Clinical Trials Register

Summary
EudraCT Number:	2010-022855-46
Sponsor's Protocol Code Number:	EWALL-PH-02
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-02-15
Trial results	View 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

2010-022855-46

A.3

Full title of the trial

AN OPEN LABEL PHASE II STUDY
TO EVALUATE THE EFFICACY AND SAFETY OF INDUCTION AND CONSOLIDATION THERAPY WITH NILOTINIB IN COMBINATION WITH CHEMOTHERAPY IN PATIENTS AGED 55 YEARS AND OVER WITH PHILADELPHIA CHROMOSOME POSITIVE (PH+ OR BCR-ABL+) ACUTE LYMPHOBLASTIC LEUKEMIA (ALL).

Studio aperto, di fase II, per valutare l'efficacia e la sicurezza della terapia di induzione e consolidamento con Nilotinib in associazione a chemioterapia in pazienti > o = 55 anni affetti da Leucemia Acuta Linfoblastica (LAL) Philadelphia positiva (Ph+ o BCR-ABL +). EWALL-PH-02

A.3.1

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

Evaluation of efficacy and safety of standard chemotherapy in combination with Nilotonib in patients of 55 years and older with Philadelphia chromosome positive Acute Lymphoblastic Leukemia.

Valutazione dell'efficacia e della sicurezza dell'uso di Nilotinib in
associazione con chemioterapia nel trattamento dei pazienti di età ≥ 55
anni affetti da Leucemia Linfoblastica Acuta con cromosoma Philadelphia o BCR-ABL positivi.

A.3.2

Name or abbreviated title of the trial where available

EWALL-PH-02

A.4.1

Sponsor's protocol code number

EWALL-PH-02

A.5.4

Other Identifiers

Name:

Novartis internal code

Number:

CAMN107ADE03

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Azienda ULSS 12 veneziana
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	U.O. di Ematologia - Ospedale dell'Angelo
B.5.2	Functional name of contact point	Renato Bassan
B.5.3	Address:
B.5.3.1	Street Address	via Paccagnella 11
B.5.3.2	Town/ city	Venezia-Mestre
B.5.3.3	Post code	30174
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390419657357
B.5.5	Fax number	+390419657361
B.5.6	E-mail	ocme.ematologia@ulss12.ve.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	Tasigna
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Farma Spa
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.3.1	Product name	Tasigna
D.3.2	Product code	AMN107
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.3.11 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

Philadelphia chromosome positive Acute Lymphoblastic Leukemia in
elderly patients (55 years and older)

Pazienti affetti da Leucemia Linfoblastica Acuta con cromosoma
Philadelphia positivo, di età superiore o uguale a 55 anni

E.1.1.1

Medical condition in easily understood language

Philadelphia chromosome positive Acute Lymphoblastic Leukemia in
elderly patients (55 years and older)

Pazienti affetti da Leucemia Linfoblastica Acuta con cromosoma
Philadelphia positivo, di età superiore o uguale a 55 anni

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10000845
E.1.2	Term	Acute lymphoblastic leukemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of a Nilotinib-based induction and consolidation therapy

Valutare l'efficacia di una terapia di induzione e consolidamento
contenente Nilotinib

E.2.2

Secondary objectives of the trial

To evaluate the safety of a Nilotinib-based induction and consolidation therapy

Valutare la sicurezza di una terapia di induzione e consolidamento
contenente Nilotinib

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients > 55 years
2. Philadelphia chromosome- or BCR-ABL positive acute lymphoblastic
leukemia
3. Not previously treated except with corticosteroids or single dose
vincristine (three doses cyclophosphamide accepted)
4. With or without documented CNS involvement
5. WHO performance status < 2
6. Normal serum levels > LLN (lower limit of normal) of potassium,
magnesium, total calcium corrected for serum albumin; or corrected to within normal limits with supplements, prior to the first dose of study medication7. Signed written inform consent
8. Molecular evaluation for BCR-ABL performed
9. Willingness of male subjects whose sexual partners are women of child-bearing potential (WOCBP), to use an effective form of
contraception (pearl index < 1%), such as complete sexual abstinence, combined oral contraceptive, hormone IUCD, vaginal hormone ring, transdermal contraceptive patch, contraceptive implant or depot contraceptive injection in combination with a second method of contraception like a condom or a cervical cap / diaphragm with spermicide or surgical sterilisation (vasectomy) in male patients during the study and at least 6 months thereafter. WOCBP are defined as sexually mature women who have notundergone a hysterectomy or surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months).

