Clinical Trials Register

Summary
EudraCT Number:	2021-002007-35
Sponsor's Protocol Code Number:	AVENHIR
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-12-27
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

2021-002007-35

A.3

Full title of the trial

Phase II study with safety run-in of Azacitidine (AZA) combined with Venetoclax (VEN) in patients with higher-risk Chronic Myelomonocytic Leukemia (CMML)

Étude de phase II avec phase pilote de tolérance visant à évaluer le vénétoclax en association avec l’azacitidine chez des patients atteints de leucémies myélomonocytaires chroniques de risque intermédiaire ou élevé

A.3.1

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

Study of safety and efficacy of Venetoclax in combination with Vidaza (Azacitidine) in higher-risk Chronic Myelomonocytic Leukemia (CMML)

Étude évaluant le traitement par vénétoclax et vidaza (azacitidine) chez des patients atteints de leucémies myélomonocytaires chroniques de risque intermédiaire ou élevé

A.4.1

Sponsor's protocol code number

AVENHIR

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	Groupe Francophone des Myélodysplasies (GFM)
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	AbbVie
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	Groupe Francophone des Myélodysplasies (GFM)
B.5.2	Functional name of contact point	Fatiha CHERMAT
B.5.3	Address:
B.5.3.1	Street Address	Hôpital Saint Louis - Service Hématologie Séniors - 1 avenue Claude Vellefaux
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	+33171 20 70 59
B.5.5	Fax number	+33171 20 70 38
B.5.6	E-mail	fatiha.chermat-ext@aphp.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	Venclyxto
D.2.1.1.2	Name of the Marketing Authorisation holder	AbbVie Deutschland GmbH & Co. KG
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Venclyxto
D.3.2	Product code	ABT-199
D.3.4	Pharmaceutical form	Film-coated 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	Venetoclax
D.3.9.1	CAS number	1257044-40-8
D.3.9.4	EV Substance Code	SUB176260
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 to 100
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	Vidaza
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Ltd
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	Vidaza MDS : EU/3/01/084
D.3 Description of the IMP
D.3.1	Product name	Vidaza
D.3.4	Pharmaceutical form	Powder for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Azacitidine
D.3.9.1	CAS number	320-67-2
D.3.9.4	EV Substance Code	SUB05624MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200 and 300
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

Newly diagnosed, HMA-naïve, higher-risk (HR, defined as CPSS risk intermediate-2 or high) CMML patients

Patients atteints de LMMC de risque élevé, nouvellement diagnostiqués, n'ayant jamais reçu d'hypométhylants

E.1.1.1

Medical condition in easily understood language

Newly diagnosed, HMA-naïve, higher-risk CMML patients

Patients nouvellement diagnostiqués d'une LMMC de risque élevé n'ayant jamais reçu d'agents hypométhylants

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10054350
E.1.2	Term	Chronic myelomonocytic leukemia
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 the efficacy and safety of venetoclax in the study population

Évaluer l'efficacité et la tolérance du vénétoclax en association avec l’azacitidine

E.2.2

Secondary objectives of the trial

To explore potential biomarkers

Rechercher des biomarqueurs potentiels

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1- Age 18 and older.
2- CMML diagnosis according to WHO 2016 criteria.
3- Intermediate-2 or high risk according to the CMML Prognostic Scoring System (CPSS, Such Blood 2013).
4- No prior treatment with HMAs. Prior treatment with Erythropoiesis Stimulating Agents (ESA) is allowed with a > 15 days washout from ESAs. Prior treatment with hydroxurea (HY) for < 6 weeks is acceptable.
5- ECOG Performance status 0-2.
6- Adequate organ function: total bilirubin < 2 times upper limit of normal (ULN), ALT and AST < 3 times ULN, creatinine clearance > 30 mL/min.
7- Signed Informed Consent Form (ICF).
8- Negative pregnancy and adequate contraception (including in male patients) if relevant.
9- Affiliation to a health insurance system.

