Clinical Trials Register

Summary
EudraCT Number:	2013-000902-40
Sponsor's Protocol Code Number:	EMR200066-012
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:	2013-12-05
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

2013-000902-40

A.3

Full title of the trial

Phase II Randomized Double Blind Placebo controlled Trial of Combination of Pimasertib with SAR245409 or of Pimasertib with SAR245409 Placebo in Subjects with Previously Treated Unresectable Low Grade Ovarian Cancer

Estudio de fase II, aleatorizado, doble ciego y controlado con placebo de la combinación de pimasertib con SAR245409 o de pimasertib con placebo de SAR245409 en pacientes con cáncer de ovario irresecable de grado bajo previamente tratado

A.3.1

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

Trial of pimasertib with SAR245409 or placebo in ovarian cancer

Ensayo de pimasertib con SAR245409 o placebo en cáncer de ovario

A.4.1

Sponsor's protocol code number

EMR200066-012

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 KGaA
B.1.3.4	Country	Germany
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 KGaA
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck KGaA
B.5.2	Functional name of contact point	Communication Center merck KGaA
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Strasse 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	D-64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496151725200
B.5.5	Fax number	+496151722000
B.5.6	E-mail	service@merckgroup.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	Pimasertib
D.3.2	Product code	MSC1936369B
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pimasertib
D.3.9.1	CAS number	1236361-78-6
D.3.9.2	Current sponsor code	Pimasertib
D.3.9.3	Other descriptive name	MSC1936369B
D.3.9.4	EV Substance Code	SUB30879
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
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: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	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	Pimasertib
D.3.2	Product code	MSC1936369B
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pimasertib
D.3.9.1	CAS number	1236361-78-6
D.3.9.2	Current sponsor code	Pimasertib
D.3.9.3	Other descriptive name	MSC1936369B
D.3.9.4	EV Substance Code	SUB30879
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
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	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.3.2	Product code	SAR245409
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SAR245409
D.3.9.1	CAS number	934493-76-2
D.3.9.2	Current sponsor code	SAR245409
D.3.9.4	EV Substance Code	SUB31965
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
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	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.3.2	Product code	SAR245409
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SAR245409
D.3.9.1	CAS number	934493-76-2
D.3.9.2	Current sponsor code	SAR245409
D.3.9.4	EV Substance Code	SUB31965
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
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: 5
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.3.2	Product code	SAR245409
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SAR245409
D.3.9.1	CAS number	934493-76-2
D.3.9.2	Current sponsor code	SAR245409
D.3.9.4	EV Substance Code	SUB31965
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 4
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 5
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Unresectable Low Grade Ovarian Cancer

Cáncer de ovario irresecable de grado bajo.

E.1.1.1

Medical condition in easily understood language

Ovarian Cancer

Cáncer de Ovario

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10033130
E.1.2	Term	Ovarian cancer NOS
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

To evaluate whether the objective tumor response of the combination therapy with pimasertib plus SAR245409 is superior to that of pimasertib plus SAR245409 placebo in subjects with previously treated unresectable low-grade ovarian carcinoma according to Response Evaluation Criteria in Solid Tumors Version 1.1. (RECIST v1.1) as determined by the investigator

El objetivo principal de este estudio es determinar si la respuesta tumoral objetiva a la combinación de pimasertib más SAR245409 en pacientes con carcinoma de ovario irresecable de bajo grado previamente tratado es superior a la conseguida con pimasertib más placebo de SAR245409 según lo determinado por el investigador con arreglo a los Criterios de evaluación de la respuesta en tumores sólidos, versión 1.1. (RECIST v. 1.1).

