Clinical Trials Register

Summary
EudraCT Number:	2010-023809-36
Sponsor's Protocol Code Number:	GIMEMAAML1310
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-20
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

2010-023809-36

A.3

Full title of the trial

Risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia.

A.3.1

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

Therapy for young and adult patients with early phase acute myeloid leukaemia, adjusted according to minimal residual disease and other risk factors for relapse.

Terapia per pazienti giovani e adulti affetti da leucemia mieloide acuta all’esordio adattata sulla base della malattia minima residua e altri fattori di rischio per la recidiva.

A.3.2

Name or abbreviated title of the trial where available

GIMEMA AML1310

A.4.1

Sponsor's protocol code number

GIMEMAAML1310

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	G.I.M.E.M.A. GRUPPO ITALIANO MALATTIE EMATOLOGICHE DELL'ADULTO
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	Associazione Italiana contro le Leucemie (AIL)
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	GIMEMA
B.5.2	Functional name of contact point	Centro Dati
B.5.3	Address:
B.5.3.1	Street Address	Via Casilina, 5
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00182
B.5.3.4	Country	Italy
B.5.4	Telephone number	06 70390526
B.5.5	Fax number	06 70390540
B.5.6	E-mail	gimema@gimema.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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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/3/03/154
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	HYDROXYCARBAMIDE
D.3.9.1	CAS number	127-07-1
D.3.9.4	EV Substance Code	NA
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	NA
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	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	ARA-C
D.3.9.1	CAS number	147-94-4
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	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: 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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	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	ETOPOSIDE
D.3.9.1	CAS number	33419420
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.3	Concentration number	NA
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	Powder for solution for injection
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	DAUNORUBICIN
D.3.9.1	CAS number	20830813
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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: 5
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	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	ARA-C
D.3.9.1	CAS number	147-94-4
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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: 6
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	Powder for solution for injection
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	DAUNORUBICIN
D.3.9.1	CAS number	20830813
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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: 7
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FLUDARABINE
D.3.9.1	CAS number	21679141
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.3	Concentration number	NA
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: 8
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	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	ARA-C
D.3.9.1	CAS number	147-94-4
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2000
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: 9
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IDARUBICIN
D.3.9.1	CAS number	58957929
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.3	Concentration number	NA
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

Acute myeloid leukaemia

Leucemia mieloide acuta

E.1.1.1

Medical condition in easily understood language

Tumoral disease affecting some bone marrow's cells, especially those who should generate a type of white cells (granulocytes).

Malattia tumorale che colpisce alcune cellule del midollo osseo, in particolare quelle che dovrebbero dare origine ad un tipo di globuli bianchi (granulociti).

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The objective of the trial is to evaluate the treatment strategy in terms of Overall Survival (OS) at 24 months

L’obiettivo dello studio è valutare la strategia del trattamento in termini di sopravvivenza globale (OS: overall survival) a 24 mesi.

E.2.2

Secondary objectives of the trial

− Disease Free Survival (DFS) − Event Free Survival (EFS) − Cumulative incidence of relapse (CIR) − Response rate after induction therapy − Safety: adverse events (AE) and serious AE (SAE) − OS, EFS, DFS and CIR in different risk groups − OS, EFS, DFS and CIR according to the MRD level − Response rate, OS, EFS, DFS and CIR according to baseline characteristics such as age, performance status, white blood cell (WBC), morphology, cytogenetic and molecular features. − Quality of Life evaluation

− Sopravvivenza libera da malattia (DFS: Disease Free Survival); − Sopravvivenza libera da eventi (EFS: Event Free Survival); − Incidenza Cumulata di Recidiva (CIR: Cumulative Incidence of Relapse); − Tasso di risposta dopo la terapia d’induzione; − Safety: eventi avversi (AE) ed eventi avversi gravi (SAE); − OS, EFS, DFS e CIR nei differenti gruppi di rischio; − OS, EFS, DFS e CIR secondo il livello di Malattia Minima Residua (MMR); − Percentuale di risposta, OS, EFS, DFS e CIR secondo le caratteristiche di base: età, performance status, globuli bianchi, morfologia, citogenetiche e molecolare; − Valutazione della qualità di vita.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

LIFE QUALITY:
Vers:1
Date:2011/03/07
Title:Quality of life evaluation
Objectives:Primary objective: to investigate the baseline (i.e. pre-treatment) prognostic value for OS of patient’s QoL parameters at 24 months. Secondary Objectives: - to depict the baseline patients’ QoL profile in relation to clinical and laboratory values (including cytogenetic data). - to investigate the prognostic value of early changes of QoL (from baseline to post-induction therapy) for OS and CR. - to investigate the baseline prognostic value of QoL parameters for CR. - to prospectively describe patients’ QoL over time.

