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Clinical Trial Results:
"Essai multicentrique de phase II randomisé évaluant la tolérance et l'efficacité du tamoxifène seul versus association Tamoxifène-RAD001 (Everolimus), chez les patientes atteintes de cancer du sein métastatique résistant aux anti-aromatases"

Summary
EudraCT number	2006-004332-79
Trial protocol	FR
Global end of trial date	12 Sep 2018

Results information
Results version number	v1(current)
This version publication date	06 Jul 2022
First version publication date	06 Jul 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GINECO-BR105

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

ARCAGY

Sponsor organisation address

1, place du Parvis Notre-Dame, HOPITAL HOTEL DIEU-B2 5ème étage, PARIS, France, 75181 cedex 4

Public contact

Sébastien ARMANET, ARCAGY, reglementaire@arcagy.org

Scientific contact

Thomas BACHELOT, ARCAGY, bachelot@lyon.fnclcc.fr

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

09 Sep 2011

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 Sep 2018

Was the trial ended prematurely?

Main objective of the trial

Evaluer pour les 2 schémas d’administration le pourcentage de bénéfice clinique à 24 semaines To assess whether concomitent use of RAD001 and tamoxifene allow better results of 2nd line hormonotherapy in metastatic breast cancer. This question is of great clinical importance as most of the metastatic patients with a tumor expressing hormonal receptor will already have received aromatase inhibitor as an adjuvant therapy and will correspond to the target population of this study. Clinical benefit percentage evaluation at 24 weeks of treatment for the two arms of this study (Tamoxifen vs Tamoxifen+RAD001)

Protection of trial subjects

Cette étude a été menée selon les recommandations : - de la loi Bioéthique n° 2004-800 du 6 août 2004; - de la "Déclaration d'Helsinki" révisée à Washington en 2002, Octobre 2000 - des bonnes pratiques cliniques de la conférence internationale d’harmonisation (ICH-E6 du 17/07/1996); - de la loi Huriet (n°88-1138) du 20 décembre 1988 relative à la Protection des Personnes se prêtant à la Recherche Biomédicale et modifiée par la loi de santé publique (n°2004-806) du 9 août 2004; - de la loi Informatique et Libertés n°78-17 modifiée par la loi n° 2004-801 du 6 août 2004 relative à la protection des personnes physiques à l'égard des traitements de données à caractère personnel; - de la direction européenne (2001/20/CE) sur la conduite des essais cliniques

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Mar 2008

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

18 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 111

Worldwide total number of subjects

111

EEA total number of subjects

111

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Les inclusions dans l’étude ont eu lieu entre le 12 mars 2008 et le 19 Mai 2009. Au total, 111 patientes ont été incluses dans l’étude, 57 (51%) dans le bras A, 54 (49%) dans le bras B.

Screening details

Avec une randomisation utilisant un ratio 1 :1 et sous l'hypothèse d'un taux de patientes perdues de vue 24 semaines après le début du traitement d’environ 5%, 110 patientes au total seront incluses dans l'étude (55 par bras). Treize patientes ont présenté au moins une violation majeure au protocole, 8 dans le bras A et 5 dans le bras B

Period 1 title

OVERALL TRIAL (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Bras A : contrôle

Arm description

Bras contrôle

Arm type

Contrôle

Investigational medicinal product name

Tamoxifène

Investigational medicinal product code

LO2BA01

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

20mg/j

Bras B: expérimental

Arm description

bras expérimental

Arm type

Experimental

Investigational medicinal product name

tamoxifène

Investigational medicinal product code

LO2BA01

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

20mg/j, jusqu'à progression ou toxicité

Investigational medicinal product name

RAD001 (évérolimus)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10mg/j (2 x 5mg/j)

Number of subjects in period 1	Bras A : contrôle	Bras B: expérimental
Started	57	54
Completed	57	54

Baseline characteristics

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Reporting group title

Bras A : contrôle

Reporting group description

Bras contrôle

Reporting group title

Bras B: expérimental

Reporting group description

bras expérimental

Reporting group values	Bras A : contrôle	Bras B: expérimental	Total
Number of subjects	57	54	111
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
median (full range (min-max))	66 (42 to 86)	62.5 (41 to 81)	-
Gender categorical
Units: Subjects
Female	57	54	111
Male	0	0	0

Subject analysis set title

Bras contrôle

Subject analysis set type

Intention-to-treat

Subject analysis set description

Bras contrôle: Ce bras jouera le rôle de bras de référence, et servira à valider la mesure du taux de non progression observé dans le bras B

