Clinical Trials Register

Summary
EudraCT Number:	2012-005213-39
Sponsor's Protocol Code Number:	CJP4.2
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-04-16
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

France - ANSM

A.2

EudraCT number

2012-005213-39

A.3

Full title of the trial

Phase II pilot study assessing efficacy of a Cisplatine – Métronomic
Cyclophosphamide treatment in Patients with Stade IV Triple Negative
breast Cancer Secondary Resistant to Anthracyclines and Taxanes

Etude Pilote de Phase II évaluant l’Efficacité d’un Traitement par Cisplatine – Cyclophosphamide Métronomique Oral chez des Patientes atteintes d’un Cancer du Sein de Stade IV de type Triple Négatif présentant une Résistance Secondaire aux Anthracyclines et Taxanes

A.3.1

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

Study assessing efficacy of a Cisplatine – Métronomic yclophosphamide
treatment in Patients with Metastatic Triple Negative breast Cancer
Secondary Resistant to Anthracyclines and Taxanes

Etude évaluant l'Efficacité d'un Traitement par Cisplatine –
Cyclophosphamide Métronomique Oral chez des Patientes Atteintes d'un
Cancer du Sein Métastatique de Type Triple Négatif présentant une Résistance Secondaire aux Anthracyclines et Taxanes

A.3.2

Name or abbreviated title of the trial where available

META2

A.4.1

Sponsor's protocol code number

CJP4.2

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	CENTRE JEAN PERRIN
B.1.3.4	Country	France
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	CENTRE JEAN PERRIN
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CENTRE JEAN PERRIN
B.5.2	Functional name of contact point	JEAN-MARC NABHOLTZ
B.5.3	Address:
B.5.3.1	Street Address	58, rue Montalembert
B.5.3.2	Town/ city	Clermont-Ferrand
B.5.3.3	Post code	63001
B.5.3.4	Country	France
B.5.4	Telephone number	+33473278482
B.5.5	Fax number	+33473278029
B.5.6	E-mail	jmnabholtz@cjp.fr

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	CISPLATIN
D.2.1.1.2	Name of the Marketing Authorisation holder	SANDOZ
D.2.1.2	Country which granted the Marketing Authorisation	France
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	CISPLATIN
D.3.4	Pharmaceutical form	Concentrate and solvent 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	CISPLATIN
D.3.9.3	Other descriptive name	CISPLATIN
D.3.9.4	EV Substance Code	SUB07483MIG
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	75
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	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	CYCLOPHOSPHAMIDE
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER
D.2.1.2	Country which granted the Marketing Authorisation	France
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	CYCLOPHOSPHAMIDE
D.3.4	Pharmaceutical form	Tablet
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	CYCLOPHOSPHAMIDE
D.3.9.1	CAS number	50-18-0
D.3.9.4	EV Substance Code	SUB06859MIG
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	2100
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

Triple negative metastatic breast cancer resistant secondary to anthracyclines and taxanes

Cancer du sein métastatique triple négatif résistant secondairement aux anthracyclines et taxanes

E.1.1.1

Medical condition in easily understood language

Triple negative metastatic breast cancer

Cancer du sein métastatique

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	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

To evaluate response rate of cisplatine - metronomic cyclophosphamide
treatment

Evaluer les taux de réponse d'un traitement à base de cisplatine et
cyclophosphamide métronomique oral

E.2.2

Secondary objectives of the trial

To evaluate disease free progression
To determine safety profile of cisplatine - metronomic cyclophosphamide association
To determine overall survival

Evaluer la survie sans progression
Déterminer le profil de tolérance de l'association cisplatine/cylclophosphamide métronomique oral
Déterminer la survie globale