E.2.2

Secondary objectives of the trial

For the combination therapy with pimasertib plus SAR245409 compared to pimasertib plus SAR245409 placebo:
- Safety and tolerability
- Progession free survival (PFS)
- Overall survival (OS)
- Disease control
- Patient reported health-related quality of life (HrQoL)
- Predictive markers of response and/or resistance
- Pharmacokinetics (PK) of pimasertib as well as SAR245409 to evaluate relationships between exposure and response as well as between expusure and adverse events (AEs)

Para la combinación de terapia con pimasertib más SAR245409 en comparación con pimasertib más placebo:

- La seguridad y la tolerabilidad.
- La supervivencia sin progresión (SSP)
- La supervivencia global (SG)
- El control de la enfermedad
- La calidad de vida relacionada con la salud percibida por las pacientes (CVRS)
- Los marcadores predictivos de la respuesta o la resistencia.
- La farmacocinética (FC) del pimasertib y del SAR245409 para evaluar las relaciones entre la exposición y la respuesta, así como entre la exposición y los acontecimientos adversos (AA)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-The female subject has a diagnosis of one of the following: a) low-grade serous ovarian or peritoneal carcinoma, or grade 1 serous ovarian or peritoneal carcinoma or well-differentiated serous ovarian or peritoneal carcinoma or b) serous borderline ovarian or peritoneal tumor, ovarian or peritoneal tumor of low-malignant potential, ovarian or peritoneal atypical proliferative serous tumor that recurs as low grade serous carcinoma or has invasive peritoneal implants.
- The subject had at least one prior line of systemic therapy and has a tumor, which is not amenable to potentially curative surgical resection.
- The subject has measurable disease by RECIST v1.1.
- The subject is at least 18 years old.
- The subject has read and understood the written informed consent form (ICF) and is willing and able to give informed consent, fully understands the requirements of the trial and is willing to comply with all trial visits and assessments, including completion of patient-reported measures. Consent must be given before any trial related activities.
- Subjects of childbearing potential must have a negative serum pregnancy test at the screening visit. Subjects of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to screening, during and at least 3 months after the last dose of trial medication.
Other protocol defined inclusion criteria may apply.

1.La paciente tiene uno de los siguientes diagnósticos: a)Carcinoma seroso de bajo grado ovárico o peritoneal, carcinoma seroso de grado 1 ovárico o peritoneal o carcinoma seroso bien diferenciado ovárico o peritoneal ó b) Tumor seroso limítrofe ovárico o peritoneal, tumor de bajo potencial de malignidad ovárico o peritoneal, tumor seroso proliferativo atípico ovárico o peritoneal que recidiva como carcinoma seroso de bajo grado o que tiene implantes peritoneales invasores.
-La paciente habrá recibido al menos una línea de tratamiento sistémico previo y presentar un tumor que no es susceptible de resección quirúrgica potencialmente curativa.
- La paciente presente una enfermedad mensurable según los RECIST v. 1.1.
-La paciente sea mayor de 18 años
- La paciente ha leído y comprendido el documento de consentimiento informado (DCI), está dispuesta a dar el consentimiento, entiende plenamente los requisitos del estudio y está dispuesta a cumplir con todas las visitas y evaluaciones del mismo, incluida la cumplimentación de los cuestionarios de resultados. El consentimiento se obtendrá antes de llevar a cabo cualquier actividad relacionada con el estudio.
-Las pacientes en edad fértil deberán tener un resultado negativo en la prueba de embarazo en suero realizada durante la selección. Las pacientes en edad fértil deben estar dispuestas a evitar el embarazo mediante el uso de un método anticonceptivo adecuado desde 2 semanas antes de la selección y durante y al menos3 meses después de la última dosis de la medicación del estudio.
Podrían aplicar otros criterios de inclusión definidos en el protocolo.

