Clinical Trials Register

Summary
EudraCT Number:	2012-002074-31
Sponsor's Protocol Code Number:	CLDK378X2103
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:	2013-06-10
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

2012-002074-31

A.3

Full title of the trial

A Phase I, open-label, dose escalation study of LDK378 in pediatric patients with malignancies that have a genetic alteration in anaplastic lymphoma kinase (ALK)

Estudio fase I, abierto, de escalado de dosis de LDK378 en pacientes pediátricos con enfermedades malignas que presentan una alteración genética en la quinasa del linfoma anaplásico (ALK)

A.3.1

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

Study of safety and efficacy in pediatric patients with ALK-activated tumors

Estudio de seguridad y eficacia en pacientes pediátricos con tumores ALK-activados

A.3.2

Name or abbreviated title of the trial where available

Phase I study of LDK378 in pediatric malignancies with a genetic alteration in ALK

Estudio de fase I de LDK378 en tumores malignos pediátricos con una alteración genética en ALK

A.4.1

Sponsor's protocol code number

CLDK378X2103

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	Novartis Farmacéutica, S.A.
B.1.3.4	Country	Spain
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farmacéutica, S.A.
B.5.2	Functional name of contact point	Departamento Médico Oncología (GMO)
B.5.3	Address:
B.5.3.1	Street Address	Gran Via de les Corts Catalanes, 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34900353036
B.5.5	Fax number	+34932479903
B.5.6	E-mail	eecc.novartis@novartis.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	No
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.3.2	Product code	LDK378
D.3.4	Pharmaceutical form	Capsule
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	LDK378
D.3.9.1	CAS number	LDK378
D.3.9.2	Current sponsor code	LDK378
D.3.9.3	Other descriptive name	LDK378
D.3.9.4	EV Substance Code	SUB31640
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
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.3.2	Product code	LDK378
D.3.4	Pharmaceutical form	Capsule
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	LDK378
D.3.9.1	CAS number	LDK378
D.3.9.2	Current sponsor code	LDK378
D.3.9.3	Other descriptive name	LDK378
D.3.9.4	EV Substance Code	SUB31640
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	150
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

malignancies characterized by genetic abnormalities in anaplastic lymphoma kinase (ALK)

neoplasias malignas caracterizadas por anormalidades genéticas en quinasa del linfoma anaplásico (ALK)

E.1.1.1

Medical condition in easily understood language

malignancies characterized by genetic abnormalities in anaplastic lymphoma kinase (ALK)

neoplasias malignas caracterizadas por anormalidades genéticas en quinasa del linfoma anaplásico (ALK)

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Estimate the MTD and/or RDE of LDK378 as a single agent when administered orally to pediatric patients with ALK-activated tumors

Calcular la DMT y/o DRE de LDK378 en monoterapia, cuando se administra por vía oral a pacientes pediátricos con tumores con activación de ALK.

E.2.2

Secondary objectives of the trial

1 -Characterize the safety and tolerability of LDK378 in the pediatric patients
2- Characterize single and multiple-dose PK of LDK378 in pediatric patients
3- Assess the anti-tumor activity of LDK378

Objetivo 1: Caracterizar la seguridad y la tolerabilidad de LDK378 en pacientes pediátricos
Objetivo 2: Caracterizar la PK de dosis múltiples y únicas de LDK378 en pacientes pediátricos
Objetivo 3: Evaluar la actividad antitumoral de LDK378

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Diagnosed with a locally advanced or metastatic malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists
- Age ? 12 months and ? 17years
- The tumor must carry a genetic alteration of ALK
- Patients must have evaluable or measurable disease

Other protocol-defined inclusion criteria may apply

Pacientes con diagnóstico de una enfermedad maligna metastásica o localmente avanzada que hayan progresado a pesar de la terapia estándar o para los que no existe terapia estándar eficaz
?Edad ? 12 meses y ? 17 años
?El tumor deberá ser portador de una alteración genética de ALK, como una mutación, translocación o amplificación
?Los pacientes deberán presentar enfermedad medible o evaluable definida por uno de los siguientes criterios: RECIST v1.1 para pacientes con enfermedades malignas no hematológicas; escáner MIBG para pacientes con neuroblastoma; criterios de grupo internacional de trabajo (IWG) para pacientes con linfoma
?Estado funcional:
?Puntuación del estado funcional de Karnofsky ? 60% para pacientes >12 años de edad
?Puntuación de Lansky ? 50% para pacientes ? 12 años de edad

E.4

Principal exclusion criteria

- Symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of steroids or local CNS-directed therapy (such as radiotherapy, surgery or intrathecal chemotherapy) to control their CNS disease
- Clinically significant, uncontrolled heart disease
- Inadequate end organ function as defined by specified laboratory values
- Use of medications that are known to be strong inhibitors or inducers of CYP3A4/5 that cannot be discontinued at least 1 week prior to start of treatment with LDK378 and for the duration of the study
- Use of medications that are mainly metabolized by CYP3A4/5 or CYP2C9 that cannot be discontinued at least 1 week prior to start of treatment with LDK378 and for the duration of the study.
Other protocol-defined exclusion criteria may apply

