Clinical Trials Register

Summary
EudraCT Number:	2014-003277-42
Sponsor's Protocol Code Number:	MCLA-128-CL01
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-11-19
Trial 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

2014-003277-42

A.3

Full title of the trial

A Phase I/II Study of MCLA-128, a full length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients with Solid Tumors

Estudio en fase I/II de MCLA-128, un anticuerpo IgG1 biespecífico completo contra HER2 y HER3, en pacientes con tumores sólidos.

A.3.1

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

A study of the investigational drug MCLA-128 which is an antibody that is specific to both HER2 and HER3 receptors that are associated with solid tumors

Un estudio del fármaco en investigación MCLA-128 que es un anticuerpo específico para los receptors HER2 y HER3, asociados a tumores sólidos

A.4.1

Sponsor's protocol code number

MCLA-128-CL01

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	Merus B.V.
B.1.3.4	Country	Netherlands
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	Merus B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Chiltern Oncology
B.5.2	Functional name of contact point	MCLA-128-CL01 Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Logan Building, Roslin Biocentre
B.5.3.2	Town/ city	Edinburgh
B.5.3.3	Post code	EH25 9TT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+3493771 32 81
B.5.5	Fax number	+3493774 23 78
B.5.6	E-mail	contact@ockham.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	Not available
D.3.2	Product code	MCLA-128
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not assigned
D.3.9.1	CAS number	Not assigned
D.3.9.2	Current sponsor code	MCLA-128
D.3.9.3	Other descriptive name	A bispecific humanized full length IgG1 antibody with enhanced ADCC
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.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

Solid Tumors

Tumores Sólidos

E.1.1.1

Medical condition in easily understood language

Solid tumors

Tumores Sólidos

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10049280
E.1.2	Term	Solid tumour
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

Part 1:
- Determination of the MTD and/or MRD of MCLA-128
- Evaluation of adverse events (AEs) and dose limiting toxicities (DLT)

Part 2 (Safety):
- To characterize the safety and tolerability of MCLA-128

Part 2 (Efficacy):
- Evaluation of anti-tumor response and CBR

Parte 1
-Determinación de la MTD (Dosis Máxima Tolerada) y/o de la MRD (Dosis Máxima Recomendada) del MCLA-128.
-Evaluación de los acontecimientos adversos (AE, por sus siglas en inglés) y de las toxicidades limitantes de dosis (DLT).

Parte 2 (Seguridad)
-Evaluar la seguridad y tolerabilidad de MCLA-128.

Parte 2 (Eficacia)
-Evaluación de la respuesta antitumoral y de la Tasa de Beneficio Clínico.

E.2.2

Secondary objectives of the trial

Part 1:
- To characterize the safety and tolerability of MCLA-128
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Evaluation of anti-tumor response and CBR
- Presence of biomarkers and pharmacodynamic (PD) responses to MCLA-128

Part 2:
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Evaluation of anti-tumor activity and clinical benefit
- Presence of biomarkers and PD responses to MCLA-128

Parte 1:
- Evaluar la seguridad y tolerabilidad de MCLA-128.
- Evaluación de las variables PK en MCLA-128.
- Immunogenicidad en MCLA-128.
- Evaluación de la respuesta antitumoral y de la Tasa de Beneficio Clínico.
- Presencia de biomarcadores y respuesta farmacodinámica en MCLA-128.

Parte 2:
- Evaluación de las variables Farmacocinética (PK) en MCLA-128.
- Immunogenicidad en MCLA-128.
- Evaluación de la actividad antitumoral y del beneficio clínico.
- Presencia de biomarcadores y respuesta farmacodinámica en MCLA-128.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

