globally recommended therapy.
- Provide a tissue sample for intratumoral immune-related GEP analysis.
- Demonstrate adequate organ function.
- Negative pregnancy test for females of child bearing potential prior to starting study and male and female subjects of childbearing potential must be willing to use an adequate method of contraception.

-Tener 18 o más años de edad el día de la firma del consentimiento informado
-Tener un diagnóstico confirmado histológica o citológicamente de adenocarcinoma o carcinoma epidermoide del esófago o adenocarcinoma de tipo I de Siewert de la UGE
-Presentar enfermedad metastásica o localmente avanzada irresecable.
-Tener una esperanza de vida mayor de tres meses.
-Presentar enfermedad mensurable conforme a los criterios RECIST 1.1, a juzgar por la evaluación del investigador del centro y la revisión radiológica local
-Presentar un estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1.
-Haber presentado progresión radiológica o clínica objetiva documentada de la enfermedad durante o después del tratamiento de primera línea recomendado a nivel local o global.
-Proporcionar una muestra de tejido para el análisis del PEG relacionado con el sistema inmunitario.
-Presentar una función orgánica adecuada
-Prueba de embarazo negativa en las mujeres y los pacientes en edad fértil deben estar dispuestas a utilizar un método anticonceptivo adecuado

E.4

Principal exclusion criteria

The subject will be excluded from participating in the trial if the subject:
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of treatment.
- Has an active autoimmune disease that has required systemic treatment in past 2 years.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
- Has had prior anti-cancer monoclonal antibody (mAb), chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., < or = to Grade 1 or at baseline) from adverse events due to a previously administered agent.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or if the subject has previously participated in Merck pembrolizumab (MK-3475) clinical trials.
- Has a diagnosed additional malignancy within 5 years prior to treatment allocation with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers.
- Has received a live vaccine within 30 days of planned start of study therapy.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subjects participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- Has known history of, or any evidence of interstitial lung disease or active, non-infectious pneumonitis.
- Has an active infection requiring systemic therapy.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
- Known allergy or hypersensitivity to paclitaxel, docetaxel, or irinotecan, or any components used in the paclitaxel/docetaxel/irinotecan preparation or other contraindication for taxane therapy.
- Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject.

Se excluirá de participar en el ensayo a todos los sujetos que cumplan
alguno de los criterios siguientes:
-Está participando actualmente y está recibiendo tratamiento del estudio o ha participado en un estudio de un medicamento experimental y ha recibido tratamiento del estudio o ha utilizado un dispositivo experimental en las 4 semanas anteriores a la administración de la primera dosis del tratamiento.
-Enfermedad autoinmunitaria activa que haya necesitado tratamiento
sistémico en los dos años precedentes
-Tener un diagnóstico de inmunodeficiencia o haber recibido corticoterapia sistémica o algún tipo de tratamiento inmunosupresor en los 7 días previos a la administración de la primera dosis del tratamiento del ensayo.
-Presentar metástasis activas en el sistema nervioso central (SNC) y/o
meningitis carcinomatosa.
-Haber recibido previamente un tratamiento con un anticuerpo monoclonal anti-tumoral (AcM), quimioterapia, terapia dirigida con moléculas pequeñas o radioterapia, en las 2 semanas anteriores al día 1 del estudio o no haberse recuperado (es decir, a un grado ? 1 o al valor basal) de los acontecimientos adversos provocados por un fármaco administrado anteriormente.
-Haber recibido inmunoterapia previa con un fármaco anti-PD-1, anti-PDL1
o anti-PD-L2 o haber participado a anteriormente en ensayos clínicos de pembrolizumab (MK-3475) de Merck.
-Presentar diagnóstico de una neoplasia maligna adicional en los 5 años
previos a la asignación del tratamiento, con la excepción del carcinoma
de células basales de la piel tratado de forma curativa, carcinoma epidermoide de la piel y/o cánceres cervicales y/o de mama resecados in situ de forma curativa.
-Haber recibido una vacuna de microorganismos vivos en los 30 días previos al comienzo previsto del tratamiento del ensayo.
-Tener antecedentes o signos actuales de cualquier trastorno, tratamiento o anomalía analítica que, en opinión del investigador, pueda confundir los resultados del ensayo, afectar a la participación del sujeto durante todo el ensayo o hacer que la participación no sea lo más conveniente para ese sujeto.
-Tener antecedentes de infección por el virus de la inmunodeficiencia
humana (VIH) (anticuerpos contra el VIH 1/2).
-Tener hepatitis B activa conocida (por ejemplo, reactividad del antígeno
de superficie de la hepatitis B) o hepatitis C (por ejemplo, ARN del VHC detectado [cualitativo].
-Presentar antecedentes conocidos o signos de neumopatía intersticial o
de neumonitis no infecciosa activa.
-Presentar una infección activa con necesidad de tratamiento sistémico.
-Presentar un trastorno psiquiátrico o por abuso de sustancias que
podría dificultar el cumplimiento de los requisitos del ensayo.
-Estar embarazada o en período de lactancia o tener intención de concebir o engendrar un hijo durante el período previsto del ensayo, desde la visita de selección hasta 120 días después de la última dosis de pembrolizumab
-Presentar alergia o hipersensibilidad o contraindicación conocida a
paclitaxel, docetaxel, o irinotecán o a cualquiera de los componentes
empleados en su preparación o cualquier otra contraindicación del
tratamiento con taxanos.
-Formar parte o tener un familiar directo (por ejemplo, cónyuge,
padre/madre o tutor legal, hermano o hijo) que forme parte del personal
del centro del estudio o del promotor implicado directamente en este
ensayo, salvo dictamen prospectivo del CEIC (presidente o persona
designada) que autorice la excepción a este criterio para un paciente
concreto.

