Clinical Trials Register

Summary
EudraCT Number:	2012-002669-37
Sponsor's Protocol Code Number:	EMR200066-007
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:	2012-10-02
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

2012-002669-37

A.3

Full title of the trial

A multicentre, open label, randomized Phase II trial of the MEK inhibitor pimasertib or dacarbazine in previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma

Ensayo fase II aleatorizado, abierto, multicéntrico de pimasertib inhibidor de MEK o dacarbazina en sujetos con melanoma cutáneo maligno localmente avanzado o metastásico con mutación de N-Ras no tratados previamente.

A.3.1

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

Clinical trial comparing the safety and efficacy of pimasertib and dacarbazine in previously untreated patients with locally advanced or metastatic malignant cutaneous melanoma showing the so-called N-Ras mutation.

Ensayo clínico para comparar la seguridad y eficacia de pimasertib y dacarbazina en sujetos con melanoma cutáneo maligno localmente avanzado o metastásico con mutación de N-Ras no tratados previamente.

A.3.2

Name or abbreviated title of the trial where available

Phase II trial of pimasertib vs. dacarbazine in N-Ras mutated cutaneous melanoma

Ensayo fase II de pimasertib frente a dacarbazina en melanoma cutáneo con mutación de N-Ras

A.4.1

Sponsor's protocol code number

EMR200066-007

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 Serono S.A. Geneva
B.1.3.4	Country	Switzerland
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 Serono S.A.
B.4.2	Country	Switzerland
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	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+ 49 6151 72 5200
B.5.5	Fax number	+ 49 6151 72 2000
B.5.6	E-mail	service@merck.de

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.3.10	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	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	Dacarbazine Medac 1000 mg, powder for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac GmbH
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	dacarbazine medac
D.3.4	Pharmaceutical form	Powder 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	Dacarbazina
D.3.9.1	CAS number	4342-03-4
D.3.9.4	EV Substance Code	SUB06882MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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.3.1	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.3.10	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.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

N-RAS mutated locally advanced or metastatic malignant cutaneous melanoma

Melanoma cutáneo maligno localmente avanzado o metastásico con mutación de N-Ras

E.1.1.1

Medical condition in easily understood language

Cancer

Cáncer

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	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10025655
E.1.2	Term	Malignant melanoma of skin
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 the progression-free survival (PFS) of previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma treated with either pimasertib or dacarbazine.

Comparar la supervivencia sin progresión (SSP) con pimasertib o dacarbazina en sujetos con melanoma cutáneo maligno localmente avanzado o metastásico con mutación de N Ras no tratados previamente.

E.2.2

Secondary objectives of the trial

Efficacy
- Compare the objective response of subjects treated with either pimasertib or dacarbazine.
- Compare the disease control of subjects treated with either pimasertib or dacarbazine.
- Evaluate the overall survival of subjects treated with either pimasertib or dacarbazine.
- Compare the Quality of Life of subjects treated with either pimasertib or dacarbazine.
Safety
- Compare the safety profile of subjects treated with pimasertib or dacarbazine.
Pharmacokinetics
- Assess the pharmacokinetics of pimasertib in melanoma subjects and to evaluate relationships between exposure and response as well as exposure and AEs.
Pharmacogenetics and Biomarkers
- Describe the relationship between basal tumor characteristics and circulating markers and pimasertib anti-tumor activity.
Explore genes that are important in the drug metabolizing enzymes and transporters of pimasertib and identify potential genetic variations that may account for differences in PK profile.

