Clinical Trials Register

Summary
EudraCT Number:	2016-000548-33
Sponsor's Protocol Code Number:	LyMa101
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:	2016-10-10
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

2016-000548-33

A.3

Full title of the trial

Phase II study to evaluate the efficacy of upfront obinutuzumab in mantle cell lymphoma patients treated by DHAP followed by autologous transplantation plus obinutuzumab maintenance then MRD driven maintenance

Etude de phase II évaluant l’efficacité de l’obinutuzumab chez des patients présentant un lymphome du manteau traité par DHAP puis par greffe autologue plus entretien par obinutuzumab suivi d’un entretien selon les résultats de la MRD

A.3.1

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

Study to evaluate the efficacy of obinutuzumab in mantle cell lymphoma patients treated by DHAP

Etude évaluant l’efficacité de l’obinutuzumab chez des patients présentant un lymphome du manteau traité par DHAP

A.4.1

Sponsor's protocol code number

LyMa101

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	LYSARC
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	ROCHE SAS
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	LYSARC
B.5.2	Functional name of contact point	Management de Projet S. Doyen
B.5.3	Address:
B.5.3.1	Street Address	CHU LYON SUD - SECTEUR STE EUGENIE - PAV 6 D
B.5.3.2	Town/ city	PIERRE BENITE
B.5.3.3	Post code	69495
B.5.3.4	Country	France
B.5.4	Telephone number	+33472669333
B.5.5	Fax number	+33426074055
B.5.6	E-mail	stephanie.doyen@lysarc.org

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	GAZYVARO
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited, UK
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	EU/3/12/1054
D.3 Description of the IMP
D.3.1	Product name	Obinutuzumab
D.3.2	Product code	GA101
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	Obinutuzumab
D.3.9.1	CAS number	949142-50-1
D.3.9.2	Current sponsor code	GA101
D.3.9.3	Other descriptive name	OBINUTUZUMAB
D.3.9.4	EV Substance Code	SUB32751
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	25
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)	Yes
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

Mantle Cell Lymphoma

Lymphome à Cellules du Manteau

E.1.1.1

Medical condition in easily understood language

Mantle Cell Lymphoma

Lymphome à Cellules du Manteau

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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10061275
E.1.2	Term	Mantle cell lymphoma
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 evaluate the efficacy of upfront Obinutuzumab (GA101) at the molecular level (MRD) in bone marrow after induction in patients with previously untreated MCL treated by DHAP.

Evaluer de l’efficacité de l’obinutuzumab (GA101) d’un point de vue moléculaire au niveau médullaire après induction chez des patients présentant un lymphome du manteau et traités en première ligne par DHAP

E.2.2

Secondary objectives of the trial

Secondary objectives:
•To evaluate the efficacy of the obinutuzumab in patients with MCL treated by DHAP before ASCT, after ASCT and every 6 months in terms of clinical response (Cheson 99), FDG-PET and MRD
•To evaluate PFS, Overall survival at study end
•To evaluate the incidence of stem cell collection failure after obinutuzumab-DHAP = GA-DHAP
•To evaluate MRD negativity after 3 years of maintenance and maintenance “on-demand”
•To evaluate PET results after 3 years of maintenance
•Duration of MRD negativity
•To evaluate tolerability of obinutuzumab at induction and then “on-demand”

Exploratory objective:
• To determine baseline prognostic factors on PFS and OS.

Objectifs secondaires :
• Evaluer l’efficacité de l’obinutuzumab chez des patients MCL traités par DHAP avant ASCT, après ASCT et tous les 6 mois d’un point de vue réponse clinique (Cheson 99), FDG-TEP et MRD
• Evaluer la survie sans progression (PFS), la survie globale (OS) à la fin de l’étude
• Evaluer l’incidence de l’échec de la collection de cellules souches après obinutuzumab-DHAP = GA-DHAP
• Evaluer la négativité de la MRD après 3 ans de maintenance et après la maintenance “sur demande”
• Evaluer les résultats des TEP après 3 ans de maintenance
• Durée de la négativité de la MRD
• Evaluer la tolérance de l’obinutuzumab à l’induction puis après la maintenance “sur demande”

