Clinical Trials Register

Summary
EudraCT Number:	2018-000397-30
Sponsor's Protocol Code Number:	Ponatinib-3001
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:	2021-01-22
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

2018-000397-30

A.3

Full title of the trial

A Phase 3, Randomized, Open-label, Multicenter Study Comparing Ponatinib Versus Imatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Studio multicentrico di fase 3, randomizzato, in aperto per confrontare ponatinib rispetto a imatinib, somministrati in combinazione con chemioterapia a intensità ridotta, in pazienti con nuova diagnosi di leucemia linfoblastica acuta positiva per il cromosoma Philadelphia (LLA Ph+)

A.3.1

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

An Efficacy Study Comparing Ponatinib Versus Imatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in Participants With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Studio di efficacia per comparare ponatinib versus imatinib, somministrati in combinazione con chemioterapia ad intensità ridotta, in pazienti con nuova diagnosi di leucemia linfoblastica acuta positiva per il cromosoma Philadelphia (LLA Ph+)

A.3.2

Name or abbreviated title of the trial where available

An Efficacy Study Comparing Ponatinib Versus Imatinib, Administered in Combination With Reduced-Inte

Studio di efficacia per comparare ponatinib versus imatinib, somministrati in combinazione con chemi

A.4.1

Sponsor's protocol code number

Ponatinib-3001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03589326

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1206-2370

A.5.4

Other Identifiers

Name:

Ponatinib-3001

Number:

Ponatinib-3001

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	MILLENNIUM PHARMACEUTICALS, INC.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Millennium Pharmaceuticals, Inc.
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	Millennium Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Drug Information Call Center
B.5.3	Address:
B.5.3.1	Street Address	40 Lansdowne St
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	02139
B.5.3.4	Country	United States
B.5.4	Telephone number	0015107402412
B.5.5	Fax number	0018008816092
B.5.6	E-mail	medical@mlnm.com