Eficacia: -Comparar la respuesta objetiva entre los sujetos tratados con pimasertib o dacarbazina. -Comparar el control de la enfermedad entre los sujetos tratados con pimasertib o dacarbazina. -Evaluar supervivencia global de los sujetos tratados con pimasertib o dacarbazina. -Comparar calidad de vida entre los sujetos tratados con pimasertib o dacarbazina.
Seguridad: -Comparar perfil de seguridad entre los sujetos tratados con pimasertib o dacarbazina.
Farmacocinética (FC): -Evaluar la FC del pimasertib en los sujetos con melanoma y las relaciones entre la exposición y la respuesta y entre la exposición y los AA. Farmacogenética y Biomarcadores: -Describir la relación entre las características basales del tumor y los marcadores circulantes y la actividad antitumoral del pimasertib. -Investigar genes de enzimas metabolizadoras y transportadores de fármacos importantes para el pimasertib e identificar las variaciones genéticas que podrían explicar las diferencias en el perfil FC.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects with measurable, histologically or cytologically confirmed, unresectable locally advanced or metastatic cutaneous melanoma (stage III c or M1a-c) N-Ras mutated. If N-Ras mutational status is unknown at screening, it must be prospectively defined before inclusion. If N-Ras mutational status is already known before screening, it must be retrospectively confirmed after inclusion by the sponsor.
2. Tumor lesions amenable to biopsy or available tumor tissue as archival samples.
3. Age >= 18 years.
4. Has read and understood the informed consent form and is willing and able to give informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments.
5. Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For the purposes of this trial, women of childbearing potential are defined as: All female subjects after puberty unless they are post-menopausal for at least two years, or are surgically sterile.
6. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to, during and four weeks after the last dose of trial medication. Effective contraception is defined as the method of contraception with a failure rate of less than 1% per year. Adequate contraception is defined as follows: two barrier methods or one barrier method with a spermicidal or intrauterine device or oral contraception for female partners of male subjects.

1. Sujetos con melanoma cutáneo localmente avanzado o metastásico (estadio III c o M1a c) mensurable e irresecable, confirmado por métodos histológicos o citológicos, con mutación de N-Ras. Si en el momento de la selección se desconoce el estado respecto a la mutación de N-Ras, este se determinará prospectivamente antes de la inclusión. Si antes de la selección ya se conocía el estado respecto a la mutación de N-Ras, el promotor lo confirmará de forma retrospectiva después de la inclusión.
2. Lesiones tumorales asequibles a la biopsia o disponibilidad de muestras de tejido tumoral archivadas.
3. Edad >= 18 años.
4. El sujeto ha leído y comprendido el documento de consentimiento informado, y está dispuesto y capacitado para otorgar su consentimiento. El sujeto comprende plenamente los requisitos del ensayo y está dispuesto a cumplir todas las visitas y las evaluaciones del ensayo.
5. Las mujeres en edad fértil deben tener un resultado negativo en la prueba de embarazo en sangre en la visita de selección. En este ensayo, se consideran en edad fértil 'todas las mujeres después de la pubertad, a menos que presenten la menopausia desde hace al menos dos años o se hayan sometido a esterilización quirúrgica'.
6. Las mujeres en edad fértil y los varones con pareja femenina en edad fértil deberán estar dispuestos a evitar el embarazo mediante un método anticonceptivo adecuado desde dos semanas antes de empezar el tratamiento del ensayo, durante el mismo y hasta cuatro semanas después de la última dosis de la medicación del ensayo. Se considera un método anticonceptivo eficaz aquel que tiene una tasa de fracasos inferior al 1 % anual. La anticoncepción adecuada se define de la manera siguiente: dos métodos de barrera, un método de barrera con espermicida o un dispositivo intrauterino, o un anticonceptivo oral en las parejas femeninas de los sujetos varones.