General Inclusion Criteria for Part 1 and Part 2
1. Age 18 years or older;
2. At least one measurable or evaluable disease according to RECIST v1.1;
3. Performance status of ECOG 0 or 1;
4. Estimated life expectancy of at least 12 weeks;
5. Toxicities incurred as a result of previous anti-cancer therapy resolved to ?Grade 1 (as defined by NCI CTCAE v4.03), except for alopecia, lymphopenia assessed as non-clinically significant, Grade 2 sensory neurotoxicity;
6. At least a 4-week interval between the last received radiotherapy and the first scheduled day of dosing with MCLA-128 (with the exception of up to 1X8 Gy for pain palliation);
7. Complete recovery from major surgery (stable and <Grade 2 toxicity acceptable);
8. Laboratory values at Screening:
a. Absolute neutrophil count ?1.5 x 10e9/L without colony stimulating factor support;
b. Platelets ?100 x 10e9/L;
c. Hemoglobin ?9 g/dL or ?2.2 mmol/L (not transfusion dependent);
d. Total bilirubin <1.5 times the upper limit of normal (ULN) (unless due to Gilbert?s syndrome);
e. AST (SGOT) ?2.5 x ULN; ALT (SGPT) ?2.5 x ULN; ?5 x ULN for patients with advanced solid tumors with liver metastases; patients with confirmed bony metastases will be permitted on study with isolated elevations in ALP <5 x ULN;
f. Serum creatinine ?1.5 x ULN or estimated glomerular filtration rate (GFR) of >50 mL/min based on the Cockroft-Gault formula;
g. Normal coagulation (elevated INR, prothrombin time or APTT <1.3 x ULN acceptable);
h. Urine protein ?2+ (as measured by dipstick);
9. Able to provide an archival tumor biopsy sample or provision of consent to obtain fresh sample at Screening;
10. Candidate patients with metastatic colorectal cancer, should have availability of a pathology report indicating mutational status of ?KRAS, NRAS, PIK3CA and BRAF? or provision of consent to obtain fresh biopsy sample at Screening;
11. Negative pregnancy test results available as defined by urine or blood human chorionic gonadotropin (hCG) test during Screening and within 7 days of Cycle 1, Day 1 in women of childbearing potential (defined as women ?50 years of age or history of amenorrhea for ?12 months prior to study entry);
12. Sexually active male and female patients of childbearing potential must agree to use an effective method of birth control (e.g., barrier methods with spermicides, oral or parenteral contraceptives and/or intrauterine devices) during the entire duration of the study and for 6 months after final administration of MCLA-128. Note that sterility in female patients must be confirmed in the patients? medical records and be defined as any of the following: surgical hysterectomy with bilateral oophorectomy, bilateral tubular ligation, natural menopause with last menses >1 year ago; radiation induced oophorectomy with last menses >1 year ago; chemotherapy induced menopause with 1 year interval since last menses;
13. Ability to give written, informed consent prior to any study-specific Screening procedures, with the understanding that the consent may be withdrawn by the patient at any time without prejudice;
14. Capable of understanding the mandated and optional protocol requirements, is willing and able to comply with the study protocol procedures and has signed the main informed consent document. For any optional biopsy sampling (tissue and/or blood) and long-term sample storage, additional consent is required.

Specific Inclusion Criterion for Part 1
14. Histologically-confirmed and documented advanced or metastatic epithelial tumors, relapsed or refractory to at least 2 prior regimens of available standard treatment(s), or for which no curative therapy is available and MCLA-128 is a reasonable treatment option. This includes, but is not limited to, patients with breast cancer, gastric cancer, colorectal cancer, lung cancer or pancreatic cancer.

Specific Inclusion Criteria for Part 2 (Group A)
15. Histologically-confirmed and documented advanced or metastatic breast cancer (mBC) which is relapsed or refractory to prior available standard therapies including trastuzumab-containing regimens (prior treatment with other approved or investigational anti-HER2 or anti-HER3 agents is allowed);
16. At least 2 prior treatments for metastatic disease;
17. Confirmed HER2 amplification based on historical pathology report prior to commencing Screening assessments.

Specific Inclusion Criteria for Part 2 (Group B)
18. Histologically-confirmed and documented advanced or metastatic colorectal cancer (mCRC) which is relapsed or refractory to at least 2 prior regimens of available standard treatments for metastatic CRC, including one anti-EGFR treatment (if RASWT);
19. Confirmed HER2 amplification based on historical pathology report prior to commencing Screening assessments.