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.2.5	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	ponatinib
D.3.2	Product code	[AP24534]
D.3.4	Pharmaceutical form	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	PONATINIB
D.3.9.1	CAS number	943319-70-8
D.3.9.2	Current sponsor code	Ponatinib
D.3.9.3	Other descriptive name	PONATINIB
D.3.9.4	EV Substance Code	SUB91901
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	15
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	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.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	Cellcristin® 1 mg/ml Injektionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	STADAPHARM GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	cellcristin® 1 mg/ml Injektionslösung
D.3.2	Product code	[Vincristina]
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	VINCRISTINA
D.3.9.1	CAS number	57-22-7
D.3.9.2	Current sponsor code	Vincristine
D.3.9.3	Other descriptive name	Vincristine
D.3.9.4	EV Substance Code	SUB00059MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	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.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.2.1.1.1	Trade name	Methotrexat-GRY® 5000 mg/50 ml Konzentrat zur Herstellung einer Infusionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Methotrexat-GRY®
D.3.2	Product code	[Metotressato]
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	METOTREXATO
D.3.9.1	CAS number	59-05-2
D.3.9.2	Current sponsor code	Methotrexate
D.3.9.3	Other descriptive name	Methotrexate
D.3.9.4	EV Substance Code	SUB08856MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	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	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.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.2.1.1.1	Trade name	Calciumfolinat-GRY® 15 mg Tabletten
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Calciumfolinat
D.3.2	Product code	[Calciumfolinat]
D.3.4	Pharmaceutical form	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	CALCIO FOLINATO
D.3.9.1	CAS number	1492-18-8
D.3.9.2	Current sponsor code	Folinic Acid
D.3.9.3	Other descriptive name	Folinic Acid
D.3.9.4	EV Substance Code	SUB13910MIG
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	15
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	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.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.2.1.1.1	Trade name	Dexamethasone Krka
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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	Desametasone
D.3.2	Product code	[Desametasone]
D.3.4	Pharmaceutical form	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	DESAMETASONE
D.3.9.1	CAS number	50-02-2
D.3.9.2	Current sponsor code	Dexamethasone
D.3.9.3	Other descriptive name	Dexamethasone
D.3.9.4	EV Substance Code	SUB07017MIG
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	20
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	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.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.2.1.1.1	Trade name	Alexan
D.2.1.1.2	Name of the Marketing Authorisation holder	EBEWE Pharma Ges.m.b.H. Nfg.
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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	Citarabina
D.3.2	Product code	[Citarabina]
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	CITARABINA
D.3.9.1	CAS number	147-94-4
D.3.9.2	Current sponsor code	Cytarabine
D.3.9.3	Other descriptive name	Cytarabine
D.3.9.4	EV Substance Code	SUB06880MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	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	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.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.2.5	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	ponatinib
D.3.2	Product code	[AP24534]
D.3.4	Pharmaceutical form	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	PONATINIB
D.3.9.1	CAS number	943319-70-8
D.3.9.2	Current sponsor code	Ponatinib
D.3.9.3	Other descriptive name	Ponatinib
D.3.9.4	EV Substance Code	SUB91901
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	45
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	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.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.2.1.1.1	Trade name	Prednison 50 mg GALEN Tabletten
D.2.1.1.2	Name of the Marketing Authorisation holder	GALENpharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Prednison 50 mg GALEN Tabletten
D.3.2	Product code	[Prednisone]
D.3.4	Pharmaceutical form	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	PREDNISONE
D.3.9.1	CAS number	53-03-2
D.3.9.2	Current sponsor code	Prednisone
D.3.9.3	Other descriptive name	Prednisone
D.3.9.4	EV Substance Code	SUB10020MIG
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	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	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.IMP: 9
D.1.2 and D.1.3	IMP Role	Comparator
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	Glivec
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	Imatinib
D.3.2	Product code	[STI571]
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	IMATINIB MESILATO
D.3.9.1	CAS number	152459-95-5
D.3.9.2	Current sponsor code	Imatinib
D.3.9.3	Other descriptive name	IMATINIB
D.3.9.4	EV Substance Code	SUB25387
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	400
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	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.IMP: 10
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	Dexagalen® 4mg injekt, Injektionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	GALENpharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Dexagalen® 4mg injekt, Injektionslösung
D.3.2	Product code	[Desametasone]
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	DESAMETASONE
D.3.9.1	CAS number	50-02-2
D.3.9.2	Current sponsor code	DEXAMETHASONE
D.3.9.3	Other descriptive name	DEXAMETHASONE
D.3.9.4	EV Substance Code	SUB07017MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
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	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.IMP: 11
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.2.5	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	ponatinib
D.3.2	Product code	[AP24534]
D.3.4	Pharmaceutical form	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	PONATINIB
D.3.9.1	CAS number	943319-70-8
D.3.9.2	Current sponsor code	Ponatinib
D.3.9.3	Other descriptive name	PONATINIB
D.3.9.4	EV Substance Code	SUB91901
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
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	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.IMP: 12
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	Calciumfolinat-GRY® 100 mg/10 ml Injektionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Calciumfolinat-GRY® 100 mg/10 ml Injektionslösung
D.3.2	Product code	[Calciumfolinat]
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	CALCIO FOLINATO
D.3.9.1	CAS number	1492-18-8
D.3.9.2	Current sponsor code	Folinic Acid
D.3.9.3	Other descriptive name	Folinic Acid
D.3.9.4	EV Substance Code	SUB13910MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	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.IMP: 13
D.1.2 and D.1.3	IMP Role	Comparator
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	Glivec
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	Imatinib
D.3.2	Product code	[STI571]
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	IMATINIB MESILATO
D.3.9.1	CAS number	152459-95-5
D.3.9.2	Current sponsor code	Imatinib
D.3.9.3	Other descriptive name	Imatinib
D.3.9.4	EV Substance Code	SUB25387
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	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	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

Newly Diagnosed Philadelphia Chromosome¿Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Nuova diagnosi di leucemia linfoblastica acuta positiva per il cromosoma Philadelphia (LLA Ph+)

E.1.1.1

Medical condition in easily understood language

Newly Diagnosed Philadelphia Chromosome¿Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Nuova diagnosi di leucemia linfoblastica acuta positiva per il cromosoma Philadelphia (LLA Ph+)

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10080018
E.1.2	Term	Philadelphia positive acute lymphocytic 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 compare the efficacy of ponatinib versus imatinib, administered as first-line therapy in combination with
reduced-intensity chemotherapy, in patients with newly diagnosed Ph+ ALL, as measured by the MRD-negative CR rate at the end of induction.

Confrontare l'efficacia di ponatinib rispetto a imatinib, somministrati come terapia di prima linea in combinazione con chemioterapia a intensità ridotta, in pazienti con nuova diagnosi di LLA Ph+, come misurata in base al tasso di CR MRD-negativa alla fine dell'induzione.

