Clinical Trials Register

Summary
EudraCT Number:	2013-000684-85
Sponsor's Protocol Code Number:	PR-30-5010-C
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:	2014-01-30
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2013-000684-85

A.3

Full title of the trial

A phase III, randomized, open label, multicenter, controlled trial of niraparib versus physician's choice in previously-treated, HER2 negative, germline BRCA mutation-positive breast cancer
patients

Ensayo controlado de fase III, aleatorizado, abierto y multicéntrico, de niraparib frente al tratamiento elegido por el médico en pacientes con cáncer de mama HER2 negativo y positivo para la mutación de la estirpe germinal del BRCA, previamente tratados

A.3.1

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

A controlled study with Niraparib versus physician's choice in patients with previously-treated, HER2 negative, BRCA mutation-positive breast cancer

Ensayo controlado de niraparib frente al tratamiento elegido por el médico en pacientes previamente tratados, HER2 negativo, con cáncer de mama con mutación-positiva BRCA

A.4.1

Sponsor's protocol code number

PR-30-5010-C

A.5.4

Other Identifiers

Name:

IND No.

Number:

117580

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	TESARO Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	TESARO Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	TESARO Inc.
B.5.2	Functional name of contact point	Robert Martell
B.5.3	Address:
B.5.3.1	Street Address	1000 Winter Street North #3300
B.5.3.2	Town/ city	Waltham
B.5.3.3	Post code	02451
B.5.3.4	Country	United States
B.5.4	Telephone number	17813251234
B.5.5	Fax number	13392303971
B.5.6	E-mail	rmartell@tesarobio.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	Niraparib
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	Niraparib
D.3.9.1	CAS number	1038915-60-4
D.3.9.2	Current sponsor code	L-001946812-005R, L-001946812 and MK-4827
D.3.9.3	Other descriptive name	NIRAPARIB
D.3.9.4	EV Substance Code	SUB93448
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	100
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.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form
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	VINORELBINE
D.3.9.1	CAS number	71486-22-1
D.3.9.4	EV Substance Code	SUB00069MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	80
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form
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	GEMCITABINE
D.3.9.1	CAS number	95058-81-4
D.3.9.4	EV Substance Code	SUB07892MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form
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	Capecitabine
D.3.9.1	CAS number	154361-50-9
D.3.9.3	Other descriptive name	CAPECITABINE
D.3.9.4	EV Substance Code	SUB12474MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	2500
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	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form
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	ERIBULIN
D.3.9.1	CAS number	253128-41-5
D.3.9.4	EV Substance Code	SUB31134
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	1.23
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

HER2 negative, BRCA germline mutated breast cancer

Cáncer de mama HER2 negativo y positivo para la mutación de la estirpe germinal del BRCA

E.1.1.1

Medical condition in easily understood language

HER2 negative, BRCA mutation-positive breast cancer

Cáncer de mama HER2 negativo y positivo para la mutación de la estirpe germinal del BRCA

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	PT
E.1.2	Classification code	10006187
E.1.2	Term	Breast cancer
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

The primary objective of this study is to compare progression-free survival (PFS), as assessed by blinded central review, of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer when treated with niraparib as compared to those treated with physician?s choice single agent chemotherapy standards (eribulin, vinorelbine, gemcitabine or capecitabine).

El objetivo principal de este estudio es comparar la supervivencia sin progresión (SSP), evaluada mediante revisión "ciega" central, de los pacientes con cáncer de mama gBRCAmut HER2-negativo avanzado/metastásico tratados con niraparib frente a los tratados con la monoquimioterapia estándar elegida por el médico (eribulina, vinorelbina, gemcitabina o capecitabina).