E.4

Principal exclusion criteria

1. Has previous systemic treatment for locally advanced or metastatic cutaneous melanoma (excluding adjuvant treatment).
2. Has non-measurable lesions, disease not evaluable by RECIST v. 1.1
3. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) >1.
4. Has bone marrow impairment as evidenced by Hemoglobin < 10.0 g/dL, Neutrophil count <1.5 x 10^9/L, platelets < 100 x 10^9/L.
5. Has renal impairment as evidenced by calculated creatinine clearance <60 mL/min (according to the Cockcroft-Gault formula).
6. Has liver function abnormality as defined by total bilirubin > 1.5 x ULN, or AST/ALT >2.5 x ULN, for subjects with liver involvement AST/ALT >5 x ULN.
7. Has significant cardiac conduction abnormalities, including QTc prolongation of >480 ms and/or pacemaker or clinically relevant impaired cardiovascular function (NYHA Class III/IV).
8. Has hypertension uncontrolled by medication
9. Has retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis, or history of retinal vein occlusion (RVO) or any eye condition that would be considered a risk factor for RVO (e.g., uncontrolled glaucoma or ocular hypertension).
10. Has known active CNS metastases unless previously radiotherapy treated, stable by CT scan for at least 3 months without evidence of cerebral edema and no requirements for corticosteroids or anticonvulsants.
11. History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease, or conditions that may hamper compliance and/or absorption of the tested product.
12. Known HIV positivity, active hepatitis C, or active hepatitis B.
13. Has undergone surgical intervention within 28 days from Day 1 of trial drug treatment.
14. Has received extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from Day 1 of trial drug treatment.
15. Has history of any other significant medical disease such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion or has a psychiatric condition that might impair the subject well-being or preclude full participation in the trial.
16. Has known hypersensitivity to dacarbazine.
17. Is a pregnant or nursing female.
18. Participated in another clinical trial within the past 28 days.

1. Ha recibido tratamiento sistémico para el melanoma cutáneo localmente avanzado o metastásico (excluido el tratamiento adyuvante).
2. Tiene lesiones no mensurables, enfermedad no evaluable mediante la versión 1.1 de los RECIST.
3. Tiene un estado funcional según el Eastern Cooperative Oncology Group (EF del ECOG) mayor de 1.
4. Presenta afectación de la médula ósea, manifestada por una hemoglobina < 10,0 g/dl, un recuento absoluto de neutrófilos < 1,5 x 10^9/l, un recuento de plaquetas < 100 x 10^9/l.
5. Tiene insuficiencia renal, demostrada por un aclaramiento de creatinina estimado < 60 ml/min (según la fórmula de Cockcroft Gault).
6. Presenta una alteración de la función hepática, definida por una bilirrubina total > 1,5 x LSN o una AST/ALT > 2,5 x LSN (> 5 x LSN en los sujetos con afectación hepática).
7. Presenta anomalías importantes de la conducción cardíaca, como una prolongación del intervalo QTc > 480 ms y/o un marcapasos, o un deterioro clínicamente importante de la función cardiovascular (clase III/IV de la NYHA).
8. Tiene hipertensión arterial que no se controla con medicación.
9. Presenta una retinopatía degenerativa (degeneración retiniana hereditaria o degeneración macular senil), antecedentes de uveítis, antecedentes de obstrucción de la vena retiniana (OVR) o cualquier trastorno ocular que se considere un factor de riesgo de sufrir OVR (por ejemplo, glaucoma no controlado o hipertensión ocular).
10. Tiene metástasis activas confirmadas en el SNC, a menos que se hayan sometido previamente a radioterapia, permanezcan estables en la tomografía computarizada (TC) durante al menos 3 meses sin signos de edema cerebral y no necesiten corticoesteroides ni antiepilépticos.
11. Tiene antecedentes de disfagia, malabsorción u otra enfermedad gastrointestinal crónica, o trastornos que puedan dificultar el cumplimiento y/o la absorción del producto investigado.
12. Presenta Seropositividad para el VIH, hepatitis C activa o hepatitis B activa.
13. Se ha sometido a una intervención quirúrgica en los 28 días previos al día 1 de tratamiento con el fármaco del estudio.
14. Ha recibido radioterapia extensa en más del 30 % de las reservas de la médula ósea, o un trasplante de médula ósea o de células madre en los 5 años previos al día 1 de tratamiento con el fármaco del estudio.
15. Tiene antecedentes de otra enfermedad importante, como una cirugía mayor gástrica o del intestino delgado, se ha sometido recientemente a un drenaje de líquido ascítico o pleural en un volumen importante, o padece una enfermedad psiquiátrica que pudiera alterar el bienestar del sujeto o impedir su participación plena en el ensayo.
16. Tiene hipersensibilidad confirmada a la dacarbazina.
17. Es una mujer embarazada o en período de lactancia.
18. Ha participado en otro ensayo clínico en los últimos 28 días.

