Clinical Trials Register

Summary
EudraCT Number:	2016-002678-11
Sponsor's Protocol Code Number:	ICO-13-001
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:	2018-04-09
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

2016-002678-11

A.3

Full title of the trial

An open label biomarker pilot study of the antitumoral acrivity of denosumab in the pre-operative setting of early breast cancer

Estudio piloto, abierto, de biomarcadores de la actividad antitumoral de denosumab en el cáncer de mama precoz.

A.3.1

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

An open label biomarker pilot study of the antitumoral acrivity of denosumab in the pre-operative setting of early breast cancer

Estudio piloto, abierto, de biomarcadores de la actividad antitumoral de denosumab en el cáncer de mama precoz.

A.4.1

Sponsor's protocol code number

ICO-13-001

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	Institut Català d’Oncologia
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	AMGEM
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	Institut Catala d'Oncologia
B.5.2	Functional name of contact point	Gestora de proyectos
B.5.3	Address:
B.5.3.1	Street Address	Av Gran Via 199-203
B.5.3.2	Town/ city	L’Hospitalet de Llobregat. - Barcelona
B.5.3.3	Post code	08908
B.5.3.4	Country	Spain
B.5.4	Telephone number	34932607139
B.5.6	E-mail	cmoreno2@iconcologia.net

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	DENOSUMAB
D.2.1.1.2	Name of the Marketing Authorisation holder	AMGEM Europe B.V.
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.3.1	Product name	Denosumab
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Denosumab
D.3.9.1	CAS number	615258-40-7
D.3.9.2	Current sponsor code	ICO-13-001
D.3.9.3	Other descriptive name	Inmunoglobin G2 Human Monoclonal Antibody to RANK Ligand
D.3.9.4	EV Substance Code	SUB29173
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	70
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

early breast cancer

cáncer de mama precoz

E.1.1.1

Medical condition in easily understood language

early breast cancer

cáncer de mama precoz

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 demonstrate the antiproliferative and/or pro-apoptotic activity of denosumab in early breast cancer.
If the Hypothesis of this study is proven right it will substantiate and provide rationale to the development of denosumab as an ant-cancer drug in breast cancer.

Demostrar la actividad antiproliferativa y/o proapoptótica del denosumab en el cáncer de mama precoz.
Si se demuestra la hipótesis de este estudio se podría sustanciar el inicio del desarrollo de denosumab como tratamiento antitumoral en cáncer de mama

E.2.2

Secondary objectives of the trial

• To correlate the antiproliferative/pro-apoptotic activity of denosumab with the expression of RANK, RANKL (protein expression) and RANK/RANKL modified ratio (mRNA).
• To characterize the differential antiproliferative/pro-apoptotic activity of denosumab among the different phenotypes of breast cancers.
• To characterize the differential antiproliferative/pro-apoptotic activity of denosumab among pre and post menopausal patients, and menstrual cycle in preneoplasic patients

• Correlacionar la actividad antiproliferativa/ proapoptótica del denosumab con la expresión de RANK, RANKL (expresión protéica) y RANK/RANKL ratio modificado (mRNA).
• Caracterizar las diferencias en la actividad antiproliferativa/proapoptótica del denosumab entre los dife-rentes fenotipos del cáncer de mama.
• Caracterizar las diferencias en la actividad antiproliferativa/proapoptótica del denosumab entre pacientes pre y postmenopáusicas y en el ciclo menstrual en las pacientes premenopaúsicas.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