1- Âge ≥ 18 ans.
2- Diagnostic de LMMC selon les critères OMS 2016.
3- LMMC de risque intermédiaire-2 ou élevé selon le score CPSS (Such Blood 2013).
4- Aucun traitement préalable par des agents hypométhylants.
Un traitement antérieur avec des agents stimulant l’érythropoïèse est autorisé si stoppé depuis plus de 15 jours.
Un traitement antérieur par hydroxyurée (HY) pendant moins de 6 semaines
est autorisé.
5- ECOG 0-2.
6- Fonctions hépatique et rénale adéquates : bilirubine totale < 2 x LSN, ALT et AST < 3 x LSN, clairance de la créatinine > 30 ml/min.
7- Formulaire de consentement éclairé signé.
8- Test de grossesse négatif et contraception adéquate (y compris chez les patients de sexe masculin).
9- Couverture sociale.

E.4

Principal exclusion criteria

1- Myeloproliferative / myelodysplastic syndrome other than CMML.
2- Bone marrow or peripheral blood blasts (including promonocytes) ≥ 20%.
3- CMML with t(5;12) or PDGFRß rearrangement that may be treated with imatinib.
4- Unavailable CPSS at inclusion (WBC prior to HY used to compute CPSS at inclusion in HY-exposed patients) or with a CPSS low or intermediate-1 at study entry.
5- Pregnant or breastfeeding.
6- Serious concomitant systemic disorder, including auto-immune or auto-inflammatory disease requiring > 20 mg/d prednisone equivalent, active bacterial, fungal or viral infection that in the opinion of the investigator, would compromise the safety of the patient and/or his/her ability to complete the study.
7- Medical condition requiring therapies with CYP3A strong or moderate inducing or inhibiting activity at screening.
8- Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, asymptomatic prostatic cancer not requiring treatment, or other tumors if not active during the last 2 years).
9- Known positive test for human immunodeficiency virus (HIV).
10- Malabsorption syndrome or other condition that precludes an enteral route of administration.
11- Previous therapy with a hypomethylating agent for CMML or any antecedent condition.
12- Previous therapy with a BH3 mimetic.
13- Antecedent allogeneic stem cell transplantation (HSCT) for CMML or an antecedent of hematological malignancy. Those never transplanted but eligible for HSCT are eligible for the trial.

1- Syndrome myéloprolifératif / myélodysplasique autre que la LMMC.
2- Blastes médullaires ou sanguins (promonocytes compris) ≥ 20 %.
3- LMMC avec t(5;12) ou réarrangement du PDGFRß pouvant être traité par imatinib.
4- Score CPSS non disponible à l'inclusion (pour les patients traités par hydroxyurée, score CPSS à calculer en prenant en compte le taux de GB avant l’initiation de l’hydroxyurée) ou avec un score CPSS faible ou intermédiaire-1 à l'inclusion.
5- Femme enceinte ou allaitante.
6- Trouble systémique concomitant grave, notamment :
maladie auto-immune ou auto-inflammatoire nécessitant une prise d'équivalent prednisone > 20 mg/j, une infection bactérienne, fongique ou virale active qui, de l'avis de l'investigateur, compromettrait la sécurité du patient et/ou sa capacité à mener à bien l'étude.
7- État pathologique nécessitant des traitements ayant une activité inductrice ou inhibitrice forte ou modérée du CYP3A.
8- Antécédents de cancer (exceptés les carcinomes in situ du col de l'utérus, les carcinomes basocellulaires limités, les cancers asymptomatiques de la prostate ne nécessitant pas de traitement, ou autres tumeurs si non actives au cours des 2 dernières années).
9- Infection connue par le virus de l'immunodéficience humaine (VIH).
10- Syndrome de malabsorption ou autre affection empêchant l'administration par voie entérale.
11- Traitement antérieur avec un agent hypométhylant.
12- Traitement antérieur avec un BH3 mimétique.
13- Antécédent de greffe de cellules souches allogéniques.
Les personnes qui n'ont jamais été greffées mais qui sont éligibles à une allogreffe sont éligibles à cet essai.