Objectif exploratoire :
• Déterminer les facteurs pronostiques présents à l’inclusion pour la PFS et l’OS.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age ≥ 18 and age ≤ 65
• Histologically confirmed (according to the WHO classification) mantle cell lymphoma. The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cyclin D1 or the t(11;14) translocation.
• Bone marrow aspiration performed at inclusion for MRD analyses
• Eligible for autologous stem cell transplant
• Previously Uuntreated MCL
• Stage Ann Arbor II-IV in need of treatment
• ECOG performance status of 0 – 2
• Life expectancy of more than 3 months
• Written informed consent
• Patient covered by any social security system

• Age ≥ 18 et ≤ 65
• Histologie confirmée (selon la classification WHO) de lymphome du manteau. Le diagnostic est confirmé par l’expression phénotypique du CD5, CD20 et de la cycline D1 ou en présence de la translocation t(11;14)
• Aspiration de la moelle osseuse réalisée à l’inclusion pour les analyses de la MRD
• Eligible pour la greffe autologue de cellules souches
• Non antérieurement traité pour le lymphome du manteau
• Stade Ann Arbor II-IV nécessitant un traitement
• Indice fonctionnelle ECOG de 0 à 2
• Espérance de vie supérieure à 3 mois
• Consentement éclairé signé
• Patient couvert par un système de sécurité sociale

E.4

Principal exclusion criteria

• Severe cardiac disease: NYHA grade 3-4
• Impaired liver (ALAT/ASAT ≥ 2.5ULN, bilirubin ≥ 1.5ULN), renal (calculated creatinine clearance < 50ml/min) or other organ function which will interfere with the treatment, if not related to lymphoma.
• History of chronic liver disease
• Hepatic veno-occlusive disease or sinusoidal obstruction syndrome
• Any of the following laboratory abnormalities, if not result of a BM infiltration:
- Absolute neutrophils count (ANC) <1,500 /mm3 (1.5 x 109/L)
- Platelet counts < 75,000/mm3 (75 x 109/L)
• Pregnancy/Nursing mothers
• Fertile men or women of childbearing potential unless:
- surgically sterile or ≥ 2 years after the onset of menopause
- willing to use a highly effective contraceptive method (Pearl Index <1) such as oral contraceptives, intrauterine device, sexual abstinence or barrier method of contraception in conjunction with spermicidal jelly during study treatment and in female patients for 18 months after end of antibody treatment
• Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix are eligible. Patients with a malignancy that has been treated but not with curative intent will also be excluded, unless the malignancy has been in remission without treatment for ≥ 5 years prior to enrollment
• Known seropositivity for HIV, HCV or other active infection uncontrolled by treatment.
• Viral infection with hepatitis B virus (HBV) defined as hepatitis B surface antigen (HBsAg) positive and/or Hepatitis B core antibody (anti-HBc) positive
Note: Patients who are immune due to hepatitis B vaccination or natural infection (HBs Ag and anti-HBc negative, anti-HBs positive) are eligible. But the patients who are immune due to hepatitis B natural infection should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis reactivation
• Prior history of Progressive Multifocal Leukoencephalopathy (PML)
• Prolonged B cell depletion
• Vaccination with a live vaccine a minimum of 28 days prior to inclusion
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products
• Psychiatric illness or condition which could interfere with their ability to understand the requirements of the study.
• Person deprived of his/her liberty by a judicial or administrative decision
• Person hospitalized without consent
• Adult person under legal protection