 Understand and sign Informed Consent for this study.
 Women ≥ than 18 years, (the inclusion process will be modified to recruit at least 24 premenopausal patients).
 Capable, under investigator judgment, to understand the non-therapeutic nature of the study.
 Diagnosed with invasive breast cancer in early, curable, stage (I or II) candidate to radical surgery as first therapeutic approach.
 Her2 negative receptor status.
 Any estrogen, progesterone status (the inclusion process will be modified to recruit at least 24 patients with TNBC tumors).
 No previous systemic treatment for any malignancy.
 No ongoing treatment with denosumab or bisphosphonates
 Tumour amenable for baseline Biopsy and punch-Biopsy after excision.
o Adequate Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL)
o No prior history or current evidence of osteonecrosis of the jaw
o No Active dental or jaw condition which requires oral surgery, including tooth extraction. No planned invasive dental procedures
 General Laboratory test within normality or with non-relevant deviations of normality as per investigator judgment
 Patients must have a normal organ and bone marrow function as defined local standards: Leukocytes, Absolute neutrophil count, Platelets, Total bilirubin, AST/ALT/GOT/GPT, Creatinine, Creatinine clearance, Magnesium, Phosphorus.
 Subject with reproductive potential must be willing to use, in combination with her partner, 2 acceptable methods of effective contraception or practice sexual abstinence throughout the study and continue for 6 months after study duration. Subjects who are surgically sterile (eg. history of bilateral tubal ligation, hysterectomy) or whose sexual partner is sterile (eg. history of vasectomy) are not required to use additional contraceptive measures”.

 Comprender y firmar en consentimiento informado de este estudio.
 Mujeres ≥ de 18 años, (el proceso de inclusión será modificado para reclutar al menos 24 pacientes premenopaúsicas)
 Los sujetos deberán ser capaces, a juicio del investigador, de comprender la naturaleza no terapéutica del estudio.
 Diagnóstico de neoplasia de mama invasiva precoz (estadios I y II), candidatas a escisión tumoral como primera maniobra terapéutica.
 Neoplasias de mama.
 Cualquier estatus de los receptores de estrógenos y progesterona (el proceso de inclusión será modificado para reclutar al menos 24 pacientes con neoplasia de mama triple negativa).
 No tratamientos previos sistémicos por cáncer.
 No tratamientos en el momento de la inclusión con bifosfonatos o denosumab.
 Tumor en el que sea posible realizar una biopsia basal y una biopsia de la pieza quirúrgica tras la escisión.
 No historia previa o actual de osteonecrosis de la mandíbula.
 No existencia de procesos/ enfermedades activas o no que requieran cirugía, incluyendo extracciones dentales. No previsión de realización de procedimientos dentales invasivos.
 Valores generales analíticos de laboratorio en el rango de la normalidad o con desviaciones no relevantes de la normalidad a juicio del investigador.
o Cifras adecuadas de calcio en suero o calcio sérico ajustado por albumina ≥2.0 mmol/L (8.0 mg/dL) y ≤ 2.9 mmol/L (11.5 mg/dL)
o Función orgánica y de médula ósea normal, definida según los estándares locales: leucocitos, recuento total de neutrófilos, plaquetas, bilirrubina total, AST/ALT/GOT/GPT, Creatinina, Aclara-miento de creatinina, magnesio y fósforo.
 Los sujetos en edad fértil, deberán estar dispuestos a utilizar, junto con su pareja, 2 aceptables métodos contraceptivos, o practicar la abstinencia sexual a lo largo del estudio y tras 6 meses de la finalización de la participación de la paciente en el mismo. Los sujetos estériles por procedimientos quirúrgicos 8 ligadura de trompas, histerectomía) o aquellos cuya pareja es estéril (p.e. vasectomía) no requieren tomar medidas contraceptivas adicionales.

