Clinical Trials Register

Summary
EudraCT Number:	2017-002094-18
Sponsor's Protocol Code Number:	REL-AML001/2017
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-06-17
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-002094-18

A.3

Full title of the trial

Prospective evaluation of a continuation therapy with Midostaurin in adult patients with
core-binding factor leukemia and integrated genetic analysis: a multi-center phase II study

Valutazione prospettica di una terapia continuativa con Midostaurina in
pazienti adulti con leucemia “core binding factor” e analisi genetica integrata: studio multicentrico di
fase II

A.3.1

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

Prospective evaluation of a continuation therapy with Midostaurin in adult patients with
core-binding factor leukemia and integrated genetic analysis: a multi-center phase II study

Studio multicentrico di fase II. Valutazione prospettica di una terapia continuativa con Midostaurina in pazienti adulti con leucemia mieloide acuta "core-binding factor"

A.3.2

Name or abbreviated title of the trial where available

Prospective evaluation of a continuation therapy with Midostaurin in adult patients with core-bindin

Valutazione prospettica di una terapia continuativa con Midostaurina in pazienti adulti con leucemia

A.4.1

Sponsor's protocol code number

REL-AML001/2017

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	AZIENDA OSPEDALIERA AO OSPEDALE NIGUARDA CA' GRANDA
B.1.3.4	Country	Italy
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	Novartis x midostaurina
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ASST Grande Ospedale Metropolitano Niguarda
B.5.2	Functional name of contact point	Roberto Cairoli
B.5.3	Address:
B.5.3.1	Street Address	Piazza Ospedale Maggiore, 3.
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20162
B.5.3.4	Country	Italy
B.5.4	Telephone number	0264444075
B.5.5	Fax number	0264443263
B.5.6	E-mail	roberto.cairoli@ospedaleniguarda.it

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.2.5	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/3/04/214
D.3 Description of the IMP
D.3.1	Product name	Midostaurina
D.3.2	Product code	[PKC412]
D.3.4	Pharmaceutical form	Capsule, soft
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	MIDOSTAURINA
D.3.9.2	Current sponsor code	Midostaurina
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)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Acute Myeloid Leukemia (AML)

Leucemia Mieloide Acuta

E.1.1.1

Medical condition in easily understood language

Acute Myeloid Leukemia (AML)

Leucemia Mieloide Acuta

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	10000886
E.1.2	Term	Acute myeloid leukemia
E.1.2	System Organ Class	100000004864

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 assess the clinical efficacy of midostaurin in combination with chemoteraphy regimes in induction and consolidation and as single agent in maintenence phase, in patient with CBF-Acute Myeloid Leucemia

Verificare l'efficacia di midostaurina con chemioterapia induzione e consolidamento e agente singolo nella fase di mantenimento, in paziente con CBF LAM

E.2.2

Secondary objectives of the trial

To assess the safety of midostaurin in combination with chemotherapy in induction and consolidation , and as single agent in maintenance phase
To futher assess the efficacy of the protocol treatment, compared to a cohort of historical controls.

Valutare la sicurezza di midostaurina in combinazione
con chemioterapia induzione e consolidamento e agente singolo nella fase di mantenimento.
Verificare l'efficacia del trattamento comparata ad una corte di controllo storica.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures.
2. Patients must be 18 to 65 years of age at the time of signing informed consent.
3. Patients must have an unequivocal diagnosis of de novo-CBFL, prior to start Midostaurin,
documented by rearrangement of Core Binding Factor (CBF) genes, namely AML1-ETO and CBFBMYH11,
either with observation of t(8;21)(q22;q22) or inv(16)(p13; q32)/t(16;16)(p13; q32) by
conventional cytogenetics or hybridization techniques or detection of fusion genes by PCR
4. Patients must be fit to receive an anthracyclin/AraC-based induction therapy (i.e. Ara-C 100
mg/m2 or 200 mg/m2 i.v. day, by continuous infusion for 7 days and Idarubicin 12 mg/m2 i.v. day or
daunomycin 60 mg/m2 on days 1, 3 and 5)
5. Patients must have an ECOG Performance Status of = 2.
6. Patients must have Total Bilirubin = 1.5 x ULN, and AST or ALT = 2.5 x ULN.
7. Patients must have Serum Creatinine = 1.5 x ULN.
8. Women of child-bearing potential must have a negative pregnancy test before starting the
protocol.

Ottenimento di un consenso informato scritto;
· pazienti con età compresa tra 18 e 65 anni al momento della firma del consenso informato;
· i pazienti devono avere una diagnosi certa di Leucemia Mielode Acuta Core-Binding Factor (CBF), ottenuta
con tecniche di biologia molecolare, citogenetica e/o FISH;
· i pazienti devono essere idonei a ricevere una chemioterapia intensiva di induzione (es. ara-C 100 mg/m2/die
o 200 mg/m2/die i.v. in infusione continua per 7 giorni e idarubicina 12 mg/m2/die i.v. o daunorubicina 60
mg/m2/die, nei giorni 1, 3 e 5);
· i pazienti devono avere un performance status ECOG di = 2;
· bilirubina totale = 1,5 x ULN, e AST o ALT = 2,5 x ULN;
· creatinina sierica = 1,5 x ULN;
· le donne in età fertile, devono avere un test di gravidanza negativo, prima di poter iniziare il trattamento