Subject analysis set title

bras expérimental

Subject analysis set type

Intention-to-treat

Subject analysis set description

bras expérimental

Subject analysis sets values	Bras contrôle	bras expérimental
Number of subjects	57	54
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
median (full range (min-max))	66 (42 to 86)	62.5 (41 to 81)
Gender categorical
Units: Subjects
Female	57	57
Male

End points

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Reporting group title

Bras A : contrôle

Reporting group description

Bras contrôle

Reporting group title

Bras B: expérimental

Reporting group description

bras expérimental

Subject analysis set title

Bras contrôle

Subject analysis set type

Intention-to-treat

Subject analysis set description

Bras contrôle: Ce bras jouera le rôle de bras de référence, et servira à valider la mesure du taux de non progression observé dans le bras B

Subject analysis set title

bras expérimental

Subject analysis set type

Intention-to-treat

Subject analysis set description

bras expérimental

Primary: primary endpoint

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End point title

primary endpoint

End point description

End point type

Primary

End point timeframe

Pourcentage de patientes ayant un bénéfice clinique à 24 semaines après le début du traitement .

End point values	Bras A : contrôle	Bras B: expérimental
Number of subjects analysed	57	54
Units: percent
number (confidence interval 95%)	42.1 (29.1 to 55.9)	61.1 (46.9 to 74.1)

Analyse du critère principal

Statistical analysis description

Le test exact de Fisher (ou du Chi-2) a été utilisé pour comparer les sous groupes, le test de log rank pour comparer les courbes de survie à des fins exploratoires

Comparison groups

Bras A : contrôle v Bras B: expérimental

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.045

Method

Chi-squared

Confidence interval

Secondary: Time to progression

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End point title

Time to progression

End point description

End point type

Secondary

End point timeframe

Le temps jusqu’à progression a été calculé de la date de randomisation jusqu’à la date de première mise en évidence d’une progression ou jusqu’à la date de décès par évolution néoplasique, et censuré à la date de dernières nouvelles ou à la date de décès

End point values	Bras A : contrôle	Bras B: expérimental
Number of subjects analysed	57	54
Units: month
median (confidence interval 95%)	4.5 (3.6 to 8.7)	8.6 (5.9 to 13.9)

temps jusqu’à progression

Statistical analysis description

Le temps jusqu’à progression (TTP) et la survie globale seront estimés dans chaque bras de traitement par la méthode de Kaplan Meier, dans la population évaluable pour le bénéfice clinique et per protocole

Comparison groups

Bras A : contrôle v Bras B: expérimental

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

0.81

Adverse events

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Timeframe for reporting adverse events

L'analyse de la tolérance a été effectuée mensuellement jusqu'à la visite du 6ème mois et ensuite tous les 3 mois jusqu'au 18ème mois

Adverse event reporting additional description

L’analyse de la tolérance sera réalisée chez toutes les patientes randomisées. Les EI ont été évalués conformément aux Critères terminologiques communs pour les événements indésirables du National Cancer Institute (CTCAE) version 3.0 . Tous les évènements indésirables graves seront décrits par bras de traitement selon le dictionnaire MedDRA