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival, defined as the time from randomization to the first documentation of objective disease progression (according to RECIST v. 1.1) as determined by the investigator or death, whichever comes first. Death will be considered as an event only if it is reported within 12 weeks after the last tumor assessment without progression.

La Supervivencia sin progresión (SSP), definida como el tiempo transcurrido desde la aleatorización hasta la primera documentación de la progresión objetiva de la enfermedad (según los RECIST, versión 1.1) determinada por el investigador o hasta la muerte, lo que ocurra antes. La muerte se considerará un episodio sólo si se notifica en el plazo de 12 semanas desde la última evaluación del tumor en la que no se detectó progresión.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline; Day 1 of cycles 3, 5, 7, 9, 11, 13 and every 4 cycles thereafter; EoT

Momento basal; Día 1 de los ciclos 3, 5, 7, 9, 11, 13 y después cada 4 ciclos; Visita de fin de tratamiento.

E.5.2

Secondary end point(s)

*Efficacy
All efficacy endpoints involving RECIST v. 1.1 criteria will be based upon investigator assessment. Independent central review of scans will be performed retrospectively for the purpose of sensitivity analyses.
- Objective response defined as complete or partial tumor response according to RECIST v. 1.1 criteria.
- Disease control defined as the proportion of subjects with complete response, partial response, or stable disease for > 3 months, according to RECIST v. 1.1 criteria.
- Progression-free survival rate at six months from the time of randomization based upon objective disease progression (according to RECIST v. 1.1 as defined for PFS above.
- Overall survival defined as the time from randomization to death from any cause.
- Overall survival rate at 12 months from the time of randomization.
- Change in patient-reported QoL (assessed by FACT-Melanoma) from baseline assessment to last assessment prior to objective disease progression (according to RECIST v. 1.1).

*Safety
- Treatment-emergent adverse events (TEAEs), SAEs, deaths.
- Clinically significant changes in safety-related laboratory parameters according to NCI-CTC v 4.0 and abnormal vital signs.

*Pharmacokinetics
- Plasma PK parameters estimates of pimasertib

* Pharmacogenetics and Biomarkers
- Gene products and genetic alterations in tumor biopsies.
- Predictive markers in plasma
- Potential genetic variations in gDNA obtained from PBMC, associated with differences in PK (i.e., DMET genes) and profile of pimasertib.

Eficacia
Todos los criterios de valoración de la eficacia relacionados con los RECIST, versión 1.1, se basarán en la evaluación efectuada por el investigador. Para los análisis de sensibilidad se realizará de manera retrospectiva una revisión centralizada independiente de las pruebas de imagen.
- Respuesta objetiva, definida como la presencia de respuesta tumoral completa o parcial según la versión 1.1 de los criterios RECIST.
- Control de la enfermedad, definido como el porcentaje de sujetos con respuesta completa, respuesta parcial o enfermedad estable (según la versión 1.1 de los criterios RECIST) durante más de 3 meses.
- Tasa de SSP a los seis meses desde el momento de la aleatorización, basada en la progresión objetiva de la enfermedad (según los RECIST, versión 1.1), de acuerdo con la definición anterior de SSP.
- Supervivencia global (SG), definida como el tiempo transcurrido desde la aleatorización hasta la muerte por cualquier causa.
- Tasa de SG a los 12 meses desde el momento de la aleatorización.
- Variación de la calidad de vida notificada por el paciente (evaluada mediante el cuestionario FACT Melanoma) desde el momento basal hasta la última evaluación realizada antes de la progresión objetiva de la enfermedad (según los RECIST, versión 1.1).