1. Pazienti di età ≥ 55 anni
2. Leucemia Acuta Linfoblastica Philadelphia o BCR-ABL positiva
3. Nessun precedente trattamento, esclusi i corticosteroidi o la singola dose di vincristina (tre dosi di ciclofosfamide sono accettate)
4. Presenza o assenza di coinvolgimento del SNC
5. Performance status WHO ≤ 2
6. Livelli sierici ≥ ai livelli minimi normali di potassio, magnesio, calcio totale (corretto per l'albumina sierica) o livelli corretti fino a rientrare nei limiti di norma precedentemente alla prima dose del farmaco in studio
7. Consenso informato scritto
8. Esecuzione della valutazione molecolare per BCR-ABL
9. Disponibilità da parte dei pazienti maschi le cui partner sono donne in età fertile ad usare una forma di contraccezione efficace (indice pearl < 1%) durante lo studio e per i sei mesi successivi. Le forme efficaci di contraccezione sono l'astinenza sessuale, contraccettivi orali combinati, contraccettivi intrauterini, anello vaginale, cerotti transdermici, impianto contraccettivo sottocutaneo o iniezione contraccettiva in combinazione con un secondo metodo di contraccezione come il preservativo o cappuccio cervicale/diaframma con spermicida o sterilizzazione chirurgica (vasectomia) nei pazienti maschi. La definizione di donna in età fertile è la seguente: donne sessualmente mature che non abbiano subito isterectomia o sterilizzazione chirurgica o che non siano in menopausa naturale per almeno 12 mesi consecutivi (cioè che abbiano avuto una mestruazione in qualsiasi momento negli ultimi 12 mesi).

E.4

Principal exclusion criteria

1. Patient previously treated with tyrosine kinase inhibitors
2. Known impaired cardiac function, including any of the following:
• LVEF < 45%
• Complete left bundle branch block
• Right bundle branch block plus left anterior hemiblock, ifascicular
block
• Use of a ventricular-paced pacemaker
• Congenital long QT syndrome
• History of or presence of clinically significant ventricular or atrial
tachyarrhythmias
• Clinically significant resting bradycardia (< 50 beats per minute)
• QTcF>450 msec on screening ECG. If QTc > 450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion.
• Myocardial infarction with 12 months prior to starting nilotinib
• Other clinical significant heart disease (e.g. unstable angina,congestive heart failure, uncontrolled hypertension)
3. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
4. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or known infection with Hepatitis B or C
5. Treatment with any, other investigational agent or participating in another trial within 30 days prior to entering this study
6. Inadequate hepatic functions defined as ASAT or ALAT > 2,5 times the institutional upper limit of normal or > 5 times ULN if considered due to leukemia
7. Total bilirubin > 2 fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to M. Gilbert / M. Meulengracht
8. Concurrent severe diseases which exclude the administration of
therapy
9. Past history of acute or chronic pancreatits
10. Patients unwilling or unable to comply with the protocol.