1. Tener 18 años o más de edad.
2. Como mínimo una enfermedad medible o evaluable según RECIST v1.1.
3. Estado funcional según la escala ECOG de 0 ó 1.
4. Expectativa estimada de vida de como mínimo 12 semanas.
5. Las toxicidades provocadas por un tratamiento contra el cáncer anterior deben haber quedado resueltas hasta Grado 1 (tal como se define en el NCI CTCAE 4.03),salvo la alopecia y la linfopenia evaluadas como clínicamente no ignificativas y la neurotoxicidad sensorial en Grado 2.
6. Como mínimo un intervalo de 4 semanas entre la última radioterapia recibida y el primer día programado de dosificación con el MCLA-128 (a excepción de hasta 1X8 Gy para el alivio del dolor).
7. Recuperación completa de una operación quirúrgica importante (toxicidad estable y en <Grado 2 aceptable).
8. Valores de laboratorio en la preselección.
a. Recuento absoluto de neutrófilos _1.5 x 109/L sin factor estimulante de colonias.
b. Plaquetas _100 x 109/L.
c. Hemoglobina _9 g/dL o _2.2 mmol/L (no dependiente de transfusión).
d. Bilirrubina total<1,5 veces el límite superior normal (ULN, por sus siglas en inglés) (salvo que se deba al síndrome de Gilbert).
e. AST (SGOT) _2,5 x ULN; ALT (SGPT) _2,5 x ULN; _5 x ULN para pacientes con tumores sólidos avanzados con metástasis en hígado; los pacientes con metástasis ósea confirmada serán admitidos en el estudio con unas elevaciones aisladas en ALP <5 x ULN.
f. Una tasa de creatinina sérica £ de 1, 5 x ULN o una tasa estimada de filtrado glomerular (GFR, por sus siglas en inglés) de >50 mL/min según la fórmula de Cockroft-Gault.
g. Una coagulación normal (INR elevado, tiempo de protrombina o APTT <1, 3 x ULN aceptable).
h. Proteínas en la orina inferior o igual a 2+ (medidas con una tira reactiva).
9. Capaz de facilitar una muestra de biopsia de tejido archivado o de dar su consentimiento para obtener una muestra fresca en la fase de preselección.
10. Los pacientes candidatos con cáncer colorrectal metastásico, deben tener disponible un informe patológico indicando el estado mutacional de " KRAS, las ANR , PIK3CA y BRAF " o proveer consentimiento para obtener la muestra durante la Pre-selección.
11. Resultados negativos en la prueba de embarazo definidos con la prueba de la
gonadotropina coriónica humana (hCG, por sus siglas en inglés) en orina o sangre
durante la preselección y 7 días después del Ciclo 1, Día 1 en mujeres en edad de
procrear (definidas como mujeres de menos o igual a 50 años de edad o con un historial de amenorrea en menos o igual a 12 meses anteriores a la entrada en el estudio).
12. Los pacientes masculinos y femeninos sexualmente activos y en edad de procrear
deberán aceptar el uso de un método anticonceptivo eficaz (por ejemplo, métodos de
barrera con espermicidas, anticonceptivos orales o parenterales y/o dispositivos
intrauterinos) durante la completa duración del estudio y durante los 6 meses posteriores a la administración final del MCLA-128. Obsérvese que la esterilidad de las pacientes femeninas deberá ser confirmada por el historial médico de la paciente y definida como: histerectomía quirúrgica con ooforectomía bilateral, ligamento tubular bilateral, menopausia natural con ausencia de menstruaciones desde hace más de 1 año; ooforectomía provocada por la radioterapia con ausencia de menstruaciones desde hace más de 1 año; menopausia provocada por la quimioterapia con ausencia de menstruaciones desde hace 1 año.
13. Disposición para dar su consentimiento informado por escrito antes de realizar los
procedimientos de preselección del estudio, entendiendo que el paciente podrá renunciar al consentimiento en cualquier momento sin perjuicio alguno.
14. Capacidad para entender los requisitos del protocolo obligatorios y opcionales y
disposición para cumplir los procedimientos del protocolo del estudio y firmar el
documento principal de consentimiento informado. Se requerirá un nuevo consentimiento para la extracción opcional de muestras para la biopsia (tejido y/o sangre) y el almacenamiento a largo plazo de la muestra.

E.4

Principal exclusion criteria

General Exclusion Criteria for Part 1 and Part 2
1. Pregnant or lactating;
2. Presence of an active infection or an unexplained fever greater than 38.5°C during Screening up to the first scheduled day of dosing. At the discretion of the Investigator, patients with tumor fever may be enrolled;
3. Known hypersensitivity to any of the components of MCLA-128 or history of severe hypersensitivity reactions to human or humanized monoclonal antibodies, including therapeutic antibodies;
4. Known HIV, Hepatitis B or Hepatitis C; patients who have previously been treated for Hepatitis C and have undetectable viral loads are eligible;
5. Documented symptomatic or uncontrolled intracranial or leptomeningeal metastases or primary intracerebral tumor(s);
6. Previous or concurrent malignancy (excluding non-basal cell carcinoma of skin or carcinoma in situ of the uterine cervix) unless the tumor was treated with curative intent more than 2 years prior to study entry;
7. Prior anti-tumor therapy including:
a. Approved anti-HER2 therapies and/or anti-EGFR approved therapies within 28 days prior to the first scheduled day of dosing with MCLA-128;
b. Investigational therapy administered within 28 days prior to the first scheduled day of dosing with MCLA-128. Dosing with MCLA-128 within 28 days of receiving investigational therapy is acceptable once a time interval equal to at least five half-lives of the investigational agent has passed;
c. Treatment with chemotherapy agents within 28 days prior to the first scheduled day of dosing with MCLA-128;
8. Presence of NYHA Class III or IV congestive heart failure or LVEF <50% or history of significant cardiac disease, unstable angina, congestive heart failure, myocardial infarction, or ventricular arrhythmia requiring medication;
9. Presence of any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate or participate in the study, or interfere with the interpretation of the results.