E.4

Principal exclusion criteria

- The subject has previously been treated with a PI3K inhibitor and taken off treatment due to treatment related AEs.
- The subject has been previously treated with a Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor.
- The subject has received chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anti-cancer therapy within 28 days or within 5 times the half life of a relevant agent prior to day 1 of trial drug treatment, whichever is shorter, or has been treated with nitrosoureas or mitomycin C within the last 6 weeks.
- The subject has not recovered from toxicity due to prior therapy to baseline level or national cancer institute common terminology criteria for adverse events version 4.0 (NCI CTCAE v4.0) grade 1 or less (except alopecia).
- The subject has poor organ and marrow function as defined in the protocol
- The subject has creatine phosphokinase (CPK) elevation NCI CTCAE grade >=2, and/or a previous history of myositis or rhabdomyolysis.
- The subject has difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the trial drug.
- The subject has a history of delayed healing/open wounds or diabetic ulcers.
- The subject has a history of congestive heart failure, unstable angina, myocardial infarction, cardiac conduction abnormalities including corrected QT interval prolongation of > 480ms or a pacemaker, clinically relevant impared cardiovascular function (NYHA class III/IV) or stroke within 3 months prior to enrollment.
- The subject has a history of retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), uveitis or retinal vein occlusion (RVO), or has other relevant abnormalities identified on screening opthalmologic examination, which may increase the risk of serous retinal detachment (SRD) or RVO.
- The subject has a history of uncontrolled intercurrent illness including but not limited to an active infection, hypertension, or uncontrolled diabetes (e.g. glycosylated hemoglobin >= 8%) that would limit compliance with treatment requirements.
Other protocol defined exclusion criteria may apply.

La paciente ha recibido tratamiento previo con un inhibidor de la PI3K que debió suspenderse por AA relacionados con el tratamiento.
La paciente ha recibido tratamiento previo con un inhibidor de la proteína activada por mitógenos/cinasa regulada por señales extracelulares-cinasa (MEK).
La paciente ha recibido quimioterapia, inmunoterapia, tratamiento hormonal, tratamiento biológico u otro tratamiento antineoplásico 28 días o 5 veces la semivida de un fármaco importante antes del día 1 de tratamiento con el fármaco del estudio, lo que suponga menos tiempo, o haber recibido nitrosoureas o mitomicina C en las 6 últimas semanas.
La paciente no se ha recuperado de la toxicidad debida al tratamiento previo que no se ha resuelto hasta la situación basal o hasta un grado 1 o menor según los criterios terminológicos comunes para acontecimientos adversos del Instituto Nacional del Cáncer de los Estados Unidos, versión 4.0 (CTCAE del NCI, v. 4.0) (salvo alopecia).
La paciente presenta un deterioro funcional orgánico o de la médula ósea, tal y como se define en el protocolo.
La paciente presenta una elevación de la creatina- fosfocinasa (CPK) de grado ? 2 o tiene antecedentes de miositis o rabdomiólisis
La paciente presenta dificultad para tragar, malabsorción u otra enfermedad digestiva crónica o trastornos que puedan dificultar el cumplimiento terapéutico o la absorción del fármaco del estudio.
La paciente tiene antecedentes de retraso de la cicatrización, heridas abiertas o úlceras diabéticas.
La paciente tiene antecedentes de insuficiencia cardíaca congestiva, angina inestable, infarto de miocardio, anomalías de la conducción cardíaca (incluidas la prolongación del intervalo QT corregido [QTc] > 480 ms o la presencia de marcapasos), deterioro clínicamente importante de la función cardiovascular (clase III/IV de la New York Heart Association) o ictus en los 3 meses anteriores al reclutamiento
La paciente tiene antecedentes de retinopatía degenerativa (retinopatía degenerativa hereditaria o degeneración macular senil), uveítis u obstrucción venosa retiniana (OVR), o se han detectado otras anomalías importantes en la exploración oftalmológica de selección, lo que aumenta el riesgo de sufrir un desprendimiento seroso de la retina (DSR) u OVR.
La paciente tiene antecedentes de enfermedad intercurrente no controlada, como una infección activa, hipertensión arterial o diabetes no controlada (por ejemplo, hemoglobina glucosilada ? 8%), que pudiera limitar el cumplimiento de los requisitos del estudio
Podrían aplicar otros criterios de exclusión incluidos en el protocolo.

E.5 End points

E.5.1

Primary end point(s)

Objective tumor response defined as complete response (CR) or partial response (PR) according to RECIST v1.1. criteria as determined by the investigator.

Respuesta tumoral objetiva, definida como respuesta completa (RC) o respuesta parcial (RP) según lo determinado por el investigador con arreglo a los RECIST v. 1.1.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to week 32, and thereafter every 12 weeks up to 30 days after last treatment.

