Clinical Trials Register

Summary
EudraCT Number:	2013-000902-40
Sponsor's Protocol Code Number:	EMR200066-012
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-11-11
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

Italy - Italian Medicines Agency

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

Sperimentazione di fase II, in doppio cieco, randomizzata, controllata con placebo su pimasertib e SAR245409 rispetto a pimasertib e placebo di SAR245409 in soggetti affetti da cancro dell'ovaio di basso grado, non resecabile, trattato in precedenza.

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

Sperimentazione su pimasertib e SAR245409 o placebo sul cancro dell'ovaio

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	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

cancro dell'ovaio di basso grado, non resecabile

E.1.1.1

Medical condition in easily understood language

Ovarian Cancer

cancro dell'ovaio

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	16.1
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

Valutare se la risposta obiettiva del tumore alla terapia di associazione con pimasertib e SAR245409 sia superiore a quella a pimasertib e placebo di SAR245409 in soggetti affetti da carcinoma dell'ovaio di basso grado, non resecabile, trattato in precedenza, secondo la versione 1.1 dei criteri di valutazione della risposta nei tumori solidi (RECIST v1.1) come determinato dallo sperimentatore.

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)

Per la terapia di associazione a base di pimasertib e SAR245409 rispetto a pimasertib e placebo di SAR245409:
- Sicurezza e tollerabilità
-Sopravvivenza libera da progressione (PFS)
-Sopravvivenza globale (OS)
-Controllo della malattia
- Qualità della vita correlata alla salute (HrQoL) riferita dalla paziente
- Marcatori predittivi di risposta e/o resistenza
-Farmacocinetica di pimasertib e di SAR245409 per valutare le correlazioni tra esposizione e risposta nonché tra esposizione ed eventi avversi (EA)

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.

-Il soggetto di sesso femminile presenta una diagnosi di:
a) Carcinoma sieroso dell'ovaio o peritoneale di basso grado, di grado 1 o ben differenziato
OPPURE
b)Tumore sieroso borderline dell'ovaio o peritoneale, tumore dell'ovaio o peritoneale a basso potenziale di malignità, tumore sieroso dell'ovaio o peritoneale proliferativo atipico che si ripresenta come carcinoma sieroso di basso grado o presenta impianti peritoneali invasivi.
-Il soggetto è stato sottoposto ad almeno una linea precedente di terapia sistemica e soffre di un tumore che non è assoggettabile a resezione chirurgica potenzialmente curativa.
-Il soggetto soffre di una malattia misurabile secondo RECIST v1.1.
-Il soggetto deve aver compiuto 18 anni di età.
-Il soggetto ha letto e compreso il modulo di consenso informato scritto, accetta ed è in grado di fornire il consenso informato, comprende interamente i requisiti della sperimentazione ed è disposto a rispettare tutte le visite e le valutazioni della sperimentazione, compresa la compilazione degli esiti riferiti dalla paziente. Il consenso deve essere fornito prima di qualsiasi attività correlata alla sperimentazione.
-I soggetti fertili devono presentare un risultato negativo del test di gravidanza sul siero alla visita di screening.
-I soggetti fertili devono essere disposti a evitare la gravidanza utilizzando un metodo adeguato di contraccezione per 2 settimane prima dello screening, durante il trattamento e per almeno 3 mesi dopo l'ultima dose di farmaco della sperimentazione.
-Potrebbero essere applicabili ulteriori criteri di inclusione definiti dal protocollo.

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.