E.2.2

Secondary objectives of the trial

To compare the rates of EFS between the 2 cohorts

Confrontare i tassi di EFS tra le 2 coorti

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients aged 18 years or older.
2. Newly diagnosed Ph+ or BCR-ABL1 positive ALL, as defined by the 2017 National Comprehensive Cancer Network guidelines.
3. Molecular assessment of BCR-ABL1 must demonstrate the presence of a p190 (ie, e1a2) or p210 (ie, e13a2 or
e14a2 [also known as b2a2 or b3a2]) transcript type.
4. Eastern Cooperative Oncology Group performance status of =2.
5. Clinical laboratory values as follows, within 30 days before randomization:
a) Total serum bilirubin =1.5× the upper limit of normal (ULN).
b) Alanine aminotransferase or aspartate aminotransferase =2.5× the ULN.
c) Serum creatinine =1.5× the ULN and estimated creatinine clearance =40 mL/minute (Cockcroft-Gault formula).
d) Serum lipase and amylase <1.5× the ULN.
6. Normal QT interval corrected per Fridericia method (QTcF) on screening electrocardiogram, defined as QTcF of
=450 ms in males or =470 ms in females.
7. Female patients who:
a) Are postmenopausal for at least 1 year before the screening visit, OR
b) Are surgically sterile, OR
c) If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 1 month after the last dose of study drug, OR
d) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal,
spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male
condoms should not be used together.)
8. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a) Agree to practice effective barrier contraception during the entire study treatment period and through
120 days after the last dose of study drug, OR
b) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal,
spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
9. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
10. Willingness and ability to comply with scheduled visits and study procedures.

1. Pazienti di entrambi i sessi di età pari almeno a 18 anni.
2. Nuova diagnosi di LLA Ph+ o BCR-ABL1 positiva, come definita in base alle linee guida 2017 del National Comprehensive Cancer Network.
3. La valutazione molecolare di BCR-ABL1 deve dimostrare la presenza di un tipo di trascritto p190 (ovvero, e1a2) o p210 (ovvero, e13a2 o e14a2 [noti anche come b2a2 o b3a2]).
4. Stato di validità =2 secondo l’Eastern Cooperative Oncology Group (Gruppo cooperativo orientale di oncologia).
5. Valori clinici di laboratorio entro 30 giorni prima della randomizzazione come indicato di seguito:
a) Bilirubina sierica totale =1,5 × il limite superiore della norma (ULN).
b) Alanina aminotransferasi o aspartato aminotransferasi =2,5 × l’ULN.
c) Creatinina sierica =1,5 × l’ULN e clearance della creatinina stimata =40 ml/minuto (formula di Cockcroft-Gault).
d) Lipasi e amilasi sierica <1,5 × l’ULN.
6. Valori normali dell’intervallo QT corretto secondo il metodo Fridericia (QTcF) all’elettrocardiogramma di screening, definiti come QTcF =450 ms negli uomini o =470 ms nelle donne.
7. Pazienti di sesso femminile che:
a) sono in post-menopausa da almeno 1 anno prima della visita di screening; oppure
b) sono chirurgicamente sterili; oppure
c) se in età fertile, accettano di utilizzare 1 metodo contraccettivo altamente efficace insieme a 1 metodo efficace (barriera) aggiuntivo dal momento della firma del consenso informato fino a 1 mese dopo l’ultima dose di farmaco dello studio; oppure
d) accettano di praticare l’astinenza totale, ove in linea con lo stile di vita preferito e abituale del soggetto (l’astinenza periodica [per es., metodi del calendario, dell’ovulazione, sintotermico, post-ovulatorio], il coito interrotto, l’uso di soli spermicidi e l’amenorrea lattazionale non sono metodi contraccettivi accettabili. Preservativi maschili e femminili non devono essere utilizzati insieme).
8. Pazienti di sesso maschile, anche se sottoposti a sterilizzazione chirurgica (ovvero, in stato post-vasectomia), che:
a) accettano di utilizzare una contraccezione barriera efficace durante tutto il periodo di trattamento dello studio e fino a 120 giorni dopo l’ultima dose di farmaco dello studio; oppure
b) accettano di praticare l’astinenza totale, ove in linea con lo stile di vita preferito e abituale del soggetto (l’astinenza periodica [per es., metodi del calendario, dell’ovulazione, sintotermico, post-ovulatorio], il coito interrotto, l’uso di soli spermicidi e l’amenorrea lattazionale non sono metodi contraccettivi accettabili. Preservativi maschili e femminili non devono essere utilizzati insieme).
9. Consenso scritto fornito volontariamente prima dell’esecuzione di qualsiasi procedura correlata allo studio che non rientri nelle cure mediche standard, con l’intesa che il consenso può essere ritirato dal paziente in qualsiasi momento senza pregiudizio per le cure mediche future.
10. Volontà e capacità di attenersi al programma di visite e procedure dello studio.