OTHER SUBSTUDIES:
v1 7/3/2011 1)MRD: to compare prospectively LAIP and molecular approach. 2)Analysis of genomic copy-number alterations:diagnosis and risk stratification. 3)Proteomic profiling:cell pathogenesis

QUALITA DELLA VITA:
Vers:1
Data:2011/03/07
Titolo:Stima della qualità di vita
Obiettivi:Obiettivo principale: verificare il valore prognostico al basale (es: pre-trattamento) per l’OS dei parametri di QoL dei pazienti a 24 mesi. Obiettivi Secondari: - descrivere il profilo di QoL dei pazienti al basale in relazione ai valori clinici e di laboratorio (inclusi i dati di citogenetica). - verificare il valore prognostico di cambiamenti precoci di QoL (dal basale alla terapia post-induzione) per OS e CR. - verificare il valore prognostico al basale dei parametri di QoL per la CR. - descrivere prospetticamente la QoL nel tempo.

ALTRI SOTTOSTUDI:
v1 7/3/2011 1)MRD:paragone prospettico di LAIP e approccio molecolare. 2)Analisi duplicazioni genomiche:diagnosi e stratificazione rischio. 3)Profilo proteomico:patogenesi cellulare.

E.3

Principal inclusion criteria

- Signed written informed consent according to ICH/EU/GCP and national/local laws - Patients aged between 18 and 60 years - Patients previously untreated for their AML by other chemotherapeutic agents (with the exception of no more than 7 days HU), radiotherapy or more than 7 days corticosteroids - Unequivocal diagnosis of untreated de novo AML according to WHO diagnostic criteria (at least 20% blasts in the bone marrow), with FAB classification other than M3 (acute promyelocytic leukemia), documented by bone marrow aspiration (or biopsy in case of dry tap) (not supervening after other myeloproliferative disease or myelodysplastic syndromes of more than 6 months duration) - WHO performance status 0-3 - Adequate renal (serum creatinine < 2 x the institutional ULN) and liver (total serum bilirubin < 2 x ULN; serum ALT and AST ≤ 3 x ULN) function, unless considered due to organ leukemic involvement - Left Ventricular Ejection Fraction (LVEF) >50%, as determined by echocardiogram - Absence of severe concomitant neurological or psychiatric diseases and congestive heart failure or active uncontrolled infection - Absence of any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and the follow-up schedule.

- Firma del consenso informato scritto in accordo con le normative ICH/EU/GCP e le leggi nazionali; - Pazienti di età compresa tra i 18 ed i 60 anni; - Pazienti affetti da leucemia mieloide acuta non precedentemente trattata con radioterapia, più di sette giorni di corticosteroidi o altri agenti chemioterapici (con l’eccezione di non più di sette giorni di idrossiurea); - Diagnosi inequivocabile di leucemia mieloide acuta all’esordio non trattata, secondo i criteri diagnostici WHO (almeno il 20% di blasti nel midollo osseo), con classificazione FAB oltre M3 (leucemia acuta promielocitica), documentato da aspirato midollare (o biopsia in caso di punctio sicca), non sopraggiunta dopo altre patologie mieloproliferative o sindromi mielodisplastiche di durata maggiore di sei mesi; - Performance status WHO 0-3; - Appropriata funzionalità renale (creatinina sierica < 2 x ULN) ed epatica (bilirubina sierica totale <2 x ULN; ALT e AST sieriche ≤ 3 x ULN), se non considerate come dovute al coinvolgimento della leucemia; - Frazione di eiezione ventricolare sinistra (LVEF) >50%, determinata con ecocardiogramma; - Assenza di gravi patologie psichiatriche o neurologiche concomitanti e insufficienza cardiaca congestizia o infezione attiva non controllata; - Assenza di qualsiasi condizione psicologica, familiare, sociologica e geografica che potenzialmente ostacoli l’aderenza al protocollo di studio ed al programma di follow up.

E.4

Principal exclusion criteria

- Patients aged less than 18 or more than 60 years - Patients already treated for their AML by other chemotherapeutic agents (with the exception of no more than 7 days HU), radiotherapy or more than 7 days corticosteroids - Acute promyelocytic leukaemia - Blast crisis of chronic myeloid leukaemia - AML supervening after other myeloproliferative disease - AML supervening after antecedent myelodysplastic syndromes of more than 6 months duration - Other progressive malignant diseases. However, secondary AML following previously cured malignancies may be included as well as secondary AML following previous exposure to alkylating agents or radiation for other reason - Inadequate renal or liver function (metabolic abnormalities > 3 times the normal upper limit) - Severe heart failure requiring diuretics - Ejection fraction < 50% - Uncontrolled infections - WHO performance status = 4 - Severe concomitant neurological or psychiatric diseases - Patients who are pregnant or adults of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of Dasatinib. Post-menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.