E.5 End points

E.5.1

Primary end point(s)

Progression Free Survival (PFS) and Overall survival (OS) per RECIST 1.1 by blinded central imaging vendor.

Supervivencia sin progresión (SSP) y supervivencia global (SG)
conforme a los criterios RECIST 1.1 y según lo determinado por el
laboratorio central de imagen

E.5.1.1

Timepoint(s) of evaluation of this end point

Interim analysis is planned after enrollment completed (24 months) and approximately 240 PFS events in GEP high subjects or when the target number of OS events is reached. Results will be reviewed by an external data monitoring committee. Final analysis will be when ? 251 OS events have been observed among GEP high subjects.

El análisis intermedio se llevará a cabo después de que se haya completado el reclutamiento (24 meses de iniciado el estudio) y se hayan observado alrededor de 240 acontecimientos de SSP entre los pacientes con PEG alto o cuando se alcance el número de eventos de SG . Los resultados serán revisados por un comité de monitorización de datos externo. El análisis final se llevará a cabo cuando se hayan observado > or = to 251 eventos de SG entre los pacientes con PEG alto.

E.5.2

Secondary end point(s)

1. PFS-RECIST 1.1 by investigator assessment
2. Overall Response Rate (ORR)-RECIST 1.1 by blinded central imaging vendor review, and RECIST 1.1 by investigator assessment
3. Safety and tolerability Endpoints

1. SSP- RECIST 1.1 por la evaluación del investigador
2. Tasa de respuesta global (TRG) - RECIST 1.1 según revisión por el
laboratorio central de imagen y evaluación del investigador
3. Seguridad y tolerabilidad

E.5.2.1

Timepoint(s) of evaluation of this end point

These end points will be evaluated at end of study.

Estas variables serán evaluadas al final del estudio.

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

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3.1

Comparator description

El IP elegirá Docetaxel, Paclitaxel, o Irinotecan

Investigator choice of Docetaxel, Paclitaxel, or Irinotecan

E.8.2.4

Number of treatment arms in the trial

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Colombia

Czech Republic

Denmark

Estonia

Finland

France

Germany

Hong Kong

Ireland

Israel

Italy

Japan

Korea, Democratic People's Republic of

Malaysia

Mexico

New Zealand

Peru

Russian Federation

Singapore

Spain

Sweden

Taiwan

Thailand

Turkey

United Kingdom

United States

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

300

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.4.2

For a multinational trial

F.4.2.1

In the EEA

160

F.4.2.2

In the whole clinical trial

600

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)

Patient care after the study will be managed by the patients primary physician.

Los pacientes serán tratados bajo criterio medico habitual

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

2015-12-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-03-14

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Orphan Designation Number:
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