1. Pazienti precedentemente trattati con inibitori delle tirosin-chinasi
2. Noti difetti della funzionalità cardiaca, come ad esempio:
a. Frazione di eiezione < 45%
b. Blocco completo di branca destra
c. Blocco di branca destra più segni di emiblocco anteriore sinistro o blocco bifascicolare
d. Uso di pace-maker ventricolare
e. Sindrome congenita del QT lungo
f. Storia o presenza di tachiaritmia atriale o ventricolare clinicamente significativa
g. Baradicardia a riposo clinicamente significativa (<50 battiti/minuto)
h. QTcF >450 millisencondi all'ECG basale. Se QTc >450 millisecondi e gli elettroliti non sono nei limiti di norma prima del nilotinib, gli elettroliti devono essere corretti e il paziente rivalutato per il criterio QTc.
i. Infarto miocardico nei 12 mesi precedenti l'inizio di nilotinib.
j. Altra significativa patologia cardiaca (tipo angina instabile, cardiopatia congestizia, ipertensione non controllata)
3. Pazienti con precedente neoplasia maligna primaria che sia ancora clinicamente significativa o che attualmente richiede trattamento
4. Diagnosi di infezione da HIV (l'esame per l'HIV non è obbligatorio) o di infezione da epatite B o C
5. Trattamento con qualsiasi altro farmaco sperimentale o la
partecipazione ad un altro studio clinico nei 30 giorni precedenti
all'arruolamento
6. Funzionalità epatica inadeguata definita come AST o ALT > 2,5 volte il limite superiore di normalità o > 5 volte tale limite se si ritiene sia dovuto alla leucemia
7. Bilirubina totale > 2 volte il limite superiore di normalità se non si
ritiene sia dovuto ad un interessamento di organo da leucemia o ad un M. di Gilbert/M. di Meulengracht
8. Malattie concomitanti severe che escludono la possibilità di
somministrare la terapia
9. Pancreatite acuta o cronica nel passato
10. Pazienti che non vogliano o che non siano in grado di seguire il
protocollo

E.5 End points

E.5.1

Primary end point(s)

Rate of patients without events at 12 months

Percentuale di pazienti senza eventi a 12 mesi

E.5.1.1

Timepoint(s) of evaluation of this end point

After 12 months of treatment. During or after 3rd year of the whole trial

Dopo 12 mesi di trattamento. Durante o dopo il terzo anno dello studio.

E.5.2

Secondary end point(s)

- The rate of complete haematological remission after induction
treatment
- The rate of major molecular response defined by a BCR-ABL/ABL <
0.1% in bone marrow (see section 11.1.1)
- The rate of complete molecular response defined by a BCR-ABL/ABL <
0.001% in bone marrow (see section 11.1.1).
- The proportion of patients with confirmed undetectable BCR-ABL level
with a test sensitivity of at least 4.5 log.
- Event free survival
- Relapse free survival
- Progression free survival
- Detection of a T315I or p-loop BCR-ABL TK domain mutation
- The proportion of patients with molecular relapse or progression
- Overall survival
- Tolerability as determined by descriptive assessment of adverse events
and discontinuation due to treatment-related SAEs
- Death during induction (all patients who started treatment)
- Death in complete remission

- La percentuale di remissioni complete ematologiche dopo il
trattamento di induzione
- La percentuale di risposta molecolare maggiore definita da una ratio
BCR-ABL/ABL < 0,1% nel midollo osseo
- La percentuale di risposta molecolare completa definita da una ratio
BCR-ABL/ABL < 0,01% nel midollo osseo
- la percentuale di pazienti con trascritto BCR-ABL confermato non
rilevabile, con una sensibilità del metodo di 4.5 logaritmi
- Sopravvivenza libera da eventi
- Sopravvivenza libera da recidiva
- Sopravvivenza libera da progressione
- Individuazione di una mutazione T315l o dell'ansa P
- La proporzione di pazienti con recidiva molecolare o progressione
- La sopravvivenza globale
- La tollerabilità del farmaco
- Morte in induzione
- Morte in remissione completa

E.5.2.1

Timepoint(s) of evaluation of this end point

After induction (week 5 of treatment), before consolidation 3 and 5
(week 16 and 24 of treatment), before maintenance 1, 3, 5 and 7 (month
8, 12, 18, 24)

Dopo la fase di induzione (sett. 5 di trattamento), prima dei cicli 3 e 5
della terapia di consolidamento (sett. 16 e 24 di trattamento), prima dei
cicli 1, 3, 5 e 7 della terapia di consolidamento (mese 8, 12, 18, 24)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

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

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

5 years, LVLS

5 anni, LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

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

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

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

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

2013-03-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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