Clinical Trials Register

Summary
EudraCT Number:	2012-002361-36
Sponsor's Protocol Code Number:	ONCOSUR-2012-01
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:	2012-07-26
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

2012-002361-36

A.3

Full title of the trial

Neurotoxicity characterization phase II randomized study of nab-paclitaxel versus conventional paclitaxel as first-line therapy of metastatic HER2-negative breast cancer.

Ensayo fase II randomizado para la caracterización de la neurotoxicidad de nab-paclitaxel versus paclitaxel convencional en primera línea de cáncer de mama metastásico HER2-negativo.

A.3.1

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

Neurotoxicity characterization study of nab-paclitaxel versus conventional paclitaxel in metastatic breast cancer.

Ensayo para la caracterización de la neurotoxicidad de nab-paclitaxel versus paclitaxel convencional en cáncer de mama metastásico.

A.4.1

Sponsor's protocol code number

ONCOSUR-2012-01

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	ONCOSUR
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Celgene España S.L.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ONCOSUR
B.5.2	Functional name of contact point	Secretaria Técnica
B.5.3	Address:
B.5.3.1	Street Address	Avda. de Cordoba s.n. Hospital 12 de Octubre, Servicio de Oncología Médica
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28041
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34913908349
B.5.5	Fax number	+34914603310
B.5.6	E-mail	secretaria_tecnica@oncosurmadrid.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	Yes
D.2.1.1.1	Trade name	Abraxane
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Limited
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	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	PACLITAXEL
D.3.9.1	CAS number	33069-62-4
D.3.9.4	EV Substance Code	SUB09583MIG
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	5
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	Concentrate 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	PACLITAXEL
D.3.9.1	CAS number	33069-62-4
D.3.9.4	EV Substance Code	SUB09583MIG
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	6
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

Metastatic HER2-negative breast cancer

Cáncer de mama matastásico HER2-negativo

E.1.1.1

Medical condition in easily understood language

Breast cancer

Cáncer de mama matastásico

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic 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

To characterize neurotoxicity according to Total Neuropathy Score

Caracterizar la neurotoxicidad según la escala TNS (Total Neuropathy Score)

E.2.2

Secondary objectives of the trial

1. Evaluate the incidence of neuropathy induced by study treatment (conventional paclitaxel vs nab-paclitaxel)
2. Evaluate the electromyographic abnormalities and the correlation of these alterations with the assessment of the TNS scale and NCI-CTCAE v4.0
3. Determine the predictive value of genetic variants (SNPs) for the development of neuropathy
4. Determine the clinical activity of both treatments.
5. Determine toxicity profile and safety of study treatments.
6. Determine time to neurotoxicity onset
7. Determine time to recovery from neurotoxicity
8. Determine time to progression (RECIST v1.1)
9. Assess quality of live (EORTC QLQ-C30 and EORTC QLQ-CIPN20).

1.Evaluar la incidencia de neuropatía inducida por el tratamiento con nab-paclitaxel frente a paclitaxel convencional.
2. Evaluar las alteraciones electromiográficas y la correlación de dichas alteraciones con la valoración de la escala TNS y con el NCI-CTCAE v4.0.
3. Determinar el valor predictivo de las variantes genéticas (SNPs) para el desarrollo de neuropatía.
4. Evaluar la eficacia clínica de los diferentes esquemas.
5. Determinar el perfil de seguridad y toxicidad de los diferentes esquemas.
6. Determinar el tiempo hasta la aparición de neurotoxidad.
7. Determinar el tiempo hasta recuperación de la neurotoxicidad.
8. Determinar el tiempo hasta la progresión evaluado por los criterios RECIST V1.1.
9. Evaluar la Calidad de Vida a través de los cuestionarios EORTC QLQ-C30 y EORTC QLQ-CIPN20.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Women with histologically or cytologically of stage IV breast cancer.
2. Non-candidate patient to trastuzumab or lapatinib treatment as not presenting HER2 oncogene amplification.
3. Metastatic disease not previously treated with chemotherapy. It is allowed pre-treatment hormone with anti-target or bisphosphonates for advanced disease.
4. Measurable or evaluable disease by RECIST criteria.
5. Previous sensory neuropathy ≤ grade 1, according to NCI-CTCAE criteria, due to any reason.
6. Age> 18 years.
7. Performance status <2 (ECOG).
8. At least 12 months after the completion of adjuvant chemotherapy with taxanes to diagnosis of metastatic disease.
9. Creatinine ≤ 1.5mg/dL, AST (SGOT), ALT (SGPT) and alkaline phosphatase ≤ 2.5 x ULN (hepatic metastases absent) in the 14 days prior to study entry.
10. Hemoglobin> 10g/dl, WBC> 3000/mm3, platelets> 100000/mm3 and bilirubin <1.5 mg / dL in the 14 days prior to study entry.
11. Women of childbearing potential with negative pregnancy test within 14 days prior to study treatment.
12. Patients using adequate contraception throughout the entire duration of the study and until 4 weeks after completion of treatment.
13. At least 4 weeks after radiotherapy or major surgery, with complete recovery.
14. Life expectancy greater than 12 weeks.
15. Patients who are able to meet the requirements of the protocol.
16. Patients able to provide with two plasma samples (each sample 5cc) for analyzing polymorphirsms.
17. Written informed consent.