-Il soggetto è stato precedentemente trattato con un inibitore di PI3K e tale terapia è stata interrotta a causa di EA correlati al trattamento.
-Il soggetto è stato precedentemente trattato con un inibitore della chinasi delle protein-chinasi attivate da mitogeno/chinasi regolate da segnali extracellulari (MEK).
-Il soggetto è stato sottoposto a chemioterapia, immunoterapia, terapia ormonale, terapia biologica o qualsiasi altra terapia anti-tumorale nei 28 giorni, o nelle 5 emivite di un farmaco rilevante, precedenti al Giorno 1 del trattamento con il farmaco della sperimentazione, a seconda di quale periodo sia più breve, oppure è stato trattato con nitrosuree o mitomicina C nelle ultime 6 settimane.
-Il soggetto non si è ripreso dalla tossicità dovuta alla terapia precedente fino al livello basale o al grado 1 o inferiore secondo la versione 4.0 dei criteri comuni della terminologia per gli eventi avversi dell'Istituto nazionale tumori statunitense (National Cancer Institute Common Terminology Criteria for Adverse Events, NCI CTCAE) (ad eccezione dell'alopecia).
-Il soggetto presenta funzionalità d'organo e del midollo inadeguata come definito nel protocollo.
-Il soggetto presenta un aumento della creatinfosfochinasi (CPK) di grado ≥ 2 secondo NCI CTCAE (ovvero  2,5 volte l'ULN) e/o un'anamnesi precedente di miosite o rabdomiolisi.
- Il soggetto presenta difficoltà a deglutire, malassorbimento o un'altra malattia gastrointestinale cronica oppure condizioni che potrebbero compromettere l'aderenza al trattamento e/o l'assorbimento del farmaco della sperimentazione.
-Il soggetto presenta un'anamnesi di ulcere diabetiche o ferite a guarigione ritardata/aperte.
-Il soggetto presenta un'anamnesi di insufficienza cardiaca congestizia, angina instabile, infarto miocardico, anomalie della conduzione cardiaca, compreso prolungamento dell'intervallo QT corretto di > 480 ms o pacemaker, compromissione clinicamente rilevante della funzionalità cardiovascolare (classe III/IV della New York Heart Association ) o ictus nei 3 mesi precedenti all'arruolamento.
-Il soggetto presenta un'anamnesi di malattia retinica degenerativa (degenerazione ereditaria della retina o degenerazione maculare correlata all'età), uveite o occlusione della vena retinica oppure presenta altre anomalie rilevanti, identificate all'esame oftalmologico eseguito allo screening, che potrebbero aumentare il rischio di distacco sieroso della retina o di occlusione della vena retinica.
-Il soggetto presenta un'anamnesi di malattia concomitante non controllata, compresi, in via esemplificativa ma non limitativa, infezione attiva, ipertensione o diabete non controllato (ad es. emoglobina glicosilata ≥ 8%), che limiterebbe la conformità ai requisiti della sperimentazione.
-Potrebbero essere applicabili ulteriori criteri di esclusione definiti dal protocollo.

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.

Risposta obiettiva del tumore, definita come risposta completa (CR) o risposta parziale (PR) secondo i criteri RECIST v.1.1, determinata dallo sperimentatore.

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.

Fino alla settimana 32, e, successivamente, ogni 12 settimane fino a 30 giorni dopo l'ultimo trattamento.

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

- Sopravvivenza libera da progressione
- Percentuale di soggetti che con controllo della malattia secondo i criteri RECIST v.1.1
- Sopravvivenza globale
- Health Related Quality of Life (HrQoL) valutata attraverso European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) Versione 3.0
- HrQoL valutata attraverso EORTC QLQ-C30 Versione 3.0 – modulo specifico per l’ovaio QLQ-OV28.
- Numero di soggetti che presentano eventi avversi emergenti dal trattamento (TEAE), eventi avversi di interesse particolare, eventi avversi seri, interruzioni del trattamento dovute a TEAE, decessi.
- Concentrazione massima di pimasertib e SAR245409 nel plasma dopo la somministrazione.
- Area sotto la curva dopo la somministrazione di pimasertib e SAR245409.
- Alterazioni molecolari dei componenti/modulatori delle vie di segnalazione MAPK e/o PI3K nel tessuto tumorale e nel sangue.

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)

Efficacia
-Sopravvivenza libera da progressione: da randomizzazione e fino alla prima osservazione di progressione di malattia o decesso fino a 30 giorni dopo l'ultimo trattamento
-Controllo della malattia: basale, sett. 8, 16, 24 e 32, e, in seguito ogni 12 settimane fino a 30 giorni dopo l'ultimo trattamento
-Sopravvivenza globale: tempo intercorso da randomizzazione al decesso fino a 12 mesi dopo l'ultimo soggetto randomizzato
-HrQoL: giorno 1 e giorno 29, sett. 8, 16, 24 e 32, e, successivamente, ogni 12 settimane fino a 30 giorni dopo l'ultimo trattamento
Sicurezza
-Dal basale fino a 30 giorni dopo l'ultimo trattamento
Farmacocinetica
-pre-dose e 0.5, 1.5, 4.5 e 8 ore dopo la dose del mattino il giorno 15,
29 e 43
Biomarcatori
-visita di screening (giorno -28 fino 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

Spain

Poland

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.

Lo studio si concluderà circa 12 mesi dopo la randomizzazione dell’ultimo soggetto. La fine dello studio è stimata essere circa 30 mesi dopo la randomizzazione del primo soggetto.

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

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

nessuno

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

2013-11-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-20

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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