Clinical Trials Register

Summary
EudraCT Number:	2010-022855-46
Sponsor's Protocol Code Number:	EWALL-PH-02
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-05-08
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

Spain - AEMPS

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).

ESTUDIO FASE II ABIERTO PARA EVALUAR LA EFICACIA Y SEGURIDAD DEL TRATAMIENTO DE INDUCCIÓN Y CONSOLIDACIÓN CON NILOTINIB, EN COMBINACIÓN CON QUIMIOTERAPIA, EN PACIENTES DE AL MENOS 55 AÑOS DE EDAD CON LEUCEMIA LINFOBLÁSTICA AGUDA (LLA) Y PRESENCIA DEL CROMOSOMA FILADELFIA (PH+ O BCR-ABL+)

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 NILOTINIB IN PATIENTS OF 55 YEARS AND OLDER WITH PHILADELPHIA CHROMOSOME POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA.

EVALUACIÓN DE LA EFICACIA Y SEGURIDAD DE LA QUIMIOTERAPIA ESTÁNDAR EN COMBINACIÓN CON NILOTINIB, EN PACIENTES DE AL MENOS 55 AÑOS DE EDAD CON LEUCEMIA LINFOBLÁSTICA AGUDA Y PRESENCIA DEL CROMOSOMA FILADELFIA.

A.4.1

Sponsor's protocol code number

EWALL-PH-02

A.5.4

Other Identifiers

Name:

Novartis internal Code

Number:

CAMN107ADE03T

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	Fundación PETHEMA
B.1.3.4	Country	Spain
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 Farmacéutica, S.A.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CABYC, S.L.
B.5.2	Functional name of contact point	Investigación Clínica
B.5.3	Address:
B.5.3.1	Street Address	Avenida Somosierra, 12. Portal Izqdo., 2ºG
B.5.3.2	Town/ city	San Sebastián de los Reyes
B.5.3.3	Post code	28703
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34916590433-
B.5.5	Fax number	+34916548969-
B.5.6	E-mail	juan.berges@cabyc.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.2.1.1.1	Trade name	Tasigna
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	Nilotinib (Tasigna (R))
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NILOTINIB
D.3.9.1	CAS number	641571-10-0
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	200
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)

Leucemia Linfoblástica aguda con presencia del cromosoma Filadelfia, en pacientes de edad avanzada (al menos 55 años de edad)

E.1.1.1

Medical condition in easily understood language

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

Leucemia Linfoblástica aguda con presencia del cromosoma Filadelfia, en pacientes de edad avanzada (al menos 55 años de edad)

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	17.0
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.

Evaluar la eficacia del tratamiento de inducción y consolidación con nilotinib

E.2.2

Secondary objectives of the trial

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

Evaluar la seguridad del tratamiento de inducción y consolidación con 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 medication
7. 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%) during the study and at least 6 months thereafter. Effective forms of contraception are 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. WOCBP are defined as sexually mature women who have not undergone 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. Pacientes de ambos sexos con al menos 55 años de edad.
2. Leucemia linfoblástica aguda con presencia del cromosoma de Filadelfia o reordenamiento BCR-ABL.
3. No haber recibido tratamiento previo (excepto corticosteroides o una única dosis de vincristina [se permite la administración de tres dosis de ciclofosfamida]).
4. Con o sin afectación documentada del SNC.
5. Estado funcional de la OMS < 2
6. Concentraciones séricas normales > LIN (límite inferior de normalidad) de potasio, magnesio, calcio total (corregida en función de la concentración de albúmina sérica), o corregidas con suplementos, hasta situarse dentro de los límites normales, antes de la primera dosis de la medicación del estudio.
7. Haber firmado el consentimiento informado por escrito
8. Realización de una evaluación molecular de la presencia del gen BCR-ABL.
9. Los pacientes varones cuyas parejas sexuales sean mujeres en edad fértil (MEF) deberán estar dispuestos a utilizar un método anticonceptivo eficaz (índice de Pearl < 1%) durante el estudio y por lo menos 6 meses después. Se consideran métodos anticonceptivos eficaces la abstinencia sexual completa, la píldora anticonceptiva oral combinada, el dispositivo intrauterino hormonal, el anillo vaginal hormonal, el parche anticonceptivo transdérmico, el implante anticonceptivo o la inyección anticonceptiva de acción prolongada, en combinación con un segundo método anticonceptivo, como preservativo o capuchón cervical / diafragma con espermicida o esterilización quirúrgica (vasectomía) en pacientes varones. Por "mujeres en edad fértil" (MEF) se entienden mujeres sexualmente maduras que no se hayan sometido a una histerectomía o a esterilización quirúrgica, o que no haya entrado en la menopausia de forma natural al menos desde hace 12 meses consecutivos (esto es, que hayan tenido menstruaciones en cualquier momento en los últimos 12 meses consecutivos).

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, bifascicular 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 pancreatitis
10. Patients unwilling or unable to comply with the protocol.