E.4

Principal exclusion criteria

 Invasive breast cancer non amenable to surgical excision as first therapeutic approach.
 HER2-positive Breast Cancer
 Metastatic breast cancer or other condition that recommends other treatment than surgery as the primary therapeutic approach.
 Prior systemic treatment for any malignancy.
 Treatment with denosumab contraindicated.
 Bleeding diathesis or other concomitant condition that contraindicate inclusion in the study as per investigator judgment.
 High risk of ONJ or hypocalcemia:
o Inadequate Serum calcium or albumin-adjusted serum calcium < 2.0 mmol/L (8.0 mg/dL) or > 2.9 mmol/L (11.5 mg/dL)
o Prior history or current evidence of osteonecrosis of the jaw
 Active dental or jaw condition which requires oral surgery, including tooth extraction. Planned invasive dental procedures.
 Subject has known sensitivity to any of the products to be administered during the study (e.g., mammalian derived products, calcium, or vitamin D).
 Subject is pregnant or breast feeding, or planning to become pregnant / breastfeed while on study through 6 months after the end of treatment.
 Subject is of child bearing potential and is not willing to use, in combination with her partner, two highly effective methods of contraception or abstinence during treatment and for 5 months after the end of treatment.
 Patients have prior history or current evidence of osteonecrosis or osteomyelitis of the jaw.
 Patients have active dental or jaw condition which requires oral surgery, including tooth extraction.
 Patients have non-healed dental or oral surgery, including tooth extraction.
 Patients with planned invasive dental procedures for the course of the study.
 Ongoing treatment with denosumab or bisphosphonates

 Diagnóstico de cáncer de mama invasivo no candidato a escisión quirúrgica como primera aproximación terapeútica.
 Cáncer de mama HER-2 positivo.
 Cáncer de mama metastasico u otra condición, que recomiende otra aproximación terapéutica inicial diferente a la quirúrgica.
 Tratamiento previo sistémico por cáncer.
 Tratamiento con denosumab o bifosfonatos previos o concurrentes están contraindicados.
 Diátesis sanguínea u otra condición concomitante que contraindique la inclusión en el estudio a juicio del investigador
 Riesgo elevado de osteonecrosis de la mandibular o hypocalcemia:
o Niveles séricos de calcio o de calcio ajustado por albumina < 2.0 mmol/L (8.0 mg/dL) o > 2.9 mmol/L (11.5 mg/dL)
o Historia previa o concurrente de osteonecrosis de la mandibular.
 Existencia de procesos/ enfermedades activas dentales o en la mandíbula que requieran cirugía, incluyendo extracciones dentales. Previsión de realización de procedimientos dentales invasivos.
 Sensibilidad conocida a cualquiera de los productos / fármacos administrados en el estudio (Productos derivados de mamíferos, calcio, vitamina D…)
 Candidata embarazada o lactando, o con deseos genésicos o de lactar inminentes durante el periodo del estudio o tras 6 meses de concluir su participación en el mismo.
 Subject is of child bearing potential and is not willing to use, in combination with her partner, two highly effective methods of contraception or abstinence during treatment and for 5 months after the end of treatment.
 No historia previa o actual de osteonecrosis u osteomielitis de la mandíbula

E.5 End points

E.5.1

Primary end point(s)

The endpoint to evaluate will be changes in the percentage of tumor cells expressing Ki67 and cleaved caspase 3 between Biopsy A and Biopsy B.

Cambios en el porcentaje de células tumorales que expresan Ki67 y /o cleaved caspasa 3 entre la Biopsa A y la Biopsia B.

E.5.1.1

Timepoint(s) of evaluation of this end point

Tras el tratamiento en el momento de la cirugia

E.5.2

Secondary end point(s)

•Ratio modificado: MR={log(RANK) ‐1.2} / log(RANKL) mRNA
•Correlacionar los cambios en Ki67 con la expresión RANKL, RANK (mRNA y proteínas).
•Correlacionar los cambios en Ki67 con la expresión de los receptores de estrógenos y progesterona. La seguridad del denosumab y de la realización de las biopsias según los criterios del CTCAE v4.

E.5.2.1

Timepoint(s) of evaluation of this end point

Tras el tratamiento en el momento de la cirugía

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

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

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

LPLV

última visita último 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:

F.1.3

Elderly (>=65 years)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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 usual for this type of patients

los habituales para este tipo de pacientes

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

2018-06-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-10

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

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