Clinical Trials Register

Summary
EudraCT Number:	2014-003467-37
Sponsor's Protocol Code Number:	14726103
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-06-22
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

2014-003467-37

A.3

Full title of the trial

Evaluation of Ixazomib, Lenalidomide, Dexamethasone Induction and extended Consolidation followed by Lenalidomide Maintenance in Newly Diagnosed Multiple Myeloma Patients ≤65 years eligible for High Dose Therapy: a phase II study of the Intergroupe Francophone du Myélome (IFM)

Evaluation de l’association Ixazomib, Lenalidomide, Dexamethasone en induction et consolidation longue suivie de Lenalidomide en entretien chez des patients d’âge
≤65 ans atteints de Myélome Multiple de novo et éligibles pour un traitement
haute dose : une étude de phase II de l’Intergroupe Francophone du Myélome
(IFM)

A.3.1

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

Evaluation of Ixazomib, Lenalidomide, Dexamethasone in Newly Diagnosed Multiple Myeloma Patients eligible for High Dose Therapy

Evaluation de l’association Ixazomib, Lenalidomide, Dexamethasone chez des patients d’âge ≤65 ans atteints de Myélome Multiple de novo et éligibles pour un traitement haute dose

A.4.1

Sponsor's protocol code number

14726103

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	CHU de Toulouse
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	MILLENNIUM
B.4.2	Country	United States
B.4.1	Name of organisation providing support	CELGENE
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHU TOULOUSE
B.5.2	Functional name of contact point	Huguet
B.5.3	Address:
B.5.3.1	Street Address	2 rue de viguerie
B.5.3.2	Town/ city	TOULOUSE
B.5.3.3	Post code	31059
B.5.3.4	Country	France
B.5.4	Telephone number	33561778490
B.5.5	Fax number	33561778490
B.5.6	E-mail	huguet.a@chu-toulouse.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	Revlimid 25 mg (Lenalidomide)
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Limited
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	Yes
D.2.5.1	Orphan drug designation number	MM:EU/3/03/177
D.3 Description of the IMP
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	LENALIDOMIDE
D.3.9.1	CAS number	191732-72-6
D.3.9.4	EV Substance Code	SUB25389
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	25
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	Revlimid 5 mg (Lenalidomide)
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Limited
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	Yes
D.2.5.1	Orphan drug designation number	MM:EU/3/03/177
D.3 Description of the IMP
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	LENALIDOMIDE
D.3.9.1	CAS number	191732-72-6
D.3.9.4	EV Substance Code	SUB25389
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	10
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	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	Yes
D.2.5.1	Orphan drug designation number	ORPHA275257
D.3 Description of the IMP
D.3.1	Product name	Ixazomib
D.3.4	Pharmaceutical form	Capsule
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	IXAZOMIB
D.3.9.1	CAS number	1072833-77-2
D.3.9.3	Other descriptive name	IXAZOMIB
D.3.9.4	EV Substance Code	SUB121332
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	4
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	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	Dexamethasone
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratoire CTRS
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	Dexamethasone
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	DEXAMETHASONE
D.3.9.1	CAS number	50-02-2
D.3.9.4	EV Substance Code	SUB07017MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	40
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

Multiple Myeloma newly diagnosed

Myelome Multiple de novo

E.1.1.1

Medical condition in easily understood language

Myeloma

Myelome

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10028566
E.1.2	Term	Myeloma
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate the sCR rate of the combination of Ixazomib, Lenalidomide with and without dexamethasone as induction and extended consolidation therapy in an intensive program in newly diagnosed MM patients, after consolidation and before maintenance therapy.

Évaluer le taux de RC stringente à la fin du traitement de consolidation.

E.2.2

Secondary objectives of the trial

Determine the safety and tolerability of the drug combination in this patient population as induction and extensive consolidation therapy.
Evaluate the sCR, CR, VGPR and PR rates, the overall response rate after induction, high dose Melphalan, early consolidation, late consolidation and maintenance therapy
Evaluate progression free survival, overall survival, time to progression and duration of response, time to response.
Evaluate the quality of stem cell harvest after induction therapy
Determine biological prognostic factors influencing outcome and response rates

- Déterminer l'innocuité et la tolérance de l’association MLN RD en induction et MLN Rd puis MLN R en traitement de consolidation
- Évaluer les taux de sRC, RC, TBRP et RP après l'induction, l’intensification, la consolidation précoce, la consolidation tardive, pendant et à la fin de l'entretien
- Évaluer le taux de réponse globale, la date de réponse, la survie sans progression, la survie globale, le temps jusqu'à progression et la durée de la réponse.
- Évaluer la faisabilité et la qualité de la collecte de cellules souches périphériques.