1. Mujeres con diagnóstico histológico o citológico de cáncer de mama estadio IV.
2. Paciente no candidata a tratamiento con trastuzumab o lapatinib por no presentar amplificación del oncogén HER2.
3. Enfermedad metastásica no previamente tratada con quimioterapia. Se permite el tratamiento previo hormonal, con fármacos anti-diana o con bifosfonatos para la enfermedad avanzada.
4. Enfermedad medible o evaluable según criterios RECIST.
5. Neuropatía sensorial previa grado ≤ 1, según los criterios NCI-CTCAE, por cualquier causa.
6. Edad > 18 años.
7. Estado funcional < 2 (ECOG).
8. Al menos 12 meses desde la finalización de quimioterapia adyuvante con taxanos hasta el diagnóstico de enfermedad metastásica.
9. Creatinina ≤ 1.5mg/dL; AST (SGOT), ALT (SGPT) y fosfatasa alcalina ≤ 2.5 x LSN (en ausencia de metástasis hepáticas) en los 14 días previos a la entrada en el estudio.
10. Hemoglobina > 10g/dL, leucocitos > 3000/mm3, plaquetas > 100000/mm3 y bilirrubina < 1.5 mg/dL en los 14 días previos a la entrada en el estudio.
11. Mujeres en edad fértil con test de embarazo negativo en los 14 días previos al inicio del tratamiento del estudio.
12. Pacientes que utilicen un método anticonceptivo adecuado a lo largo de toda la duración del estudio y hasta 4 semanas después de la finalización del tratamiento.
13. Al menos 4 semanas desde radioterapia o cirugía mayor, con recuperación completa.
14. Expectativa de vida superior a 12 semanas.
15. Pacientes que sean capaces de cumplir con los requerimientos del protocolo.
16. Pacientes con posibilidad de suministrar dos muestras de plasma (5cc cada muestra) para el análisis de polimosfirmos.
17. Consentimiento informado por escrito.

E.4

Principal exclusion criteria

1. Prior chemotherapy treatment for metastatic disease.
2. Brain metastases.
3. Concomitant treatment with hormone therapy or immunotherapy for breast cancer, or during the two weeks prior to inclusion in the study.
4. Any concomitant medical or psychiatric illness including active infection.
5. History of any malignancy other than breast cancer in the past 5 years except carcinoma or basal cell skin carcinoma or carcinoma in situ of cervix.
6. Prior treatment with an investigational drug within the last 2 weeks.
7. Known hypersensitivity to paclitaxel or Cremophor.
8. Pregnant or breastfeeding.
9. Have any acute, subacute or chronic peripheral nerve or spinal cord in grade, at the time of inclusion, greater than or equal to 2 (NCI CTC AE v4.0).

1. Tratamiento previo con quimioterapia para enfermedad metastásica.
2. Metástasis cerebrales.
3. Tratamiento concomitante con hormonoterapia o inmunoterapia para el cáncer de mama, o durante las dos semanas previas a la inclusión en el estudio.
4. Cualquier enfermedad intercurrente médica o psiquiátrica, incluyendo infección activa.
5. Historia de cualquier malignidad distinta de cáncer de mama en los últimos 5 años a excepción de carcinoma de piel de células basales o escamosas o carcinoma in situ de cérvix.
6. Tratamiento previo con un fármaco en investigación en las últimas 2 semanas.
7. Hipersensibilidad conocida a paclitaxel o Cremophor.
8. Mujeres embarazadas o en período de lactancia.
9. Haber sufrido cualquier enfermedad aguda, subaguda o crónica de los nervios periféricos o de la médula espinal en grado en el momento de la inclusión mayor o igual a 2 (NCI CTC AE v4.0).

E.5 End points

E.5.1

Primary end point(s)

Total Neuropathy Score

Puntuación de la escala TNS

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 12 weeks

Cada 12 semanas

E.5.2

Secondary end point(s)

1. Electromyographic alterations.
2. Cumulative dose of paclitaxel or nab-paclitaxel.
3. Assessment of neurotoxicity according to NCI-CTCAE v4.0 criteria.
4. Polymorphisms of cytochrome P450 (CYP2C8 and CYP3A5) and other genes (eg, ABCB1, RWDD3 and TECTA).
5. Classification of toxicity according to NCI CTCAE, version 4.0. The endpoint associated with toxicity will consist of the duration, intensity and time to onset of toxicity. The endpoints are safety adverse events of all kind, in addition to laboratory safety assessments, ECOG performance status and vital signs.

1. Alteraciones electromiográficas.
2. Dosis acumulada del fármaco paclitaxel o nab-paclitaxel.
3. Valoración de la neurotoxicidad según los criterios NCI-CTCAE v4.0.
4. Polimorfismos de enzimas del citocromo P450 (CYP2C8 y CYP3A5) y otros genes (por ejemplo, ABCB1, RWDD3 y TECTA).
5. Clasificación de la toxicidad con arreglo a CTCAE del NCI, versión 4.0. El criterio de valoración relacionado con la toxicidad estará formado por la duración, la intensidad y el tiempo hasta la aparición de la toxicidad. Los criterios de valoración de la seguridad serán los acontecimientos adversos de todo tipo, además de las valoraciones de laboratorio para seguridad, el estado funcional del ECOG y las constantes vitales.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Each 3 cycles
2. End of treatment
3. Every other week
4. Initial visit
5. Every other week

1. Cada tres ciclos
2. Al final del tratamiento
3. Cada dos semanas
4. Visita basal
5. Cada dos semanas

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

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)

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.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)

The expected normal treatment of that condition

El tratamiento habitual para la enfermedad

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

2012-10-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-10-09

P. End of Trial
P.	End of Trial Status	Completed

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