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age > 18 ans,
Performance status < 2,
Patient with metastatic breast cancer stade IV triple negative
histologically confirmed
Mesurable or not disease but radiologically evaluable (RECIST 1.1),
Negative Hormonal Receptors (Estrogens and/or Progesterone),
HER-2 negative (Score 0 or 1 by Immunochemistry (IHC), negative FISH if score IHC 2),
Patient exposed to anthracyclines and/or taxanes in neo-adjuvant or adjuvant setting,
Patient with a progression and for whom anthracyclines and/or
taxanes treatment cannot be delivered and according to a resistance defined as :
- In the last 12 months after the last dose of taxanes or anthracyclines in adjuvant or neoadjuvant setting or,
- During or after a first metastatic chemtotherapy line and where taxanes and anthracyclines cannot be delivered according to :
- either a secondary resistance after an initial response to chemotherapy but a relapse observed either during the treatment or in the 4 months after the end of chemotherapy.
- either a sensitivity to treatment defined by a relapse after more than 4 months after the first chemotherapy metastatic line,
- either intolerance to anthracyclines (doxorubicin 240-400 mg/m² ou equivalent to doxorubicin (epirubicin) 300-550mg/m²)
Patient non previously treated by platinum salts,
Hematological Functions: Neutrophiles ≥ 1,5.109/L, Platelets ≥
100.109/L, Leucocytes > 3 000/mm3, Hb > 9g/dL,
Hepatic Functions : total Bilirubin ≤ 1,5 time upper normal value (UNV), ASAT ≤ 2 ,5 time UNV, ALAT ≤ 2,5 time UNV, Alcaline Phosphatase ≤ 2,5 time UNV (< 5 time UNV if case of hepatic metastasis),
Renal Functions: Serum Creatinine ≤ 1,5 time UNV (and if value > 1,5 time UNV, so Clearance ≥ 50 mL/min) or Clearance ≥ 40 mL/min in case of RMI,
Patient signed the consent study form,
Patient affilated to a social security regimen (law of 9 August 2004).

Age > 18 ans,
Statut de Performance < 2 (selon les critères de l’OMS),
Patiente atteinte d’un cancer du sein métastatique de stade IV de type triple négatif histologiquement confirmé,
Maladie mesurable ou non mais évaluable sur le plan radiologique (RECIST 1.1),
Récepteurs Hormonaux (Œstrogènes et/ou Progestérone) négatifs,
HER-2 négatif (Score 0 ou 1 en Immuno-histochimie (IHC), FISH négatif si score IHC 2),
Ayant reçu une chimiothérapie à base d’anthracyclines et/ou de taxanes en traitement néo-adjuvant ou adjuvant,
Ayant présenté une progression et n’étant plus candidate à une chimiothérapie par taxanes et anthracyclines soit :
o Dans les 12 mois suivant la dernière dose de taxanes ou d'anthracyclines en situation adjuvante ou néoadjuvante,
o Pendant ou après une chimiothérapie de 1ère ligne métastatique et n’étant plus candidate à une chimiothérapie par taxanes et anthracyclines selon :
- Une résistance secondaire après réponse initiale à la chimiothérapie, rechute survenant soit pendant la chimiothérapie ou dans les 4 mois suivant la fin de la chimiothérapie.
- Sensibilité: rechute survenant plus de 4 mois après la fin d’une chimiothérapie de 1ère ligne
- Pour intolérance à l’une de ces médications selon une dose cumulée d’anthracyclines : doxorubicine 240-400 mg/m² ou équivalents doxorubicine (épirubicine) 300-550mg/m²
Patiente non préalablement traitée par sels de platine,
Fonctions Hématologiques : Neutrophiles ≥ 1,5.109/L, Plaquettes ≥ 100.109/L, Leucocytes > 3 000/mm3, Hb > 9g/dL,
Fonctions Hépatiques : Bilirubine totale ≤ 1,5 fois la valeur supérieure normale (VSN), ASAT ≤ 2 ,5 fois VSN, ALAT ≤ 2,5 fois VSN, Phosphatases Alcalines ≤ 2,5 fois VSN,
Fonctions Rénales : Créatinine Sérique ≤ 1,5 fois VSN (et si valeur > 1,5 fois VSN, alors Clairance ≥ 50 mL/min) ou Clairance ≥ 40 mL/min en cas d’IRM,
Patiente ayant signé le formulaire de consentement et de participation à l’étude,
Patiente affiliée à un régime de Sécurité Sociale (loi du 9 Août 2004).