E.4

Principal exclusion criteria

1. Patients with a history or current diagnosis of chronic phase, accelerated phase, or blast phase chronic myeloid
leukemia.
2. Prior/current treatment with any systemic anticancer therapy (including but not limited to any TKI) and/or
radiotherapy for cancer, with the exception of an optional prephase therapy, which should be discussed with the
sponsor’s medical monitor/designee.
3. Treatment with any investigational products within 30 days before randomization or 6 half-lives of the agent,
whichever is longer.
4. Currently taking drugs that are known to have a risk of causing prolonged QTc or torsades de pointes (unless these can be changed to acceptable alternatives or discontinued) (Appendix E).
5. Taking any medications or herbal supplements that are known to be strong inhibitors or strong inducers of
cytochrome P450 3A4 within at least 14 days before the first dose of study drug.
6. Active serious infection requiring antibiotics within 14 days before the first dose of study drug.
7. Major surgery within 28 days before randomization (minor surgical procedures such as catheter placement or BM biopsy are not exclusionary criteria).
8. Ongoing or active systemic infection, known seropositive HIV, or known active hepatitis B or C infection.
9. History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis.
10. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
11. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are excluded if they have not undergone complete resection.
12. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis,
aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome,
or psychosis.
13. Active ALL in the CNS (confirmed by cerebrospinal fluid analysis).
14. Autoimmune disease with potential CNS involvement.
15. Known significant neuropathy of Grade =2 severity.

1. Anamnesi o attuale diagnosi di leucemia mieloide cronica in fase cronica, in fase accelerata o in fase blastica. 2. Precedente/attuale trattamento con qualsiasi terapia antitumorale sistemica (tra cui, in modo non limitativo, qualsiasi TKI) e/o radioterapia antitumorale, fatto salvo per una terapia prefase facoltativa, che dovrà essere discussa con il responsabile del monitoraggio medico/l’incaricato dello sponsor. 3. Trattamento con prodotti sperimentali entro 30 giorni prima della randomizzazione o 6 emivite dell’agente, a seconda di quale sia il periodo più lungo. 4. Attuale trattamento con farmaci noti per comportare il rischio di prolungamento del QTc o sviluppo di torsade de pointes (a meno che non possano essere sostituiti con alternative accettabili o interrotti) (Appendice E).
5. Assunzione di farmaci o integratori erboristici noti per essere inibitori potenti o induttori potenti del citocromo P450 3A4 nei 14 giorni precedenti l’assunzione della prima dose di farmaco dello studio. 6. Infezione attiva grave che richieda un trattamento antibiotico entro 14 giorni prima della prima dose di farmaco dello studio. 7. Intervento chirurgico maggiore entro 28 giorni prima della randomizzazione (le procedure chirurgiche minori come il posizionamento di catetere o la biopsia del BM non sono criteri di esclusione). 8. Infezione sistemica in corso o attiva, sieropositività nota per il virus dell’immunodeficienza umana (HIV) o infezione attiva nota da epatite B o C. 9. Anamnesi di pancreatite acuta entro 1 anno dallo screening dello studio o anamnesi di pancreatite cronica. 10. Ipertrigliceridemia non controllata (trigliceridi >450 mg/dl). 11. Tumore cutaneo non melanoma o carcinoma in situ di qualsiasi tipo, a meno che non sia stato sottoposto a resezione completa. 12. Anamnesi o presenza di patologia clinicamente rilevante del SNC come epilessia, crisi convulsiva del bambino o dell’adulto, paresi, afasia, ictus, gravi lesioni cerebrali, demenza, malattia di Parkinson, malattia cerebellare, sindrome cerebrale organica o psicosi. 13. LLA attiva a livello del SNC (confermata mediante analisi del liquido cerebrospinale). 14. Malattia autoimmune con potenziale coinvolgimento del SNC. 15. Neuropatia significativa nota con gravità di grado =2

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoint: MRD-negative CR (BCR-ABL/ABL1 =0.01% and meeting criteria for CR)

Endpoint primario di efficacia: CR MRD-negativa (BCR-ABL/ABL1 =0,01% e soddisfacimento dei criteri per la CR)

E.5.1.1

Timepoint(s) of evaluation of this end point

End of 3 cycle induction

Termine di 3 cicli di induzione

E.5.2

Secondary end point(s)

The key secondary endpoint for this study is the rate of event-free survival (EFS). Other secondary endpoints will include rates of CR and incomplete CR (CRi) at the end of Cycle 1, Cycle 2, and the end of induction; rates of molecular response 3-log reduction (MR3, BCR-ABL1/ABL1 =0.1%), MRD negativity (molecular response 4 log reduction [MR4, BCR-ABL1/ABL1 =0.01%]), and molecular response 4.5-log reduction (MR4.5, BCR-ABL1/ABL1 =0.0032%) at the end of Cycle 1, the end of Cycle 2, and the end of induction; rates of primary induction failure (PIF) and overall response rate (ORR) at the end of induction; duration of MRD negative CR; duration of CR; time to treatment failure; rates of MR4.5 at multiple intervals after the end of induction, including best response; duration of MR4.5 in patients who achieved MR4.5; subgroup analyses for on-study patients with and without HSCT (including rates of overall survival [OS] and relapse from CR), and OS. (See Table 13.a for endpoint definitions.)