E.5 End points

E.5.1

Primary end point(s)

Safety run-in: dose-limiting toxicity occurring within the first two cycles of treatment.

Phase II: Overall response rate (ORR) after 3 and 6 cycles according to protocol-defined criteria modified from MDS/MPN IWG criteria (Savona Blood. 2015 Mar 19; 125(12): 1857–1865). Overall response includes complete remission (CR), partial remission (PR), marrow response (MR) and clinical benefit (CB).

Phase pilote : évaluation au cours des 2 premiers cycles de traitement de la dose toxique limitante.

Phase II : taux de réponse globale après 3 et 6 cycles selon les critères IWG SMD/SMP modifiés (Savona Blood. 2015 Mar 19; 125(12) : 1857-1865). La réponse globale comprend la rémission complète (RC), la rémission partielle (RP), la réponse médullaire (RCm) et le bénéfice clinique (BC).

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety run in : after cycle 2

Phase II : after 3 and 6 cycles

Phase pilote : après le cycle 2

Phase II : après 3 et 6 cycles

E.5.2

Secondary end point(s)

CR rate after 3 and 6 cycles according to MDS/MPN IWG criteria.
ORR at best response according to MDS/MPN IWG criteria.
ORR after 3 and 6 cycles, and at best response according to DACOTA response criteria (ie modified MDS IWG 2006 criteria, Braun Blood 2011).
Duration of Response (according to MDS/MPN IWG criteria).
Safety profile (both hematological and non-hematological) of venetoclax in combination with azacitidine.
Overall Survival (OS).
AML-free survival (AMLFS).
Progression-free survival (PFS).
Event-free survival (EFS).
Cumulative incidence of AML and cumulative risk of death without AML.
Cumulative incidence of progressive disease (or AML transformation) and cumulative risk of death without progression or AML transformation.
Rate of HSCT and post-HSCT OS and AMLFS.
OS, AMLFS and PFS censoring at HSCT.
Rate and description of subsequent therapy.
OS, AMLFS and PFS censoring at subsequent therapy.

Taux de RC après 3 et 6 cycles selon les critères IWG SMD/SMP.
Taux de réponse globale à la meilleure réponse selon les critères IWG SMD/SMP.
Taux de réponse globale après 3 et 6 cycles, et à la meilleure réponse selon les critères IWG 2006 modifiés utilisés dans le cadre de l’étude DACOTA.
Durée de la réponse (réponse selon les critères IWG SMD/SMP).
Profil de toxicité (hématologique et non hématologique) du vénétoclax en association avec l'azacitidine.
Survie globale.
Survie sans transformation en LAM.
Survie sans progression.
Survie sans événement.
Incidence cumulative de transformation en LAM et risque cumulatif de décès sans transformation en LAM.
Incidence cumulative de progression (ou de transformation en LAM) et risque cumulatif de décès sans progression ou transformation en LAM.
Taux d’allogreffe et survie globale et sans transformation en LAM post allogreffe.
Survie globale, survie sans transformation en LAM, survie sans progression censurées à l’allogreffe.
Thérapie ultérieure (description).
Survie globale, survie sans transformation en LAM, survie sans progression censurées à l’initiation du traitement ultérieur.

E.5.2.1

Timepoint(s) of evaluation of this end point

after LPLV (EOS)

A la fin de l'essai

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.8.2.4

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

LVLS

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

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)

After conclusion of the clinical trial, patients will receive further standard medical care as usual for this kind of disease.

Après la fin de l'essai clinique, les patients recevront des soins médicaux standard habituels pour ce type de maladie.

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

2023-01-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-03-02

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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