E.4

Principal exclusion criteria

Male Patients,
Unknown hormonal Receptors
Positive HER-2 (Score 3 in IHC or positive FISH)
Pregnant or breastfeeding patient, or in age of pregnancy or predicting to be pregnant in the 6 months after the end of treatment,
Patient not using contraceptive treatment during the treatment or after the 6 months after the end of treatment,
Patient is a ward,
Patient suffering from a non compatible disease with the enrollment in the study,
Cardiac, renal, medullar, respiratory or hepatic insuffisancy,
clinically significant cardiovascular disease (including myocardic
infarctus, unstable angina, symptomatic congestive heart failure,
uncontrolled cardiac arrhythmia) < 1 year before the study enrollment or randomisation,
Patient with pulmonary lymphangitis or symptomatic pleural effusion (grade≥2), meningeal known carcinoma or symptoms of cerebromeningeal invasion, brain metastases unless treatment and stability for at least 4 weeks (no steroids or anti-convulsives).
Uncontrolled diabetes,
Psychiatric or neurological significant abnormality,
Peripheric Neuropathy > grade 2,
Antecedent of hypersensibility to one of study treatment or one of used excipients,
Urinary tract infection or acute hemorrhagic cystitis in progress
Concomitant treatment with a medicine containing phenytoin or
medication received in the context of a trial, or participation in another therapeutic clinical trial within <30 days prior treatment with chemotherapy.
Geographically unstable patient in the next 6 months or remaining
distance to the treatment center making it difficult to follow in the study,
Known history of abuse of narcotic or other drug or alcohol
History of surgery within 28 days before the start of treatment,
Patient unwilling or unable to comply with the requirements of the
study.

Patients de sexe masculin,
Récepteurs Hormonaux inconnus
HER-2 positif (Score 3 en IHC ou FISH positif)
Patiente enceinte ou allaitant, ou en âge de procréer ou prévoyant d'être enceinte dans les 6 mois après la fin du traitement,
Patiente n'utilisant pas de moyen efficace de contraception pendant le traitement et durant les 6 mois après la fin du traitement,
Patiente sous tutelle,
Patiente atteinte de toute autre maladie non compatible avec l'inclusion dans le protocole,
Insuffisance cardiaque, rénale, médullaire, respiratoire ou hépatique,
Maladie cardiovasculaire jugée comme cliniquement significative
(incluant un infarctus du myocarde, une angine instable d'angor, une insuffisance cardiaque congestive symptomatique, une arythmie cardiaque non contrôlée) < 1 an avant l'inclusion ou la randomisation dans l'essai,
Patiente avec une lymphangite pulmonaire ou une effusion pleurale
symptomatique (grade≥2), carcinome méningé connu ou symptômes évocateurs d'un envahissement cérébro-méningé, métastases cérébrales sauf si traitement et stabilité depuis au moins 4 semaines (pas de corticoïdes ni d'anti-convulsifs).
Patiente présentant un diabète non contrôlé,
Toute anomalie significative neurologique ou psychiatrique,
Neuropathie périphérique > grade 2,
Antécédent d'une hypersensibilité à un des traitements à l'étude ou un des excipients utilisés,
Infection urinaire aigüe ou cystite hémorragique en cours,
Traitement concomitant par un médicament contenant de la phénytoïne ou, médicament reçu dans le cadre d'un essai ou, participation à un autre essai clinique thérapeutique dans un délai < 30 jours ou traitement antérieur par chimiothérapie.
Patiente non stable géographiquement dans les 6 prochains mois ou demeurant à distance du centre de traitement rendant difficile son suivi dans l'étude,
Antécédents connus de consommation abusive de narcotiques ou tout autre substance médicamenteuse ou d'alcool
Antécédents de chirurgie dans les 28 jours avant le début du traitement,
Patiente réticente ou incapable de se conformer aux exigences de
l'étude.

E.5 End points

E.5.1

Primary end point(s)

To evaluate response rate of cisplatine - metronomic cyclophosphamide treatment

Evaluer les taux de réponse d'un traitement à base de cisplatine et
cyclophosphamide métronomique oral

E.5.1.1

Timepoint(s) of evaluation of this end point

At the last visit of the last subject undergoing the trial

A la dernière visite du dernier patient inclus dans l'étude

E.5.2

Secondary end point(s)

To evaluate disease free progression
To determine safety profile of cisplatine - metronomic cyclophosphamide association
To determine overall survival

Evaluer la survie sans progression
Déterminer le profil de tolérance de l'association
cisplatine/cylclophosphamide métronomique oral
Déterminer la survie globale

E.5.2.1

Timepoint(s) of evaluation of this end point

At the last visit of the last subject undergoing the trial

A la dernière visite du dernier patient inclus dans l'étude

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

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)

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

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

E.8.2.3

Other

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

last visit of the last subject undergoing the trial

dernière visite du dernier patient inclus dans l'étude

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

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

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)

Standard Treatment for metastatic breast cancers

Traitement standard des cancers du sein métastatiques

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

2013-04-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-07

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

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Orphan Designation Number:
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