E.2.2

Secondary objectives of the trial

(1) Key Secondary Objective: To compare overall survival of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer when treated with niraparib as compared to those treated with physician's choice single agent chemotherapy standards.
(2) Other Secondary Objectives:
- To evaluate safety and tolerability as measured by all AEs
- To compare PFS using investigator assessment of progression
- To evaluate time to treatment failure
- To compare response rate and duration of response
- To compare time to deterioration of health-related quality of life (HRQoL)
- To describe subsequent therapies and potential relationships with outcomes
- To assess genetic and non-genetic biomarkers relating to treatment efficacy.
- To assess outcomes by germline mutation BRCA1 vs BRCA2

(1) Objetivo Secundario Clave: Comparar la supervivencia global de los pacientes con cáncer de mama gBRCAmut HER2-negativo avanzado/metastásico tratados con niraparib frente a los tratados con la monoquimioterapia estándar elegida por el médico.
(2) Otros Objetivos Secundarios:
- Evaluar la seguridad y tolerabilidad, en su medición a través de todos los acontecimientos adversos
- Comparar la SSP, utilizando la evaluación de la progresión por el investigador
- Evaluar el tiempo hasta el fracaso del tratamiento
- Comparar la tasa de respuesta y la duración de la respuesta
- Comparar el tiempo hasta el deterioro de la calidad de vida relacionada con la salud (HRQoL)
- Describir los tratamientos posteriores y su posible relación con los desenlaces terapéuticos
- Evaluar los biomarcadores, genéticos y no genéticos, que puedan estar relacionados con la eficacia del tratamiento
- Evaluar la mutación de la estirpe germinal del BRCA1 vs BRCA2

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically or cytologically confirmed HER2-negative metastatic or locally advanced breast cancer that is not amenable to resection or radiation with curative intent.
2. Female and male patients age at least 18 years.
3. Germline BRCA1 or BRCA2 mutation that is considered deleterious or suspected deleterious (include those mutations or translocations termed "deleterious" or "suspected deleterious" according to Myriad reporting) by analysis at a reference laboratory (Myriad Genetic Laboratories, Salt Lake City, UT, USA, or Myriad GmbH, Martinsried, Germany).
4. Measurable disease by RECIST v1.1 or non- measurable disease that is clinically evaluable (except sclerotic-only bone disease; bone-only disease that has a lytic component is allowed).
5. Patients must not have symptomatic uncontrolled brain metastases To be considered controlled, central nervous system (CNS) disease must have undergone treatment (whole brain radiation, radiosurgery or equivalent) at least 1 month previously and the patient has no new or progressive signs or symptoms related to the CNS disease, and are off steroid therapy two weeks.
6. Up to 2 prior cytotoxic regimens for advanced or metastatic breast cancer (not including adjuvant or neo-adjuvant therapy); patients with no prior cytotoxic regimens for advanced or metastatic disease will only be allowed if they relapsed during or within 12 months of (neo-) adjuvant cytotoxic therapy that included a taxane and anthracycline, if not contraindicated.
7. Prior therapy should have included an anthracycline and a taxane (unless contraindication to those) in the neoadjuvant, adjuvant, or advanced/metastatic setting.
a. Hormone receptor positive patients must also have hormone resistant disease (progression during at least one prior hormonal therapy) for which chemotherapy is indicated.
8. Patients must not have received anticancer chemotherapy, radiotherapy, hormonal therapy, biological therapy, or any other investigational therapy within 3 weeks prior to the start of study treatment. Patients with persistent toxicity (except alopecia) > grade 1 from prior cancer therapy will also be excluded. Bisphosphonate and denosumab is allowed.
9. No prior treatment with a known or putative PARP inhibitor (except iniparib). No other anticancer agent (chemotherapy, hormonal therapy, or other agent) is to be permitted during the course of the study for any patient.
10. Patients must not be platinum resistant defined as: progression of cancer during or within 6 months of completion of prior platinum treatment.
11. ECOG performance status 0-2 (Appendix G).
12. Adequate organ function (assessed within 72 hours prior to the first dose):
a. Absolute neutrophil count (ANC) ? 1,500 cells/?L
b. Platelets ? 100,000 cells/?L
c. Hemoglobin ? 9 g/dL
d. Serum creatinine ? 1.5 × upper limit of normal (ULN) or ? 60 mL/min using Cockcroft-Gault equation
e. Total bilirubin ? 1.5 × ULN OR direct bilirubin ? ULN
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ? 2.5 × ULN or < 5 × ULN with liver metastases
13. Patients able to swallow and retain oral tablets
14. Female patients must not be pregnant or breast feeding
a. Female patient of childbearing potential must have a negative serum pregnancy test.
15. Patients of child bearing potential and their partners with whom they are sexually active must agree to the use of 2 highly effective forms of contraception from randomization, throughout the study and until 3 months after the last dose of study drug.
16. No known hypersensitivity to the components of niraparib or any of its analogs.
17. No major surgery within 2 weeks prior to registration. Patients must have recovered from earlier major surgery before registration.
18. No prior diagnosis of Stage IV ovarian cancer
-Patients with history of Stage III ovarian cancer must have a 5-year disease-free interval and a normal serum carcinoma antigen 125 (CA125)
-Patients with Stage I or II ovarian cancer must have a disease-free interval of 2 years and a normal serum carcinoma antigen 125 (CA 125)
19. No prior diagnosis, detection, or treatment of invasive cancer other than breast cancer within 2 years (except basal or squamous cell carcinoma of the skin that has been definitively treated)
20. Patients must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection.