1. Embarazo o período de lactancia.
2. Existencia de una infección activa o de una fiebre inexplicable superior a 38,5 ºC durante la fase de preselección hasta el primer día de dosificación programado. El investigador será quien decida si pueden reclutarse los pacientes con fiebre tumoral.
3. Reconocida hipersensibilidad a alguno de los componentes del MCLA-128 o historia de reacciones de hipersensibilidad severas a anticuerpos monoclonales humanos o humanizados, incluidos los anticuerpos terapéuticos.
4. VIH, hepatitis B o C reconocidas; los pacientes que hayan sido anteriormente tratados de hepatitis C y tengan cargas virales indetectables podrán ser elegidos.
5. Metástasis intracraneales o leptomeníngeas sintomáticas o no controladas o tumores intracerebrales primarios documentados
6. Malignidad previa o concurrente (sin incluir el carcinoma de células no basales de piel o el carcinoma in situ del cuello uterino) salvo que el tumor haya sido tratado con intención curativa más de 2 años antes de la entrada en el estudio.
7. La terapia antitumoral anterior incluye:
a. Terapias anti-HER2 aprobadas y/o terapias anti-EGFR aprobadas en el plazo de los 28 días previos al primer día programado de dosificación del MCLA-128.
b. Terapia experimental administrada en el plazo de los 28 días previos al primer día
programado de dosificación del MCLA-128 Se acepta la dosificación de MCLA-
128 en el plazo de los 28 días siguientes a la administración de una terapia experimental cuando el intervalo de tiempo transcurrido equivalga a como mínimo
cinco semividas del agente experimental.
c. Tratamiento con agentes de quimioterapia en el plazo de los 28 días previos al
primer día programado de dosificación del MCLA-128.
8. Existencia de insuficiencia cardíaca congestiva NYHA de Clase III o IV o LVEF <50% o historial de enfermedad cardíaca importante, angina de pecho inestable, insuficiencia cardíaca congestiva, infarto de miocardio o arritmia ventricular que requieran medicación.
9. Existencia de cualquier otra condición médica o psicológica que el investigador
considere que pueda interferir en la capacidad de un paciente para firmar un consentimiento informado, colaborar o participar en el estudio, o interferir en la
interpretación de los resultados.

E.5 End points

E.5.1

Primary end point(s)

Part 1:
- Determination of MTD/MRD and tolerability
- Number and nature (severity and seriousness) of ADRs including DLTs

Part 2:
Primary Safety End Point:
- Number and nature (severity and seriousness) of ADRs and tolerability

Primary Efficacy End Point:
- Proportion of patients in whom at completion of study treatment period, a CBR (PR + CR + SD) is observed, based on RECIST.

Parte 1:
- Determinación de la MTD (Dosis Máxima Tolerada) y/o de la MRD (Dosis Máxima Recomendada) del MCLA-128.
- Evaluación de los acontecimientos adversos (AE, por sus siglas en inglés) y de las
toxicidades limitantes de dosis (DLT).

Parte 2:
Evaluación de Seguridad.
-Determinación de la MTD (Dosis Máxima Tolerada) y/o de la MRD (Dosis Máxima Recomendada) del MCLA-128.

Determinación Eficacia.
-Proporción de pacientes en los que a la finalización del periodo de tratamiento del estudio, un CBR (PR + CR + SD) basados en los criterios RECIST.