1. Pacientes que hayan recibido tratamiento previo con inhibidores de la tirosina quinasa
2. Deterioro conocido de la función cardiaca, incluidos cualquier de los siguientes parámetros:
- FEVI < 45%
- Bloqueo completo de rama izquierda
- Bloqueo de rama derecha y hemibloqueo anterior izquierdo, bloqueo bifascicular
- Uso de un marcapasos ventricular
- Síndrome congénito del QT prolongado
- Antecedentes o presencia de taquiarritmias ventriculares o auriculares clínicamente significativas
- Bradicardia en reposo clínicamente significativa (< 50 latidos por minuto)
- QTcF > 450 ms en el ECG que se realice durante la selección. En caso de que el QTcF sea > 450 ms y los electrolitos no se encuentren dentro de los rangos normales antes de la administración de nilotinib, deberá corregirse la concentración de electrolitos y volver a evaluar al paciente en relación con el criterio relativo al intervalo QTcF
- Infarto de miocardio en el transcurso de los 12 meses previos al inicio del tratamiento con nilotinib
- Otras cardiopatías clínicamente significativas (por ejemplo, angina inestable, insuficiencia cardiaca congestiva, hipertensión sin controlar)
3. Pacientes con antecedentes de otra neoplasia maligna primaria que en la actualidad sea clínicamente significativa o requiera una intervención activa.
4. Diagnóstico conocido de infección por el virus de la inmunodeficiencia humana (VIH) [no es obligatorio realizar la prueba del VIH] o infección conocida con hepatitis B o C.
5. Tratamiento con cualquier otro fármaco en fase de investigación, o haber participado en otro ensayo en el transcurso de los 30 días previos a la inclusión en este estudio.
6. Función hepática inadecuada, esto es, concentración de ASAT o ALAT > 2,5 veces el límite superior de la normalidad del centro o > 5 veces el LSN si se considera que se debe a la leucemia.
7. Concentración total de bilirrubina > 2 veces el límite superior de la normalidad del centro, a menos que se considere que se deba a que el órgano está afectado con leucemia o a la presencia del síndrome de M.Gilbert / M. Meulengracht.
8. Enfermedades concomitantes graves que impidan la administración de tratamiento
9. Antecedentes de pancreatitis aguda o crónica
10. Pacientes que no estén dispuestos o no puedan cumplir el protocolo, a juicio de su médico.

E.5 End points

E.5.1

Primary end point(s)

Rate of patients without event at 12 months

Tasa de pacientes sin eventos al cabo de 12 meses

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.

Después de 12 meses de tratamiento. Durante o después del tercer año del ensayo completo.

E.5.2

Secondary end point(s)

a. The rate of complete hematological remission after induction treatment
b. The rate of major molecular response defined by a BCR-ABL/ABL ratio < 0.1% in bone marrow
c. The rate of complete molecular response defined by a BCR-ABL/ABL ratio < 0.01% in bone marrow
d. The proportion of patients with confirmed undetectable BCR-ABL transcripts with an assay sensitivity of at least 4.5 log
e. Event free survival
f. Relapse free survival
g. Progression free survival
h. Detection of a T315I or p-loop mutation
i. The proportion of patients with molecular relapse or progression
j. Overall survival
k. Tolerability
l. Death during induction
m. Death in complete remission

a. Tasa de remisión hematológica completa tras el tratamiento de inducción.
b. Tasa de respuesta molecular mayor, definida como una relación BCR-ABL/ABL < 0,1% en médula ósea.
c. Tasa de respuesta molecular completa, definida como una relación BCR-ABL/ABL < 0,01% en médula ósea.
d. Proporción de pacientes con transcritos BCR-ABL indetectables confirmados, mediante un ensayo de sensibilidad de al menos 4,5 log
e. Supervivencia libre de eventos
f. Supervivencia libre de recidiva
g. Supervivencia libre de progresión
h. Detección de una mutación T315I o mutación del bucle p (p-loop)
i. Proporción de pacientes con recidiva o progresión molecular
j. Supervivencia global
k. Tolerabilidad
l. Muertes durante el tratamiento de inducción
m. Muertes en remisión completa

E.5.2.1

Timepoint(s) of evaluation of this end point

If not defined different (see above E.5.2), the timepoints of evaluation of the scondary end points are the timepoints of bone marrow aspiration according to the protocol: 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).

Si no se define de forma diferente (ver más arriba E.5.2), los momentos de evaluación de las variables secundarias son los momentos de realización de aspirado de médula ósea, de acuerdo con el protocolo: Después de la inducción (semana 5 de tratamiento), antes de consolidación 3 y 5 (semanas 16 y 24 de tratamiento), antes de mantenimiento 1, 3, 5 y 7 (meses 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

Total duration is 7 years. Core trial ends after 6 years (4 yrs accrual time, 2 yrs treatment). During subsequent follow-up period (1 year), analysis will be performed according each centers procedures and general recommendations in hematologic malignancies. No formal visits are performed. Information on survival and remission will be collected by paper forms. Follow-up investigations and aftercare are not part of the study. Aftercare will be performed according to the general state of the art.

La duración total es de 7 años. El estudio principal termina después de 6 años (4a de reclutamiento, 2a de tratamiento). Durante el periodo de seguimiento posterior (1a), se realizarán análisis de acuerdo a los procedimientos de cada centro y las recomendaciones generales para neoplasias hematológicas. No se realizarán visitas formales. Se recogerá información sobre superviviencia y remisión en formularios en papel. El seguimiento posterior se realizará de acuerdo a la práctica médica habitual.

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

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

Ninguno

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

2014-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-03-10

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