Clinical Trials Register

Summary
EudraCT Number:	2014-001603-42
Sponsor's Protocol Code Number:	AIL0115
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:	2014-11-07
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

2014-001603-42

A.3

Full title of the trial

“Arrest Imatinib or Dasatinib in CML patients with Deep Molecular Responses” (AID MORE)

"Interruzione di Imatinib o Dasatinib in pazienti con LMC con risposta molecolare profonda" (AID MORE)

A.3.1

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

Arrest Imatinib or Dasatinib in CML patients with Deep Molecular Responses

Interruzione della somministrazione di Imatinib o Dasatinib in pazienti con leucemia mieloide cronica con risposta molecolare profonda

A.3.2

Name or abbreviated title of the trial where available

AID MORE

A.4.1

Sponsor's protocol code number

AIL0115

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	AIL CATANIA ASSOCIAZIONE ITALIANA CONTRO LEUCEMIE-LINFOMI E MIELOMA ONLUS
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	Bristol-Myers Squibb S.r.l.
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	Clinical Trial Consulting ss di Aquilani e Scala
B.5.2	Functional name of contact point	Regulatory Manager
B.5.3	Address:
B.5.3.1	Street Address	Viale Angelico 78
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00195
B.5.3.4	Country	Italy
B.5.4	Telephone number	0699704781
B.5.5	Fax number	0699704962
B.5.6	E-mail	e.scala@clinicaltrialconsultin.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.2.1.1.1	Trade name	SPRYCEL
D.2.1.1.2	Name of the Marketing Authorisation holder	BRISTOL-MYERS SQUIBB PHARMA EEIG
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	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	DASATINIB
D.3.9.1	CAS number	302962-49-8
D.3.9.2	Current sponsor code	n.a.
D.3.9.3	Other descriptive name	DASATINIB
D.3.9.4	EV Substance Code	SUB23322
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DASATINIB
D.3.9.1	CAS number	302962-49-8
D.3.9.2	Current sponsor code	n.a.
D.3.9.3	Other descriptive name	DASATINIB
D.3.9.4	EV Substance Code	SUB23322
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	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DASATINIB
D.3.9.1	CAS number	302962-49-8
D.3.9.2	Current sponsor code	n.a.
D.3.9.3	Other descriptive name	DASATINIB
D.3.9.4	EV Substance Code	SUB23322
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	No
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.IMP: 2
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	United Kingdom
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	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	Imatinib
D.3.9.1	CAS number	152459-95-5
D.3.9.2	Current sponsor code	n.a.
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	No
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

Chronic phase CML patients with BCR-ABL/ABLIS transcript levels below MR3 (<0.1%) and above
MR4.5 (>0.0032%) at the time of accrual.

Pazienti con LMC in fase cronica e con livelli di trascrizione del gene BCR-ABL/ABLIS compresi tra MR3 (<0.1%) e MR4.5 (>0.0032%) da almeno 3 mesi al momento dell’arruolamento.

E.1.1.1

Medical condition in easily understood language

Early chonic phase CML patients.

Pazienti con leucemia mieloide cronica in fase cronica.

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10009015
E.1.2	Term	Chronic 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

Rates of MR4.5 by 12 months of treatment.

Tasso di MR4.5 dopo 12 mesi di trattamento.

E.2.2

Secondary objectives of the trial

• Rates of confirmed MR4.5 at 12 months of treatment;
• Rates of undetectable BCR-ABL1 transcripts;
• Rates of confirmed undetectable BCR-ABL1 transcripts;
• Rates of treatment discontinuation;
• Duration of treatment discontinuation without disease relapse;
• Rates of disease relapse after treatment discontinuation;
• Rates of disease response to TKI treatment after relapse occurring following drug discontinuation;
• Overall Survival;
• Progression-Free Survival;
• Event-Free Survival;
• Failure-Free Survival;
• Quality of Life (using EORTC forms: QLQ-C30 and QLQ-CML).

- Tasso di MR4.5 confermata a 12 mesi
- Tasso di BCR-ABL1 non rilevabile
- Tasso di BCR-ABL1 stabilmente non rilevabile
- Incidenza delle interruzioni del trattamento
- Durata dell’interruzione del trattamento in assenza di ricadute della malattia
- Percentuale di ricadute della malattia in seguito ad interruzione del trattamento
- Tempo di risposta al trattamento con TKI dopo una eventuale ricaduta verificatasi in seguito alla sospensione del farmaco
- Tasso complessivo di sopravvivenza
- Tasso di sopravvivenza senza progressione della malattia
- Tasso di sopravvivenza in assenza di eventi
- Tasso di sopravvivenza in assenza di recidive
- Qualità della vita (valutata sulla base dei questionari EORTC: QLQC30 e QLQ-CML24).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Chronic phase CML patients with BCR-ABL/ABLIS transcript levels below MR3 (<0.1%) and above MR4.5 (>0.0032%) at the time of accrual. BCR-ABL/ABLIS transcripts will be validated in the
Laboratory of Experimental Oncology and Hematology directed by the Coordinator Center. MR3 must be confirmed by 2 consecutive RT-Q-PCR with MR3.
2. Female or male >18 years of age at the time of accrual.
3. Patients currently receiving IM 400 mg/qd as the first line of treatment for no less than 3 months.
Prior exposure to Hydroxyurea is permitted.
4. Female patients of childbearing potential, and male patients, must agree to use an effective
barrier method of birth control, as appropriate, throughout the study and for up to 24 months
following TKI discontinuation.
5. Written informed consent will be signed prior to any study procedures being performed.