• Maladie cardiaque sévère: NYHA grade 3-4
• Insuffisance hépatique (ALAT/ASAT ≥ 2.5ULN, bilirubine ≥ 1.5ULN), insuffisance rénale (clairance calculée de la créatinine < 50ml/min) ou tout autre insuffisance qui pourrait interférer avec le traitement, si ce n’est pas relié au lymphome.
• Histoire de maladie chronique hépatique
• Maladie veino-occlusive hépatique ou syndrome d’obstruction sinusoïdale
• Toutes anomalies biologiques suivantes si non associées à une atteinte médullaire :
- Neutrophiles <1,500 /mm3 (1.5 x 109/L)
- Plaquettes < 75,000/mm3 (75 x 109/L)
• Femme enceinte ou allaitante
• Homme ou Femme en âge de procréer sauf si:
- stérile chirurgicalement ou ménopausée depuis plus de 2 ans
- prêt à utiliser un moyen de contraception efficace (Indice de Pearl <1) tel que les contraceptifs oraux, les dispositifs intra-utérins, l’abstinence sexuelle ou une méthode de contraception mécanique en association avec de la gelée spermicide et ce pendant toute la durée de l’étude et pour les femmes, jusqu’à 18 mois après la dernière prise d’obinutuzumab.
• Patients ayant des antécédents de carcinome épidermoïde ou d’un mélanome de la peau ou d’un carcinome in situ du col de l’utérus sont incluables. Les patients atteints d’une tumeur maligne sont exclus sauf si les patients sont en rémission depuis plus de 5 ans avant inclusion
• Sérologie positive pour le VIH et l’hépatite C ou présentant une infection active non contrôlée
• Infection au virus de l’hépatite B (HBV) définie par la positivité de l’antigène HBs et/ou l’anticorps HBc
Note : les patients vaccinés pour l’hépatite B sont éligibles (HBs Ag et anti-HBc négatif, anti-HBs positif). Mais les patients immunisés suite à une infection naturelle de l’hépatite B doivent consulter un hépatologue avant de commencer le traitement, doivent être suivi et traités selon les pratiques locales afin de prévenir toute réactivation de la maladie
• Antécédent de leucoencéphalopathie multifocale progressive (PML)
• Déplétion prolongée des cellules B
• Vaccination avec un vaccin vivant dans les 28 jours qui précèdent l’inclusion
• Antécédent d’allergie sévère ou de réaction anaphylactique à un anticorps humanisé ou murin. Sensibilité ou allergie connue à un produit murin
• Maladie ou condition psychiatrique pouvant interférer avec la capacité à comprendre les exigences de l’étude
• Personne privée de sa liberté sur décision judiciaire ou administrative
• Personne hospitalisée sans son consentement
• Personne sous protection légale

E.5 End points

E.5.1

Primary end point(s)

MRD

E.5.1.1

Timepoint(s) of evaluation of this end point

- every 6 months during 3 years then every 3 months

- tous les 6 mois pendant 3 ans puis tous les 3 mois

E.5.2

Secondary end point(s)

•clinical response (Cheson 99), FDG-PET
•PFS, Overall survival
•incidence of stem cell collection failure
•MRD negativity
•PET results
•Duration of MRD negativity
•tolerability of obinutuzumab
•baseline prognostic factors on PFS and OS

• réponse clinique (Cheson 99), FDG-TEP
• survie sans progression (PFS), la survie globale (OS)
• incidence de l’échec de la collection de cellules souches
• négativité de la MRD
• résultats des TEP
• durée de la négativité de la MRD
• tolérance de l’obinutuzumab
• facteurs pronostiques présents à l’inclusion pour la PFS et l’OS

E.5.2.1

Timepoint(s) of evaluation of this end point

•clinical response (Cheson 99), FDG-PET = every 6 months
•PFS, Overall survival = study end
•incidence of stem cell collection failure = after obinutuzumab-DHAP
•MRD negativity = after 3 years of maintenance and maintenance “on-demand”
•PET results = after 3 years of maintenance
•duration of MRD negativity = over the study
•tolerability of obinutuzumab = at induction and then “on-demand”
•baseline prognostic factors on PFS and OS = end of study

• réponse clinique (Cheson 99), FDG-TEP = tous les 6 mois
• survie sans progression (PFS), survie globale (OS) = fin d’étude
• incidence de l’échec de la collection de cellules souches = après obinutuzumab-DHAP
• négativité de la MRD = après 3 ans de maintenance et après la maintenance “sur demande”
• résultats des TEP = après 3 ans de maintenance
• durée de la négativité de la MRD = sur la durée de l'étude
• tolérance de l’obinutuzumab = à l’induction puis après la maintenance “sur demande”
• facteurs pronostiques présents à l’inclusion pour la PFS et l’OS = fin d'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

Yes

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

LVLP

Dernière visite du dernier patient

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)

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

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)

None

Aucun

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	LYSA
G.4.3.4	Network Country	France

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-07-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-07

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

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IMP with orphan designation in the indication
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