Hasta 32 semanas, y posteriormente a intervalos de 12 semanas hasta 30 días despúes del final del tratamiento

E.5.2

Secondary end point(s)

- Progression-free survival
- Percentage of subjects with disease control according to RECIST v.1.1
- Overall survival time
- Health Related Quality of Life (HrQoL) assessed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) Version 3.0
- HrQoL assessed using EORTC QLQ-C30 Version 3.0 - ovarian-specific module QLQ-OV28
-Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Adverse Events (AEs) of special interest, Serious Adverse Events (SAEs), discontinuation of treatment due to TEAEs, death
- Maximum Plasma Concentration (Cmax) After Dose of pimasertib and SAR245409
- Area under the curve (AUC) After Dose of pimasertib and SAR245409
- Molecular Alterations in MAPK and/or PI3K signaling pathway components/modulators in tumor tissue and blood

Supervivencia sin progresión (SSP)
-Porcentaje de pacientes con control de la enfermedad según los RECIST v. 1.1
- Tiempo de supervivencia global.
Resultados percibidos por las pacientes (se cumplimentarán el cuestionario C30 sobre calidad de vida de la Organización Europea para la Investigación y el Tratamiento del Cáncer [QLQ-C30 de la EORTC], versión 3.0,
-Resultados percibidos por las pacientes (se cumplimentarán el cuestionario C30 sobre calidad de vida de la Organización Europea para la Investigación y el Tratamiento del Cáncer QLQ-C30 Versión 3.0- módulo para el cáncer de ovario QLQ-OV28
-Número de Pacientes con Acontecimientos adversos aparecidos durante el tratamiento (AAAT), acontecimientos adversos de especial interés, acontecimientos adversos graves, suspensión del tratamiento por AAAT y muertes.
-Concentración máxima de plasma (Cmax) después de la dosis de pimasertib y SAR245409
-Área bajo la curva (AUC) después de la dosis de pimasertib o SAR245409
-Alteraciones moleculares en los componentes o moduladores de la vía de señalización de la MAPK o de la PI3K en el tejido tumoral y la sangre.

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy
- PFS: from randomization until first observation of progressive disease or death, up to 30 days after last treatment
- DC: baseline, week 8, 16, 24 and 32, and thereafter every 12 weeks up to 30 days after last treatment
OS: time from randomization to death up to 12 months after last subject randomized
- HrQoL: day 1 and day 29, week 8, 16, 24 and 32, and thereafter every 12 weeks up to 30 days after last treatment

Safety
-Baseline up to 30 days after last treatment

PK
- predose and 0.5, 1.5, 4.5 and 8 hours after the morning dose at day 15, 29 and 43
Biomarkers
- Screening visit (day -28 to 1)

Eficacia
- SSP: desde la aleatorización hasta la primera documentación de la progresión objetiva de la enfermedad o hasta la muerte, hasta 30 días después del tratamiento.
- DC: basal, semana 8, 16, 24 y 32 y posteriormente, cada 12 semanas hasta 30 días después del último tratamiento
-OS: tiempo desde la aleatorización hasta la muerte hasta 12 meses después de la aleatorización de la última paciente.
- HrQoL: día 1 y día 29, semanas 8, 16, 24 y 32, y posteriormente cada 12 semanas hasta 30 días después del último tratamiento.

Seguridad
-Basal hasta 30 días después del último tratamiento.

PK
-Antes de la dosis y 0,5, 1,5, 4,5 y 8 horas después de la dosis matutina en los días 15, 29 y 43.
Biomarcadores
Visita de selección (día-28 a 1)

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

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

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

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

Australia

Belgium

Canada

France

Italy

Poland

Spain

United States

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

The trial will be completed approximately 12 months after randomization of the last subject. Trial end is estimated to be approximately 30 months after the first subject is randomized.

El ensayo finalizará aproximadamente 12 meses después de la aleatorización del último sujeto. Se calcula que el final del ensayo tendrá lugar alrededor de 30 meses después de la aleatorización del primer sujeto.

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

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

110

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

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

2013-12-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-12-08

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