Clinical Trials Register

Summary
EudraCT Number:	2018-001467-23
Sponsor's Protocol Code Number:	RC31/17/0450
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:	2019-02-25
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

2018-001467-23

A.3

Full title of the trial

Dexamethasone plus salvage chemotherapy versus salvage chemotherapy alone in patients with first relapsed or refractory acute myeloid leukemia: a randomized, controlled, open-label, multicenter, phase III study.

Essai de phase III multicentrique, contrôlé, randomisé, en ouvert, évaluant l’efficacité de l’addition de la dexamethasone à la chimiothérapie de rattrapage versus la chimiothérapie de rattrapage seule chez les patients atteints de Leucémie Aiguë Myéloïde réfractaire ou en rechute

A.3.1

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

Dexamethasone in first relapsed or refractory acute myeloid leukemia

Dexaméthasone chez les patients atteints de Leucémie Aiguë Myéloïde réfractaire ou en rechute

A.3.2

Name or abbreviated title of the trial where available

DEXAML-03

A.4.1

Sponsor's protocol code number

RC31/17/0450

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03765541

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	Celgene
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	Janssen Pharmaceutica NV
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	Millenium Pharmaceuticals
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHU de Toulouse
B.5.2	Functional name of contact point	BOGDANOVITCH
B.5.3	Address:
B.5.3.1	Street Address	2 rue 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	330561778437
B.5.5	Fax number	330561778411
B.5.6	E-mail	bogdanovitch.l@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	No
D.2.1.1.1	Trade name	DEXAMETHASONE MYLAN
D.2.1.1.2	Name of the Marketing Authorisation holder	MYLAN
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	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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

Relapse or refractory Acute Myeloid Leukemia

Leucémie Aiguë Myéloïde réfractaire ou en rechute

E.1.1.1

Medical condition in easily understood language

Acute Myeloid Leukemia

Leucémie Aiguë Myéloïde

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10060558
E.1.2	Term	Acute myeloid leukemia recurrent
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10000889
E.1.2	Term	Acute myeloid leukemia without mention of remission
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

To evaluate if Dexamethasone plus salvage chemotherapy versus salvage chemotharapy alone provide significant improvement of overall survival in patient with first relapse or refractory acute myeloid leukemia

Evaluer si l’ajout de la Dexaméthasone au traitement standard de rattrapage améliore de façon significative le temps de survie chez les patients de 18 ans ou plus atteints de LAM réfractaire ou en rechute après chimiothérapie intensive.

E.2.2

Secondary objectives of the trial

- to evaluate the response to therapy
- to evaluate the minimal residual disease (MRD) positivity
- to evaluate the allogeneic hematopoietic stem cell transplantation as alternative therapy
- to evaluate the time of remission
- to evaluate the relapse-free survival
- to evaluate quality of life
- to evaluate adverse events

- évaluer la réponse à la thérapie
- évaluer le taux de maladie résiduelle
- évaluer la transplantation de cellules souches hématopoïétiques allogéniques comme thérapie alternative
- évaluer la durée de la rémission
- évaluer le aux de survie sans progression
- évaluer la qualité de vie des patients
- évaluer les effets secondaires

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- 18 years of age or older
- Diagnosis of acute myeloid leukemia (AML) by World Health Organization (WHO) classification. First relapsed or refractory AML with at least 5% blasts by bone marrow biopsy or aspirate, or at least 1% blasts in peripheral blood, and meeting the following criteria :
First relapsed AML:
* First relapse occurred at least 90 days to 24 months after the first CR or CRi.
* The first CR or CRi had to result from no more than 2 cycles of cytotoxic chemotherapy. At least 1 induction cycle must have consisted of an anthracycline and cytarabine combination with a reasonable schedule/dose of anthracycline in the judgment of the investigator.
* The re-emergence of at least 5% leukemic blasts in bone marrow is not attributable to other causes, regardless of new or recurrent dysplastic changes or extramedullary disease, or the re-emergence of at least 1% blasts in the peripheral blood is not attributable to other causes such as regenerating marrow.
Refractory AML:
* Persistent AML was documented by bone marrow biopsy or aspirate at least 28 days after day 1 of the first induction cycle of 1 or 2 cycles of cytotoxic chemotherapy.
* Re-emergence of at least 5% leukemic blasts in bone marrow or at least 1% blasts in peripheral blood is not attributable to other causes such as regenerating marrow, and was less than 90 days after the first CR or CRi.
* Prior induction therapy had to include no more than 2 cycles of cytotoxic chemotherapy. At least 1 induction cycle must have consisted of an anthracycline and cytarabine combination with a reasonable schedule/dose of anthracycline in the judgment of the investigator.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram or multi-gated acquisition (MUGA) scan; only applicable for patients who will receive intensive chemotherapy
- Serum creatinine ≤ 150 µmol/L and/or total bilirubin ≤ 1.5 × the upper limit of normal (ULN) and/or, aspartate aminotransferase (AST) ≤ 2.5 × ULN and/or alanine aminotransferase (ALT) ≤ 2.5 × ULN (unless related to AML or due to Gilbert’s syndrome)
- Any clinically significant non-hematological toxicity after prior chemotherapy must be resolved or of grade 1 as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
- Women must be surgically or biologically sterile, or in post-menopause (amenorrheic for at least 12 months), or if of childbearing potential, must have a negative urine or serum pregnancy test within 14 days prior to the randomization, and agree to use a highly effective method of contraception throughout the entire duration of the study treatment (including dose interruptions) and until 3 months after the last study treatment administration. Men must be surgically or biologically sterile, or agree to use a highly effective method of contraception throughout the entire duration of the study treatment (including dose interruptions) and until 6 months after the last study treatment administration
- Registered to, or beneficiary of, social security insurance or equivalent
- Signed written informed consent by both the patient and the investigator prior to perform any study-relayed procedure not part of normal medical care