- Pazienti con meno di 18 anni e più di 60; - Pazienti la cui leucemia mieloide acuta sia già stata trattata con radioterapia, più di sette giorni di corticosteroidi o altri agenti chemioterapici (con l’eccezione di non più di sette giorni di idrossiurea); - Leucemia acuta promielocitica; - Crisi blastica di leucemia mieloide cronica; - Leucemia mieloide acuta manifestatesi dopo un’altra patologia mieloproliferativa; - Leucemia mieloide acuta manifestatesi dopo una precedente sindrome mielodisplastica della durata di più di sei mesi; - Altre patologie maligne in progressione. Comunque, la leucemia mieloide acuta a seguito di precedenti malignità guarite può essere inclusa come leucemia mieloide acuta secondaria, successiva ad una precedente esposizione ad agenti alchilanti o a radiazioni per altri motivi; - funzionalità renale ed epatica inappropriate (anormalità metaboliche >3 volte il valore normale limite superiore); - Grave deficit cardiaco che necessiti di diuretici; - Frazione di eiezione <50%; - Infezioni non controllate; - Performance status WHO=4; - Gravi patologie neurologiche o psichiatriche concomitanti; - Pazienti in gravidanza o adulti potenzialmente fertili che non utilizzino metodi anticoncezionali. Donne potenzialmente in gravidanza devono avere un test sierico di gravidanza negativo entro le quarantotto ore precedenti la somministrazione del trattamento. Le donne in post-menopausa devono essere amenorroiche per almeno dodici mesi al fine di essere considerate non potenzialmente fertili. I pazienti maschi e femmine devono acconsentire all’utilizzo di un efficace metodo anticoncezionale di barriera durante tutto lo studio e fino ai tre mesi successivi l’interruzione del trattamento in studio.

E.5 End points

E.5.1

Primary end point(s)

To determinate if the Risk-adapted, MRD-directed therapy improves the estimation of Overall Survival (OS) at 24 months from study entry.

Determinare se la terapia rischio adattata, orientata verso la malattia minima residua, migliora la stima di sopravvivenza globale a 24 mesi dall'entrata nello studio.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months

24 mesi

E.5.2

Secondary end point(s)

Secondary study end-points are: 1. Estimation of Disease Free Survival (DFS) from CR evaluation. 2. Estimation of Event Free Survival (EFS) from study entry. 3. Estimation of Cumulative incidence of relapse (CIR) from CR evaluation. 4. Rate of patients in CR after induction therapy 5. Toxicity according to CTCAE version 4.0 6. Estimation of OS, EFS, DFS and CIR according to risk groups (Low, Intermediate, High) 7. Estimation of OS, EFS, DFS and CIR according to the MRD level at each evaluation step 8. Rate of CR patients and estimation OS, EFS, DFS and CIR according to baseline characteristics such as age, performance status, white blood cell (WBC), morphology, cytogenetic and molecular features. 9. Quality of Life evaluation

Gli endpoint secondari dello studio sono: 1 Stima della sopravvivenza libera da malattia, a partire dalla valutazione della remissione completa. 2 Stima della sopravvivenza libera da evento, a partire dall’entrata nello studio. 3 Stima dell’incidenza cumulata di recidiva, a partire dalla valutazione della remissione completa. 4 Percentuale di pazienti in remissione completa, dopo la terapia di induzione. 5 Tossicità secondo il CTCAE v.4.0. 6 Stima della sopravvivenza globale, della sopravvivenza libera da malattia, della sopravvivenza libera da evento e dell’incidenza cumulata di recidiva stratificate per i gruppi di rischio (basso, intermedio, alto). 7 Stima della sopravvivenza globale, della sopravvivenza libera da malattia, della sopravvivenza libera da evento e dell’incidenza cumulata di recidiva stratificate per il livello di malattia minima residua ad ogni valutazione. 8 Percentuale di pazienti in remissione completa e stima della sopravvivenza globale, della sopravvivenza libera da malattia, della sopravvivenza libera da evento e dell’incidenza cumulata di recidiva stratificate per le caratteristiche al basale come età, performance status, conta dei globuli bianchi, caratteristiche morfologiche, citogenetiche e molecolari. 9 Valutazione della qualità di vita.

E.5.2.1

Timepoint(s) of evaluation of this end point

During and at the end of the treatment

Durante ed alla fine del trattamento

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

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

Information not present in EudraCT

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

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:

237

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

237

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)

Observation during follow up

Osservazione al follow up

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

2011-05-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-10-26

P. End of Trial
P.	End of Trial Status	Completed

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