1. Cáncer de mama HER2-negativo, metastásico o localmente avanzado, confirmado histológica o citológicamente, no susceptible de resección o de radioterapia con intención curativa.
2. Mujeres y hombres de como mínimo 18 años de edad.
3. Mutación de la estirpe germinal del BRCA1 o del BRCA2 que se considera deletérea o que se sospecha que es deletérea (comprende las mutaciones o translocaciones denominadas "deletéreas" o "presuntamente deletéreas", de acuerdo al resultado de Myriad) por análisis en un laboratorio de referencia.
4. Enfermedad medible por RECIST v1.1 o enfermedad no medible que es clínicamente evaluable (excepto la enfermedad solamente ósea de tipo escleroso; se permite la enfermedad solamente ósea que tiene un componente lítico).
5. Pacientes no podrán tener metástasis cerebrales sintomáticas no controladas. Para que pueda ser considerada como controlada, la enfermedad en sistema nervioso central (SNC) deberá haber recibido tratamiento (radioterapia cerebral total, radiocirugía o equivalente) como mínimo 1 mes antes y el paciente no presenta signos o síntomas nuevos o progresivos de enfermedad en SNC, y no ha recibido corticosteroides en las dos últimas semanas.
6. Un máximo de 2 regímenes citotóxicos previos por cáncer de mama avanzado o metastásico (no se incluye la terapia adyuvante o neoadyuvante); sólo se permitirán pacientes sin regímenes citotóxicos previos por enfermedad avanzada o metastásica si han presentado recidiva durante o en el plazo de los 12 meses siguientes a una terapia citotóxica (neo)adyuvante que incluía un taxano y una antraciclina, si no estaban contraindicados.
7. El tratamiento previo deberá haber incluido un antraciclina y un taxano (salvo en caso de contraindicación) en el marco neoadyuvante, adyuvante o por enfermedad avanzada/metastásica.
a. Los pacientes con receptores hormonales positivos deberán presentar también enfermedad hormonorresistente (progresión durante como mínimo una terapia hormonal previa) para la que está indicada quimioterapia.
8. Pacientes no deberán haber recibido quimioterapia, radioterapia, hormonoterapia, terapia biológica o cualquier otro tratamiento antineoplásico experimental en el plazo de las 3 semanas previas al comienzo del tratamiento del estudio. Tampoco podrán participar los pacientes con toxicidad persistente (excepto alopecia) de grado > 1 consecuencia del tratamiento antineoplásico anterior. Se permiten los bisfosfonatos y el denosumab.
9. No se permite el tratamiento previo con un inhibidor conocido o posible de la familia de las PARP (excepto iniparib). No se permite durante el curso del estudio en ningún paciente ningún otro tratamiento antineoplásico (quimioterapia, hormonoterapia u otro agente).
10. Pacientes no deberán presentar resistencia al platino, definida como: progresión del cáncer durante o en el plazo de los 6 meses siguientes a la finalización del tratamiento con platino previo.
11. Estado funcional del ECOG 0-2 (Apéndice G).
12. Función orgánica adecuada (evaluada en el plazo de las 72 horas previas a la primera dosis):
a. Recuento absoluto de neutrófilos (RAN) ? 1.500/?L
b. Plaquetas ? 100.000/vL
c. Hemoglobina ? 9 g/dL
d. Creatinina sérica ? 1,5 × límite superior de la normalidad (LSN) o ? 60 mL/min utilizando la fórmula de Cockcroft-Gault
e. Bilirrubina total ? 1,5 × LSN o bilirrubina directa v LSN
f. Aspartato transaminasa (AST) y alanina transaminasa (ALT) v 2,5 × LSN, o < 5 × LSN en caso de metástasis hepáticas
13. Pacientes deben ser capaces de deglutir y retener los comprimidos orales.
14. Las pacientes no deben estar embarazadas o en período de lactancia
a. Las pacientes potencialmente fértiles deben tener un resultado negativo en una prueba de embarazo en suero.
15. Las pacientes potencialmente fértiles y las parejas con las que tengan relaciones sexuales deberán mostrar su conformidad en utilizar 2 métodos anticonceptivos altamente eficaces a partir de la aleatorización, a lo largo del estudio y hasta 3 meses después de la última dosis del fármaco del estudio.
16. No hipersensibilidad conocida a los componentes del niraparib o de cualquiera de sus análogos.
17. No cirugía mayor en las dos semanas anteriores al registro. Los pacientes deberán haberse recuperado de cualquier cirugía mayor antes del registro en el estudio.
18. No diagnóstico previo de cáncer de ovario en Estadio IV.
- Pacientes con antecedentes de cáncer de ovario en Estadio III deberán encontrarse libres de enfermedad desde hace como mínimo 5 años
-Pacientes con antecedentes de cáncer de ovario en Estadios I o II deberán encontrarse libres de enfermedad desde hace como mínimo 2 años
19. No diagnóstico, detección o tratamiento previos de un cáncer invasivo distinto del carcinoma de mama en los 2 años anteriores.
20. Los pacientes no deberán considerarse de mal riesgo médico debido a un trastorno médico grave no controlado, enfermedad sistémica no maligna o infección activa no controlada.