?Pacientes con metástasis del sistema nervioso central (SNC) sintomáticas que sean neurológicamente inestables o precisen dosis crecientes de esteroides o terapia local dirigida al SNC (como radioterapia, cirugía o quimioterapia intratecal) para controlar su enfermedad
?Pacientes con enfermedad cardíaca incontrolada, clínicamente significativa o intervalo QT (QTc) corregido > 480 milisegundos, utilizando la corrección de Fridericia (QTcF)
?Pacientes con los siguientes valores de laboratorio durante la selección:
?Creatinina > 1.5 x LSN para la edad
?Bilirrubina total > 1.5 x LSN para la edad, excepto para pacientes con síndrome de Gilbert, que pueden ser incluidos si la bilirrubina total es ? 3.0 x LSN y la bilirrubina directa es ? 1.5 x LSN
?Alanina aminotransferasa (ALT) > 3 x LSN para la edad, excepto para pacientes con tumor con afectación hepática, que deberán tener un valor ? 5 x LSN
?Aspartato aminotransferasa sérica (AST) > 3 x LSN para la edad, excepto para pacientes con tumor con afectación hepática, que deberán tener un valor ? 5 x LSN
?Recuento absoluto de neutrófilos (RAN) < 0.75 x 109/L sin uso de factor de crecimiento de granulocitos durante ? 14 días
?Recuento de plaquetas < 50 x 109/L
?Hemoglobina (Hgb) < 8 g/dL
?Area de superficie corporal (BSA) < 0.35 m2
?Presencia de toxicidad ? grado 2 de los CTCAE (excepto alopecia, neuropatía periférica, ototoxicidad y linfopenia) debido a la terapia previa para el cáncer
?Anomalías en el potasio, magnesio, calcio o fósforo > grado 1 de los CTCAE
?Pacientes que reciban medicaciones que se conoce que son inhibidores o inductores potentes de CYP3A4/5 que no puedan suspenderse durante por lo menos 1 semana antes del tratamiento con LDK378 o durante todo el estudio
?Pacientes que reciban medicaciones que son metabolizadas principalmente por CYP3A4/5 o CYP2C9 con bajo índice terapéutico que no puedan ser suspendidas por lo menos 1 semana antes de iniciar el tratamiento con LDK378 y durante todo el estudio.
?Pacientes que reciban medicaciones que presentan un riesgo conocido de prolongación del intervalo QT o de inducir Torsades de Pointes
?Otras condiciones psiquiátricas o médicas crónicas o agudas severas o anomalías de laboratorio que puedan interferir con la interpretación de los resultados del estudio y, a criterio del investigador podrían convertir al paciente en inapropiado para el estudio

E.5 End points

E.5.1

Primary end point(s)

Incidence rate of Dose Limiting Toxicities (DLT)

Tasa de incidencia de toxicidades limitantes de dosis (TLD) durante el primer ciclo de tratamiento con LDK378

E.5.1.1

Timepoint(s) of evaluation of this end point

up to day 21 after the patient's first dose

hasta el día 21 después de la primera dosis del paciente

E.5.2

Secondary end point(s)

1- Number of patients with Adverse events and serious adverse events; Changes in laboratory values ; Assessments of physical examinations; Assessments of vital signs and electrocardiograms; Plasma concentration time profiles

2- PK parameters, including AUClast, AUCtau, Cmin, Cmax, Tmax, Racc T1/2 and acc

3- Overall response rate (ORR) and duration of response (DOR), progression-free survival (PFS) as per RECIST 1.1; Changes in disease burden in patients with lymphoma.

1) Acontecimientos adversos y acontecimientos adversos graves, cambios en los valores de laboratorio, evaluaciones de exámenes físicos, constantes vitales y electrocardiogramas
(2) Perfiles de tiempo-concentración plasmática, parámetros PK, incluyendo pero no limitado a AUClast, AUCtau, Cmin, Cmax, Tmax, Racc y T1/2,acc
(3) Tasa de respuesta global (TRG) y duración de la respuesta (DR), supervivencia libre de progresión (SLP), según los RECIST 1.1 en pacientes con neuroblastoma y otros tumores sólidos y con los criterios del grupo internacional de trabajo (IWG) en pacientes con linfoma. Respuesta a MIBG en pacientes con neuroblastoma. Resolución de la enfermedad de la médula ósea en pacientes con neuroblastoma.

E.5.2.1

Timepoint(s) of evaluation of this end point

1- 30 months
2- 30 months
3- 30 months

1 - 30 meses
2 - 30 meses
3 - 30 meses

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

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)

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.8.2.4

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

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

France

Germany

Italy

Netherlands

United Kingdom

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

Última visita del último paciente.

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patient age >= 12 months

Edad de los pacientes > = 12 meses

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)

Expected normal treatment of that condition

Tratamiento normal previsto para esta condición

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

2013-08-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-04-26

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