L'endpoint secondario principale per questo studio è rappresentato dal tasso di sopravvivenza libera da eventi (EFS). Altri endpoint secondari includeranno i tassi di CR e CR incompleta (CRi) alla fine del Ciclo 1, del Ciclo 2 e dell'induzione; i tassi di riduzione di 3 log della risposta molecolare (MR3, BCR-ABL1/ABL1 =0,1%), della negatività MRD (riduzione di 4 log della risposta molecolare [MR4, BCR-ABL1/ABL1 =0,01%] e di riduzione di 4,5 log della risposta molecolare (MR4,5, BCR-ABL1/ABL1 =0,0032%) alla fine del Ciclo 1, del Ciclo 2 e dell'induzione; i tassi di fallimento dell'induzione primaria (PIF) e il tasso di risposta complessiva (ORR) alla fine dell'induzione; la durata della CR MRD-negativa; la durata della CR; il tempo al fallimento del trattamento; i tassi di MR4,5 in corrispondenza di vari intervalli dopo la fine dell'induzione, compresa la migliore risposta; la durata della MR4,5 nei pazienti che hanno raggiunto la MR4,5; analisi di sottogruppo per i pazienti in studio sottoposti e non sottoposti ad HSCT (compresi i tassi di sopravvivenza complessiva [OS] e recidiva dopo CR) e l'OS (vedere Tabella 13.a per le definizioni degli endpoint).

E.5.2.1

Timepoint(s) of evaluation of this end point

-EFS: Baseline up to 3 years -% of Pts with CR and CRi: End of C1 (approximately 1 month), C2 (approximately 2 months) and C3 (approximately 3 months) -% of Pts with Molecular Response: End of cycle 1 (approximately 1 month), cycle 2 (approximately 2 months) and cycle 3: approximately 3 months -Percentage of PIF: Up to 3 months -% of Participants with ORR: Up to 3 months -Duration of MRD-Negative CR: Up to 5 years -Duration of CR: Up to 5 years -Time to Treatment Failure: Every year after 3 years up to 5 years -% of Pts with MR4.5 Including Best Response: Up to 5 years -Duration of MR4.5: Up to 5 years -% of On-Study Pts with OS: Every year after 3 years up to 5 years -% of On-Study Pts with Relapse From CR: Every year after 3 years up to 5 years -OS:Up to 5 years

- EFS: basale fino a 3 anni - % di pz. con CR e CRi: al termine di C1 (approssimativamente 1 mese), C2 (approssimativamente 2 mesi) e C3 (approssimativamente 3 mesi) - % di pazienti con risposta molecolare: fine ciclo 1 (approssimativamente 1 mese), ciclo 2 (approssimativamente 2 mesi) e ciclo 3 (approssimativamente 3 mesi) - % d PIF: fino a 3 mesi - % di pz. con ORR: fino a 3 mesi - Durata CR MRD-negativa: fino a 5 anni - Durata CR: fino a 5 anni - Tempo di fallimento del trattamento: ogni anno dopo 3 anni fino a 5 anni - % di pz. con MR4.5 inclusa miglior risposta: fino a 5 anni -Durata di MR4.5: fino a 5 anni - % di pz in studio con OS: ogni anno dopo 3 anni fino a 5 anni - % di pz in studio con recidiva da CR: ogni anno dopo 3 anni fino a 5 anni - OS: fino a 5 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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Belarus

Brazil

Canada

Israel

Japan

Korea, Republic of

Russian Federation

Taiwan

Turkey

United States

Bulgaria

Finland

Greece

Hungary

Italy

Poland

Romania

Spain

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

The study will be considered completed when the death of all patients has been recorded or when the study has been terminated by the sponsor.

Lo studio sarà considerato completato alla registrazione della morte di tutti i pazienti o quando sarà chiuso dallo Sponsor

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:

272

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

123

F.4.2.2

In the whole clinical trial

320

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Nessuno

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

2019-01-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-07

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

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