OBJECTIFS EXPLORATOIRES:
- Déterminer les facteurs pronostiques biologiques qui influent sur les taux de réponse et la survie.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Male or female patients ≥ 18 years and ≤ 65 years at the time of signing informed consent form
- Patients diagnosed with multiple myeloma based on the new International Myeloma Working Group Diagnostic Criteria for plasma cells disorders (leukemia 2009)
-Subjects must have symptomatic myeloma with CRAB criteria
- Subjects must have measurable disease requiring systemic therapy defined by serum M-component ≥ 5g/l or urine M-component ≥ 200 mg/24h or serum FLC ≥ 100 mg/l.
-Subjects must not have been treated previously with any systemic therapy for multiple myeloma. Prior treatment with corticosteroids or radiation therapy does not disqualify the subject (the maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone in a 2-week period before initiation therapy). Two weeks must have elapsed since the date of the last radiotherapy treatment
-Subjects must be eligible for high dose therapy.
-Life expectancy ≥ 3 months

- Un âge ≥ 18 ans et ≤ 65 ans au moment de la signature du formulaire de consentement éclairé
- Un diagnostic de Myélome Multiple de novo selon les Critères diagnostiques du Groupe de travail international des dyscrasies plasmocytaires (Leukemia 2009)
- Un Myélome Multiple symptomatique de novo avec atteinte organique liée au Myélome ou critères CRAB
- Une maladie mesurable définie par un composant monoclonal
sérique ≥ 5 g / l, ou un composant monoclonal urinaire ≥ 200 mg/24 h
ou des chaines légères libres sériques ≥ 100 mg / l.
- Les sujets ne doivent pas avoir été traités antérieurement par un traitement systémique pour le myélome multiple. Un traitement antérieur avec des corticostéroïdes ou de la radiothérapie ne disqualifie pas le sujet. La dose maximale de corticostéroïdes ne doit pas dépasser l'équivalent de 160 mg de dexaméthasone dans une période de 2 semaines avant le début du traitement. L’inclusion des sujets qui nécessitent une radiothérapie concomitante (qui doit être localisée) doit être reportée jusqu'à ce que la radiothérapie soit terminée et que 2 semaines se soient écoulées depuis la dernière dose délivrée.
- Etre éligible pour un traitement à haute dose avec autogreffe de cellules souches.
- Une espérance de vie ≥ 3 mois
- Un indice de performance ECOG 0-2

E.4

Principal exclusion criteria

-Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test
-Evidence of mucosal or internal bleeding and/or platelet refractory.
-Prior myeloma systemic therapy
-Central nervous system involvement
-Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to first dose of study drug=
-Infection requiring systemic antibiotic therapy or other serious infection within 14 days before first dose of study drug.
-Evidence of current uncontrolled cardiovascular conditions...
-Systemic treatment, within 14 days before first dose of study drug, with strong inhibitors of CYP1A2, strong inhibitors of CYP3A or strong CYP3A inducers or use of Ginkgo biloba or St. John’s wort
-Ongoing or active systemic infection, known human immunodeficiency virus (HIV) positive, known active hepatitis B virus hepatitis, or known active hepatitis C virus hepatitis and history of hepatitis B or C virus hepatitis.
-Diagnosed or treated for another malignancy within 5 years before study enrollment
-Patient has significant neuropathy

- Les femmes enceintes ou qui allaitent
- un syndrome hémorragique cutanéo-muqueux ou interne et/ou état
réfractaire aux transfusions plaquettaires
- Un traitement systémique antérieur du myélome
une hypertension non contrôlée ou un diabète non contrôlé dans les 14 jours précédant la 1ère dose de traitement à l’étude.
- une fonction cardiovasculaire instable non contrôlée
- Un traitement systémique, dans les 14 jours avant la première dose
de médicament à l'étude, avec des inhibiteurs puissants du CYP1A2 du CYP3A ou inducteurs puissants du CYP3A ou l'utilisation de Ginkgo biloba ou le millepertuis.
- Une infection connue par le virus d'immunodéficience humaine
- Une hépatite virale active ou des antécédents d'hépatite B ou C
- Patients diagnostiqués ou traités pour une autre tumeur maligne dans les 5 ans avant l’inclusion
- une Neuropathie significative de Grade 3-4 ou grade 2 avec douleurs dans les 14 jours précédant l'enregistrement

E.5 End points

E.5.1

Primary end point(s)

The sCR rate

Le taux de réponse complète stringente

E.5.1.1

Timepoint(s) of evaluation of this end point

After consolidation and before maintenance therapy

Après la consolidation et avant la phase de mainteanance

E.5.2

Secondary end point(s)

1-the safety and tolerability
2-the sCR, CR, VGPR and PR rates, the overall response rate
3-évaluate progression free survival, overall survival, time to progression and duration of response, time to response
4-the quality of stem cell harvest
5-biological prognostic factors influencing outcome and response rates

1- Innocuité et la tolérance
2- les taux de sRC, RC, TBRP et RP
3-le taux de réponse globale, la date de réponse, la survie sans progression, la survie globale, le temps jusqu'à progression et la durée de la réponse.
4- la faisabilité et la qualité de la collecte de cellules souches périphériques.
5-les facteurs pronostiques biologiques qui influent sur les taux de réponse et la survie.

E.5.2.1

Timepoint(s) of evaluation of this end point

1-induction and consolidation
2-after induction, high dose Melphalan, early consolidation, late consolidation and maintenance therapy
3-end of study
4-after stem celsl harvest
5-end of study

1-induction et consolidation
2-après induction, aute dose de Melphalan, consolidation précoce, consolidation tardive et maintenance
3-fin de l'étude
4-après la collecte de cellules souches
5-fin de 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

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

66th month to complete secondary objectives

66ème mois pour répondre au objectif secondaires de 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

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

Yes

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