- Age ≥ 18 ans
- Leucémie Aiguë Myéloïde (LAM) diagnostiquée selon la classification du WHO. LAM en première rechute ou réfractaire avec réémergence d'au moins 5% de blastes leucémiques documentée par aspiration de la moelle osseuse, et d'au moins 1% de blastes dans le sang périphérique et présentant les critères suivants :
LAM en première rechute :
* Première rechute survenant au moins 90 jours à 24 mois après la première RC ou RCi
* La chimiothérapie d'induction qui ne devait pas inclure plus de 2 cycles de chimiothérapie cytotoxique et qui devait avoir comporté au moins un cycle combinant une anthracycline avec de la cytarabine
* La réémergence d'au moins 5% de blastes leucémiques dans la moelle osseuse et ou d'au moins 1% de blastes dans le sang périphérique ne doit pas être attribuable à d'autres causes (régénération médullaire)
LAM réfractaire :
* LAM persistante documentée par aspiration de moelle osseuse au moins 28 jours après le jour 1 du 1er ou 2nd cycle de chimiothérapie d’induction
* Réémergence d'au moins 5% de blastes leucémiques dans la moelle osseuse ou d'au moins 1% de blastes dans le sang périphérique non attribuable à d'autres causes (régénération médullaire) dans un délai inférieur à 90 jours après la première RC ou RCi
* La première thérapie d'induction ne doit inclure pas plus de 2 cycles de chimiothérapie cytotoxique dont un cycle ayant comporté au moins un cycle combinant une anthracycline avec de la cytarabine
- Indice de performance ECOG ≤ 2
- Fraction d'éjection du ventricule gauche (FEVG) d'au moins 50% par échographie ou scintigraphie ; critère applicable uniquement aux patients qui recevront la chimiothérapie intensive amsacrine-cytarabine en traitement standard de rattrapage
- Créatinine sérique ≤ 150 μmol/L ou bilirubine totale ≤ 1,5 X la limite supérieure de la normale (LSN) ou aspartate amino-transférase (AST) ≤ 2,5 X LSN ou alanine amino-transférase (ALT) ≤ 2,5 X LSN (à moins d'être considérée comme due à une atteinte leucémique ou à une maladie de Gilbert)
- Toute toxicité non hématologique cliniquement significative après une chimiothérapie antérieure doit être résolue ou de grade 1 selon les critères communs de terminologie pour les événements indésirables (CTCAE) version 4.03
- Les femmes doivent être chirurgicalement ou biologiquement stériles ou en post-ménopause (aménorrhées pendant au moins 12 mois). Les femmes en âge de procréer doivent avoir un test de grossesse négatif dans les 14 jours précédant la randomisation et accepter d'utiliser une méthode de contraception adéquate pendant toute la durée de traitement et jusqu’à 3 mois après le dernier traitement. Les hommes doivent être chirurgicalement ou biologiquement stériles ou accepter d'utiliser une méthode de contraception adéquate pendant toute la durée de traitement et jusqu'à 6 mois après le dernier traitement
- Patients affiliés ou bénéficiaires d’un régime de sécurité sociale (Sécurité Sociale ou Couverture Médicale Universelle)
- Consentement libre, éclairé et écrit, signé par le patient et l’investigateur (avant tout examen nécessité par la recherche)