Seguridad
- Acontecimientos adversos aparecidos durante el tratamiento (AAAT), AAG, muertes.
- Variaciones de importancia clínica en los parámetros analíticos relacionados con la seguridad según los CTCAE del NCI, versión 4.0, y alteraciones de las constantes vitales.

Farmacocinética
- Cálculo de los parámetros de FC plasmática del pimasertib

Farmacogenética y biomarcadores
- Alteraciones genéticas y expresión de proteínas en biopsias tumorales.
- Marcadores predictivos en plasma.
- Posibles variaciones genéticas del ADN genómico obtenido de las CMSP que expliquen las diferencias en el perfil farmacocinético del pimasertib (por ejemplo, genes de las enzimas metabolizadoras y los transportadores de fármacos).

E.5.2.1

Timepoint(s) of evaluation of this end point

- OR & Disease control: Baseline; Day 1 of cycles 3, 5, 7, 9, 11, 13 and every 4 cycles thereafter; EoT
- PFS rate: 6 months from time of randomization
- OS: time of death from any cause.
- OS rate: 12 months from time of randomization.
- Change in patient-reported QoL: at last assessment prior to objective disease progression

- TEAEs, SAEs, deaths.: Screening up to Post treatment assessment (30+/- 3 days after last drug intake).
- Vital signs: Baseline; Pre-dose on day 1, 8 of cycle 1, 2; Day 1 of every cycles thereafter; EoT; PTP

- PK: Day 8, 15 of cycle 1; Day 1 of cycle 2

- Gene products and genetic alterations: Baseline
- Predictive markers in plasma: Day 1 of cycle 1
- Potential genetic variations: Cycle 1 day 1 for pimasertib arm only.

- Respuesta objetiva/Control enfermedad: Momento basal; D1 ciclos 3, 5, 7, 9, 11, 13 y después cada 4 ciclos; FDT. - Tasa SSP: 6 meses desde aleatorización. - SG: tiempo hasta muerte por cualquier causa. - Tasa SG: 12 meses desde aleatorización. - Variación CdV paciente: hasta última evaluación antes de progresión objetiva de enfermedad. - AAAT, AAG, muertes: Desde selección hasta evaluación después del tratamiento (30+/-3 días después de la última dosis del fármaco).- Constantes vitales: Momento basal; antes de la dosis del D1, 8 ciclo 1, 2; después, el D1 de cada ciclo; FDT; PPT. - FC: D8, 15 ciclo 1; D1 ciclo 2. - Productos genéticos y alteraciones genéticas: M. basal. - Marcadores predictivos en plasma: D1 ciclo 1. - Posibles variaciones genéticas: Ciclo 1 D1 sólo brazo de pimasertib.

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

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

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)

Yes

E.8.2.2

Placebo

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

France

Germany

Israel

Italy

Netherlands

New Zealand

Norway

South Africa

Spain

Sweden

Switzerland

United Kingdom

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

LVLS

Última visita del ultimo paciente

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

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:

157

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

131

F.4.2.2

In the whole clinical trial

184

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)

After leaving the trial, e.g., due to progressive disease or withdrawal of consent, the subjects will have full and unrestricted access to appropriate diagnostic or therapeutic care at the discretion of the investigator or another treating physician.

Después de dejar el estudio, por ejemplo, por progresión de la enfermedad o por retirada del consentimiento, los pacientes tendrán acceso pleno e ilimitado a la asistencia diagnóstica o terapéutica que proceda a criterio del investigador u de otro médico a cargo del tratamiento.

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

2012-11-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-11-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-10-24

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