E.4

Principal exclusion criteria

No exclusion criteria are defined per protocol

No están definidos criterios de exclusión en el Protocolo

E.5 End points

E.5.1

Primary end point(s)

Progression free survival per central review

Supervivencia sin progresión de acuerdo a la revisión central

E.5.1.1

Timepoint(s) of evaluation of this end point

Per Protocol

Por Protocolo

E.5.2

Secondary end point(s)

1. Overall survival.
2. Determine concordance between gBRCAmut tests for the purpose of developing a commercial companion diagnostic test.
3. Safety and tolerability, as documented by AEs and laboratory values
4. PFS using investigator assessment of progression
5. Time to treatment failure
6. Response rate and duration of response
7. Health-related quality of life: QLQ-C30 and EQ5D-5L (see chapter 10).
8. Subsequent therapies and potential relationships with outcomes
9. To assess outcomes by germline mutation BRCA1 vs BRCA2

1. Supervivencia global.
2. Determinación de la concordancia entre las pruebas de gBRCAmut a fin de desarrollar una prueba diagnóstica complementaria a comercializar.
3. Seguridad y tolerabilidad, documentadas por los acontecimientos adversos y los valores de laboratorio
4. SSP, utilizando la evaluación de progresión según el investigador
5. Tiempo hasta el fracaso del tratamiento
6. Tasa de respuesta y duración de la respuesta
7. Calidad de vida relacionada con la salud: QLQ-C30 y EQ5D-5L (véase la sección 10).
8. Tratamientos posteriores y posible relación con el desenlace clínico
9. Evaluación de los desenlaces clínicos según mutación de la estirpe germinal de BRCA1 vs BRCA2

E.5.2.1

Timepoint(s) of evaluation of this end point

Per Protocol

Por Protocolo

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

Belgium

Canada

France

Greece

Italy

Netherlands

Portugal

Hungary

Iceland

Spain

Israel

Poland

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

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

End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of overall survival as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis

El fin del estudio tendrá lugar cuando se hayan cumplido todos los criterios siguientes:
1. Han transcurrido 30 días de la suspensión del tratamiento del protocolo por todos los pacientes
2. El ensayo se encuentra maduro para el análisis de la supervivencia global de acuerdo a su definición por el protocolo
3. Se ha limpiado por completo y se ha congelado la base de datos para este análisis

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:

153

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

153

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

190

F.4.2.2

In the whole clinical trial

306

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)

At the description of the investigator

Según criterio del investigador

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Breast International Group (BIG)
G.4.3.4	Network Country	Belgium

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-03-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-03-07

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

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