E.5.1.1

Timepoint(s) of evaluation of this end point

- Tumor assessment at Screening (up to 28 days prior to Cyc 1 D1), Cyc 2 D21; Cyc 4 D21, Cyc 5 onwards - after every 4 cyc D21, FSV, LTF
- AEs recorded at Cyc 1 D1, D2 - 4, D8, D15; Cyc 2-4 D1, D8 D15, D21; Cyc 5 onwards D1, D15, D21; EOT; FSV

- Evaluación del tumor en Screening (hasta 28 días antes de Cic 1 D1), Cic 2 D21; Cic 4 D21, Cic 5 en adelante – cada 4 ciclos D21, FSV, LTF.
- Acontecimientos Adversos registrados en Cic 1 D1, D2 - 4, D8, D15; Cic 2-4 D1, D8 D15, D21; Cyc 5 en adelante D1, D15, D21; EOT; FSV.

E.5.2

Secondary end point(s)

Part 1:
- Number and nature (severity and seriousness) of ADRs and tolerability
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Proportion of patients in whom at completion of study treatment period, a CBR (PR + CR + SD) is observed, based on RECIST
- Presence of biomarkers and pharmacodynamic (PD) responses to MCLA-128

Part 2:
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Proportion of patients in whom at completion of study treatment period, a CBR (PR + CR + SD) is observed, based on RECIST
- Presence of biomarkers and PD responses to MCLA-128

Parte 1:
-Evaluación de los acontecimientos adversos (AE, por sus siglas en inglés) y de las
toxicidades limitantes de dosis (DLT).
-Evaluación de las variables PK en MCLA-128.
-Immunogenicidad en MCLA-128.
-Proporción de pacientes en los que a la finalización del periodo de tratamiento del estudio, un CBR (PR + CR + SD) basados en los criterios RECIST.
-Presencia de biomarcadores y respuesta farmacodinámica en MCLA-128.

Parte 2:
- Evaluación de las variables PK en MCLA-128.
- Immunogenicidad en MCLA-128.
-Proporción de pacientes en los que a la finalización del periodo de tratamiento del estudio, un CBR (PR + CR + SD) basados en los criterios RECIST.
- Presencia de biomarcadores y respuesta farmacodinámica en MCLA-128.

E.5.2.1

Timepoint(s) of evaluation of this end point

- PK assessed at Cyc 1 D1, D2 - 4, D8, D15; Cyc 2-4 D1
- Immongenicity assessed at Cyc 1 D1; Cyc 2-4 D1; EOT; FSV
- Biomarker/PD: Biopsy assessed at Screening (up to 28 days prior to Cyc 1 D1), end of Cyc 2, EOT; Blood assessed at Cyc 1 D1 (pre-dose), end of Cyc 2, EOT
- Tumor assessment at Screening (up to 28 days prior to Cyc 1 D1), Cyc 2 D21; Cyc 4 D21, Cyc 5 onwards - after every 4 cyc D21, FSV, LTF
- AEs recorded at Cyc 1 D1, D2 - 4, D8, D15; Cyc 2-4 D1, D8 D15, D21; Cyc 5 onwards D1, D15, D21, EOT, FSV

-Farmacocinética en Cic 1 D1, D2 - 4, D8, D15; Cic 2-4 D1.
-Inmunogenicidad Ciclo 1 D1; Ciclo 2-4 D1, EOT, FSV.
-Biomarcadores/PD: Biopsia en el Screening (hasta 28 días antes del Cic 1 D1), final de Cic 2, EOT; Evaluación toma de Sangre a Cic 1 D1 (pre-dosis), al final del Cic 2, EOT.
-Evaluación del tumor en Screening (hasta 28 días antes de Cic 1 D1), Cic 2 D21; Cic 4 D21, Cic 5 en adelante - después cada 4 ciclos D21, FSV, LTF.
-Registro de Acontecimientos Adeversos en Cic 1 D1, D2 - 4, D8, D15; Cic 2-4 D1, D8 D15, D21; Cic 5 en adelante D1, D15, D21, EOT, FSV.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

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)

Yes

E.7.1.1

First administration to humans

Yes

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Part 2 is parallel design, Part 1 is not

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

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:

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

120

F.4.2.2

In the whole clinical trial

120

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients in both Parts 1 and 2 of the study may remain on treatment until disease progression, death, unacceptable toxicity, or discontinuation for any other reason. Following study completion, patients will be followed up every 3 months for up to 2 years (approximately) to check their disease and/or survival status and commencement of their next anticancer treatment. In case of treatment termination the investigator will discuss next treatment options outside of this study.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-01-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-22

P. End of Trial
P.	End of Trial Status	Ongoing

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