1. Pazienti con LMC in fase cronica e con livelli di trascrizione del gene BCR-ABL/ABLIS compresi tra MR3 (<0.1%) e MR4.5 (>0.0032%) da almeno 3 mesi al momento dell’arruolamento. I valori di trascritto di BCR-ABL/ABLIS saranno validati dal Laboratorio di Oncologia e di Ematologia Sperimentale diretto dal Centro Coordinatore. La
risposta di tipo MR3 deve essere confermata da almeno 2 RT-Q-PCR consecutive.
2. Donne e uomini di età >18 anni al momento dell’arruolamento.
3. Pazienti che stiano ricevendo, da almeno 3 mesi, IM 400 mg/die come trattamento di prima linea. E’ consentita una precedente esposizione ad Idrossiurea.
4. Pazienti di sesso femminile in età fertile e pazienti di sesso maschile che accettino di utilizzare, per tutta la durata dello studio e fino a 24 mesi dopo l'interruzione del trattamento, un metodo di
barriera efficace nel controllo delle nascite.
5. Pazienti che abbiano firmato il consenso informato prima dell’esecuzione di una qualsiasi procedura prevista dallo studio.

E.4

Principal exclusion criteria

1. Prior treatment with a TKI other than IM or Interferon.
2. Known severe hypersensitivity to DAS treatment or any of the excipients of this product.
3. Previous history of Pulmonary Arterial Hypertension or Pleural Effusions.
4. Any medical condition that might be aggravated by treatment or that can not be controlled: i.e.
active infection, unstable diabetes mellitus or all serious concomitant disorders incompatible with
the study including active autoimmune disorders.
5. Concurrent treatment with any other experimental or anti-cancer therapy.
6. Patients with a history of other malignancies, except if there is a disease-free interval of at least 5
years.
7. Women who are pregnant or breast feeding, or of childbearing potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test at the enrollment. Post-menopausal women must have amenorrhoea for at least 12 months to be considered of non-childbearing potential.
8. Patients with overt cognitive dysfunctions hampering a self-reported QoL evaluation.

1. Pazienti che abbiano assunto in precedenza un TKI diverso da IM o che siano stati trattati con interferone.
2. Ipersensibilità al trattamento con Dasatinib o ad uno qualsiasi degli eccipienti di questo prodotto.
3. Precedenti eventi di ipertensione arteriosa polmonare o versamento pleurico.
4. Qualsiasi condizione medica che potrebbe essere aggravata dal trattamento o che non possa essere controllata, ad esempio:
infezioni attive, diabete mellito instabile o qualsiasi comorbidità incompatibile con lo studio.
5. Trattamento concomitante con qualsiasi altro farmaco sperimentale o terapia anti-tumorale.
6. Pazienti che abbiano nella loro storia clinica altri tumori maligni, a meno che non sia intercorso un intervallo di almeno 5 anni dall’ultima terapia per una patologia tumorale maligna.
7. Donne in gravidanza, in allattamento o in età fertile e che non utilizzino un efficace metodo anticoncezionale (le donne in età fertile devono aver eseguito un test di gravidanza sul siero). Le
donne in menopausa devono avere avuto amenorrea per almeno 12 mesi per essere considerate non fertili.
8. Pazienti con disfunzioni cognitive evidenti che ostacolino una autovalutazione della QoL (Qualità della Vita).

E.5 End points

E.5.1

Primary end point(s)

Rates of MR4.5 by 12 months of treatment.

Tasso di MR4.5 dopo 12 mesi di trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

12 mesi

E.5.2

Secondary end point(s)

Rates of confirmed undetectable BCR-ABL1 transcripts.

Raggiungimento e mantenimento di una
risposta molecolare completa (CMR - un livello di trascritto di BCRABL1 non rilevabile in Real-Time RQ-PCR con >50.000 copie del gene di riferimento ABL)

E.5.2.1

Timepoint(s) of evaluation of this end point

24 months

24 mesi

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

111

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

111

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

222

F.4.2

For a multinational trial

F.4.2.1

In the EEA

222

F.4.2.2

In the whole clinical trial

222

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)

n.a.

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

2015-09-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-21

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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