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

14.0

Reporting group title

Bras A : contrôle

Reporting group description

Bras contrôle

Reporting group title

Bras B: expérimental

Reporting group description

bras expérimental

Serious adverse events	Bras A : contrôle	Bras B: expérimental
Total subjects affected by serious adverse events
subjects affected / exposed	22 / 57 (38.60%)	28 / 54 (51.85%)
number of deaths (all causes)	26	13
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningeal carcinomatosis
subjects affected / exposed	1 / 57 (1.75%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Thrombosis
subjects affected / exposed	4 / 57 (7.02%)	5 / 54 (9.26%)
occurrences causally related to treatment / all	4 / 4	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	2 / 57 (3.51%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 2
Asthenia
subjects affected / exposed	1 / 57 (1.75%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	2 / 57 (3.51%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
mucositus
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
foot sprain
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 57 (1.75%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Mood altered
subjects affected / exposed	1 / 57 (1.75%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Decompensation cardiac
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Leukaemia
subjects affected / exposed	1 / 57 (1.75%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	0 / 57 (0.00%)	2 / 54 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	1 / 57 (1.75%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Retinal detachment
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastric ulcer
subjects affected / exposed	1 / 57 (1.75%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 57 (1.75%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reduced general condition
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin necrosis
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute renal insufficiency
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder prolapse
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Fracture
subjects affected / exposed	1 / 57 (1.75%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 57 (1.75%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Infection
subjects affected / exposed	3 / 57 (5.26%)	5 / 54 (9.26%)
occurrences causally related to treatment / all	0 / 3	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	1 / 57 (1.75%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Type II diabetes
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of control of diabetes
subjects affected / exposed	0 / 57 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Bras A : contrôle	Bras B: expérimental
Total subjects affected by non serious adverse events
subjects affected / exposed	57 / 57 (100.00%)	54 / 54 (100.00%)
Vascular disorders
HOT FLASHES
subjects affected / exposed	19 / 57 (33.33%)	12 / 54 (22.22%)
occurrences all number	19	12
Oedema
subjects affected / exposed	6 / 57 (10.53%)	12 / 54 (22.22%)
occurrences all number	6	12
Epistaxis
subjects affected / exposed	2 / 57 (3.51%)	13 / 54 (24.07%)
occurrences all number	2	13
Thrombosis
subjects affected / exposed	5 / 57 (8.77%)	7 / 54 (12.96%)
occurrences all number	5	7
General disorders and administration site conditions
Pain
subjects affected / exposed	49 / 57 (85.96%)	44 / 54 (81.48%)
occurrences all number	30	39
Fatigue
subjects affected / exposed	30 / 57 (52.63%)	39 / 54 (72.22%)
occurrences all number	30	39
Blood and lymphatic system disorders
decreased hemoglobin
subjects affected / exposed	20 / 57 (35.09%)	37 / 54 (68.52%)
occurrences all number	20	37
decreased leukocyte count
subjects affected / exposed	10 / 57 (17.54%)	29 / 54 (53.70%)
occurrences all number	10	29
decreased lymphocyte count
subjects affected / exposed	12 / 57 (21.05%)	26 / 54 (48.15%)
occurrences all number	12	26
polymorphonuclear neutrophil
subjects affected / exposed	11 / 57 (19.30%)	26 / 54 (48.15%)
occurrences all number	11	26
Gastrointestinal disorders
Nausea
subjects affected / exposed	20 / 57 (35.09%)	19 / 54 (35.19%)
occurrences all number	20	19
Stomatitis
subjects affected / exposed	4 / 57 (7.02%)	30 / 54 (55.56%)
occurrences all number	57	54
diarrhea
subjects affected / exposed	6 / 57 (10.53%)	21 / 54 (38.89%)
occurrences all number	57	54
Constipation
subjects affected / exposed	13 / 57 (22.81%)	9 / 54 (16.67%)
occurrences all number	13	9
Vomiting
subjects affected / exposed	7 / 57 (12.28%)	9 / 54 (16.67%)
occurrences all number	7	9
Respiratory, thoracic and mediastinal disorders
Pneumonitis
subjects affected / exposed	2 / 57 (3.51%)	9 / 54 (16.67%)
occurrences all number	2	9
Cough
subjects affected / exposed	6 / 57 (10.53%)	7 / 54 (12.96%)
occurrences all number	6	7
DYSPNEA
subjects affected / exposed	11 / 57 (19.30%)	14 / 54 (25.93%)
occurrences all number	11	14
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	4 / 57 (7.02%)	24 / 54 (44.44%)
occurrences all number	4	24
Nail disorder
subjects affected / exposed	0 / 57 (0.00%)	8 / 54 (14.81%)
occurrences all number	0	8
Prurit
subjects affected / exposed	1 / 57 (1.75%)	7 / 54 (12.96%)
occurrences all number	1	7
Infections and infestations
Infection
subjects affected / exposed	11 / 57 (19.30%)	19 / 54 (35.19%)
occurrences all number	11	19
Metabolism and nutrition disorders
ANOREXIA
subjects affected / exposed	10 / 57 (17.54%)	23 / 54 (42.59%)
occurrences all number	10	23

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
"Essai multicentrique de phase II randomisé évaluant la tolérance et l'efficacité du tamoxifène seul versus association Tamoxifène-RAD001 (Everolimus), chez les patientes atteintes de cancer du sein métastatique résistant aux anti-aromatases"

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: primary endpoint

Primary: primary endpoint

Secondary: Time to progression

Secondary: Time to progression

Adverse events

Adverse events

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Clinical trials

Clinical Trial Results: "Essai multicentrique de phase II randomisé évaluant la tolérance et l'efficacité du tamoxifène seul versus association Tamoxifène-RAD001 (Everolimus), chez les patientes atteintes de cancer du sein métastatique résistant aux anti-aromatases"

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: primary endpoint

Primary: primary endpoint

Secondary: Time to progression

Secondary: Time to progression

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
"Essai multicentrique de phase II randomisé évaluant la tolérance et l'efficacité du tamoxifène seul versus association Tamoxifène-RAD001 (Everolimus), chez les patientes atteintes de cancer du sein métastatique résistant aux anti-aromatases"