E.4

Principal exclusion criteria

- Acute promyelocytic leukemia (M3 subtype of AML)
- More than 2 cycles of first line induction chemotherapy
- AML with Philadelphia chromosome or BCR-ABL1 or blast crisis stage of chronic myeloid leukemia
- Known or suspected central nervous system leukemia
- Undergoing allogeneic hematopoietic stem cell transplantation within 90 days prior to randomization, or being on immunosuppressive therapy for prophylaxis of graft-versus-host disease (GVHD), or experiencing GVHD within 2 weeks prior to randomization
- Use of any experimental, cytotoxic, or targeted, anti-leukemic therapy within 14 days prior to randomization, with the exception of hydroxyurea
- Formal contraindication to glucocorticoids
- Non-AML-associated organic or psychiatric severe disease that contraindicates use of study treatment
- Patients who may not be followed regularly in consultation because of psychological, family, social, or geographical reasons
- History of uncontrolled other malignancy for at least two years, with the exception of basal cell carcinoma and in situ cervix carcinoma
- Severe uncontrolled infection at time of inclusion
- Positive serology for HIV-1 or 2, and/or HTLV-1 or 2, and/or active viral infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV)
- Pregnant (beta HCG positive) or breastfeeding woman
- Incapable patient of age, under guardianship, curatorship or safeguard of justice
- Patient Under State Medical Assistance
- Patient participating in any other interventional clinical trial or having participated in an interventional clinical trial of which the exclusion period is still ongoing.

- Leucémie aigüe promyélocytaire (soustype M3 de LAM)
- Plus de 2 cycles de chimiothérapie d’induction reçus en première ligne
- LAM avec chromosome Philadelphie ou réarrangement BCR-ABL1 ou crise blastique d’une leucémie myéloïde chronique
- Atteinte leucémique du système nerveux central connue ou suspectée
- Allogreffe de cellules souches hématopoïétiques dans les 90 jours avant la randomisation ou traitement immunosuppresseur pour la prophylaxie de la maladie greffon contre l'hôte (GVHD) ou GVHD dans les 2 semaines avant la randomisation
- Tout traitement anti-leucémique expérimental, cytotoxique ou ciblé dans les 14 jours précédant la randomisation à l’exception de l’hydroxyurée
- Patients présentant une contre-indication formelle aux glucocorticoïdes
- Patients atteints d'une pathologie organique ou psychiatrique sévère, présumée indépendante de la LAM et contre-indiquant le traitement
- Patients qui, pour des raisons psychologiques, familiales, sociales ou géographiques, ne pourraient être suivis régulièrement en consultation
- Antécédent de cancer non contrôlé depuis au moins deux ans à l’exception des carcinomes cutanés baso-cellulaires et des carcinomes in situ du col utérin
- Infection sévère non contrôlée au moment de l'inclusion
- Sérologie positive pour VIH-1 ou 2 ou HTLV-1 ou 2, ou infection virale active à VHB ou à VHC
- Femme enceinte (bêta HCG positives) ou en cours d'allaitement
- Patient incapable majeur, sous tutelle, curatelle ou sauvegarde de justice
- Patient sous Aide Médicale d’Etat
- Patient participant à un autre essai interventionnel ou ayant participé à un essai interventionnel dont la période d’exclusion est toujours en cours

E.5 End points

E.5.1

Primary end point(s)

Overall survival

Survie globale

E.5.1.1

Timepoint(s) of evaluation of this end point

from randomization up to the end of the study

depuis la randomisation jusqu'à la fin de l'étude

E.5.2

Secondary end point(s)

- response to therapy
- minimal residual disease positivity
- allogenein hematopoeitic stem cell transplantation therapy
- duration of remission
- relapse-free survival
- event-free survival
- quality of life
- adverse events

- réponse à la thérapie
- taux de maladie résiduelle positive
- transplantation de cellules souches hématopoïétiques allogéniques
- durée de rémission
- survie sans progression
- survie sans événement
- qualité de vie
- événements indésirables

E.5.2.1

Timepoint(s) of evaluation of this end point

from randomisation up to the end of the study for all secondary end points exepted for quality of life (at baseline, at evaluation of the complete remission, on Day 1 before dosing of each post-remission cycle, at end of the study treatment) and for adverse events (during the whole study period)

depuis la randomisation jusqu'à la fin de l'étude pour tous les critères de jugement secondaires sauf pour la qualité de vie (avant tout traitement, lors de l'évaluation de la rémission complète, le premier jour après chaque cycle post-remission et à la fin du traitement) et pour les événements indésirables (durant toute la durée 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)

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)

Yes

E.8.2.2

Placebo

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

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

DVDP

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

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

142

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)

It is not different from expected in progressive disease. It will be decided as per usual center practice

Il n'est pas différent de celui en cas de progression. Il sera décidé conformément à la pratique habituelle des centres

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

2019-04-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-16

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

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