E.4

Principal exclusion criteria

Patients eligible for this study must not meet any of the following criteria:
1. Prior therapy for AML with the following exceptions:
a. emergency leukapheresis
b. emergency treatment for hyperleukocytosis with hydroxyurea for = 7 days
2. Central nervous system involvement
3. Presence of any uncontrolled bacterial, viral or fungal infection
4. Known human immunodeficiency virus (HIV) positive
5. An active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection. Patients whose disease is
controlled under antiviral therapy should not be excluded.
6. Presence of other active malignancies
7. QTc > 470 msec (Bazett formula) on screening ECG
8. Presence of significant uncontrolled or active cardiovascular disease, specifically including,
but not restricted to:
a. Myocardial infarction, unstable angina and/or congestive heart failure within 3 months prior to
randomization
b. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any
ventricular arrhythmia
c. Uncontrolled hypertension
d. Taking medications that are known to be associated with Torsades de Pointes.
9. History of hypersensitivity to any drugs or metabolites of similar chemical classes as the study
treatment.
10. Pregnancy statements and contraception requirements:
Women of child-bearing potential, defined as all women physiologically capable of becoming
pregnant, unless they are using highly effective methods of contraception during dosing and for at
least 4 months after stopping medication. Highly effective contraception methods include:
· Total abstinence (when this is in line with the preferred and usual lifestyle of the subject).
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and
withdrawal are not acceptable methods of contraception
· Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy),
total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of
oophorectomy alone, only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment
· Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be
the sole partner for that subject
· Use of oral, injected or implanted hormonal methods of contraception or placement of an
intrauterine device or intrauterine system, or other forms of hormonal contraception that have
comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone
contraception.

· chemioterapia precedente per AML con le seguenti eccezioni:
1. leucaferesi di emergenza:
2. terapia citoriduttiva con idrossiurea per = 7 giorni, in caso di iperleucocitosi;
· coinvolgimento del sistema nervoso centrale;
· presenza di qualsiasi infezione batterica, virale o fungina attiva e non controllata;
· virus di immunodeficenza umana (HIV) positivo;
· infezione attiva da virus dell'epatite B (HBV) o da virus dell'epatite C (HCV). I pazienti con infezione
controllata, in corso di terapia antivirale, non dovrebbero essere esclusi;
· presenza di altre neoplasie attive;
· QTc > 470 msec (formula Bazett) su ECG dello screening;
· presenza di una significativa malattia cardiovascolare incontrollata o attiva, in particolare, ma non limitato a:
a. infarto miocardico, angina instabile e/o insufficienza cardiaca congestizia entro 3 mesi prima della
randomizzazione;
b. anamnesi clinicamente significativa per aritmia atriale o qualsiasi aritmia ventricolare;
c. ipertensione non controllata;
d. assunzione di farmaci che sono noti per essere associati a rischio di torsione delle punte;
· storia di ipersensibilità a qualsiasi principio attivo o metabolita di classi chimiche simili al farmaco sperimentale;
· gravidanza;
· donne in età fertile, che non utilizzano metodi altamente efficaci di contraccezione durante la somministrazione
del farmaco e per almeno 4 mesi dalla sospensione del farmaco.

E.5 End points

E.5.1

Primary end point(s)

To demonstrate that 2-years Relapse Incidence (RI) in patients treated according to the protocol
treatment plan is 28% or below.

Dimostrare che l'incidenza di recidiva a 2 anni (ri) nei pazienti trattati secondo il piano di trattamento del
protocollo è del 28% o inferiore.

E.5.1.1

Timepoint(s) of evaluation of this end point

two years

2 anni

E.5.2

Secondary end point(s)

· Proportion of patients with AEs, Grade 3 and 4 AEs, SAEs, AEs leading to discontinuation, and deaths.
· To evaluate the Overall Survival rate in the study cohort, compared to a cohort of historical controls.
· To evaluate the Disease Free Survival rate in the study cohort, compared to a cohort of historical controls.
· To evaluate the Event Free Survival rate in the study cohort, compared to a cohort of historical controls.
· To analyze the clinical relevance of molecular mutations (KIT, DNMT3A, FLT3, NPM1, TRKA) in
homogeneously treated CBFL .
· To analyze the kinetics of minimal residual disease (MRD), as measured with PCR techniques and flow
cytometry.

Valutare gli eventi avversi (AE) di grado 3 e 4, gli eventi avversi gravi (SAE) e gli eventi che portano a
sospensione del trattamento.
· Valutare la percentuale di sopravvivenza complessiva nel gruppo coinvolto nello studio, comparandola con i
dati storici del gruppo di controllo.
· Valutare la percentuale di sopravvivenza libera da malattia nel gruppo coinvolto nello studio comparandola con
i dati storici del gruppo di controllo.
· Valutare la percentuale di sopravvivenza libera da eventi nel gruppo coinvolto nello studio, comparandola con i
dati storici del gruppo di controllo.
Analizzare la rilevanza clinica delle mutazioni molecolari (KIT, DNMT3A, FLT3, NPM1, TRKA) in pazienti
con Core-Binding Factor Leukemia.
· Analizzare la cinetica della malattia minima residua con tecniche di PCR e citofluorimetria

E.5.2.1

Timepoint(s) of evaluation of this end point

seven years

7 anni

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

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

Information not present in EudraCT

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

LVLS

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

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

2018-05-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-15

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

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