Clinical Trials Register

Summary
EudraCT Number:	2015-000449-21
Sponsor's Protocol Code Number:	CLAG525X2101C
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:	2015-07-31
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

2015-000449-21

A.3

Full title of the trial

A Phase I/II, open label, multicenter study of the safety and efficacy of LAG525 single agent and in combination with PDR001 administered to patients with advanced malignancies

Estudio de fase I/II, multicéntrico, abierto para evaluar la seguridad y la eficacia de LAG525 en monoterapia y en combinación con PDR001 en pacientes con tumores malignos avanzados

A.3.1

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

An interventional study of LAG525 alone and in combination with PDR001 in patients with advanced malignancies

Estudio de intervención de LAG525 solo y en combinación con PDR001 en pacientes con neoplasias avanzadas

A.4.1

Sponsor's protocol code number

CLAG525X2101C

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 Vía 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	LAG525
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
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	LAG525
D.3.9.1	CAS number	LAG525
D.3.9.2	Current sponsor code	LAG525
D.3.9.3	Other descriptive name	LAG525
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	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	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	Yes
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	PDR001
D.3.4	Pharmaceutical form	Lyophilisate for solution for infusion
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	PDR001
D.3.9.1	CAS number	PDR001
D.3.9.2	Current sponsor code	PDR001
D.3.9.3	Other descriptive name	PDR001
D.3.9.4	EV Substance Code	SUB171710
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	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	Yes
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

Solid tumors

Tumores sólidos

E.1.1.1

Medical condition in easily understood language

Solid tumors

Tumores sólidos

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

Phase I part - To estimate the RP2D or MTD for:
? Single agent LAG525
? Combination of LAG525 and PDR001.
Phase II part - To estimate the overall response rate per RECIST V1.1:
? Single agent LAG525
? Combination of LAG525 and PDR001

Fase I
Calcular la RP2D o la MTD de LAG525 en monoterapia y en la combinación de LAG525 y PDR001.
Fase II
Calcular la tasa de respuesta global según RECIST V1.1 de LAG525 en monoterapia y en la combinación de LAG525 y PDR001

E.2.2

Secondary objectives of the trial

Key Secondary Objectives:
1) To characterize the safety and tolerability of single agent LAG525 given alone and in combination with PDR001
2) To characterize the pharmacokinetic profile of single agent LAG525 given alone and in combination with PDR001
3) To assess emergence of anti-LAG525, and anti-PDR001 antibodies following one or more intravenous (i.v.) infusions of single agent LAG525 given alone or in combination with PDR001
4) To evaluate the preliminary antitumor activity of single agent LAG525 given alone or in combination of PDR001
Other Secondary Objectives are defined in the protocol.

? Determinar el perfil de seguridad y tolerabilidad de LAG525 en monoterapia y en combinación con PDR001
? Determinar el perfil farmacocinético de LAG525 en monoterapia y en combinación con PDR001
? Evaluar la aparición de anticuerpos anti-LAG525 y anti-PDR001 después de una o más infusiones intravenosas (i.v.) de LAG525 en monoterapia o en combinación con PDR001
? Evaluar los posibles predictores de eficacia de LAG525 en monoterapia y en combinación con PDR001
? Evaluar la actividad antitumoral preliminar de LAG525 en monoterapia o en combinación con PDR001
? Analizar los biomarcadores de selección de pacientes y farmacodinámicos en las muestras de tejido tumoral.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent must be obtained prior to any procedures
2. Age ? 18 years
3. Phase I part: Patients with advanced/metastatic solid tumors, with measurable or non-measurable disease as determined by RECIST version 1.1 (refer to Appendix 1), who have progressed despite standard therapy
or are intolerant of standard therapy, or for whom no standard therapy exists.
4. Phase II part: Patients with advanced/metastatic solid tumors, with at least one measurable lesion as determined by RECIST version 1.1, who have had disease progression following their last prior therapy.
5. ECOG Performance Status ? 2.
6. Patient must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution?s guidelines. Patient must be willing to undergo a new tumor biopsy at baseline, and during therapy on this study.

1. Se debe obtener un consentimiento informado por escrito antes de realizar cualquier procedimiento.
2. Edad ? 18 años.
3. Fase I: Pacientes con tumores sólidos avanzados o metastásicos, con enfermedad medible o no medible determinada por RECIST versión 1.1 (véase el Anexo 1), que hayan presentado progresión al tratamiento estándar, que sean intolerantes a este o para los que no exista tratamiento estándar.
4. Fase II: Pacientes con tumores sólidos avanzados/metastásicos, con al menos una lesión medible según RECIST versión 1.1, que hayan presentado progresión de la enfermedad después del último tratamiento previo.
5. Estado funcional ECOG ? 2.
6. Al paciente ha de poder realizársele una biopsia y ser candidato para una biopsia del tumor según las pautas del centro responsable del tratamiento. El paciente debe estar dispuesto a que se le realice una nueva biopsia tumoral en el momento basal y durante el tratamiento a lo largo del estudio.

E.4

Principal exclusion criteria

1. History of severe hypersensitivity reactions to other mAbs
2. Active autoimmune disease or a documented history of autoimmune disease within three years prior to screening.
3. Active infection requiring systemic antibiotic therapy.
4. Known history of HIV infection.
5. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
6. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, 4 weeks is indicated as washout period.
7. Phase II only: Prior PD1- or PD-L1-directed therapy with the exception of patients with renal cell cancer will have been previously treated with anti-PD-1 or anti-PD-L1 inhibitors.
8. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
9. Presence of ? CTCAE grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if ? CTCAE grade 3) due to prior cancer therapy.
Other protocol-defined exclusion criteria may apply.

1. Presencia de metástasis sintomáticas del sistema nervioso central (SNC) o metástasis del SNC que requieran tratamiento local dirigido al SNC (como radioterapia o cirugía) o aumento de las dosis de corticosteroides en las 2 semanas anteriores.
2. Antecedentes de reacciones graves de hipersensibilidad a otros AM
3. Pacientes con valores de laboratorio fuera de rango
4. Enfermedad cardíaca o deterioro de la función cardíaca clínicamente significativos.
5. enfermedad autoinmune activa o Historia documentada de enfermedad autoinmune dentro de los tres años previos a la selección.
6. Infección activa que requiera tratamiento sistémico con antibiótico. Los pacientes que requieran antibióticos sistémicos por infección deben haber finalizado el tratamiento antes de la selección.
7. Antecedentes conocidos de infección por VIH No se requiere prueba de VIH salvo que esté clínicamente indicada.
8. Virus de la hepatitis B (VHB) activo o infección por virus de hepatitis C (VHC). No es necesario realizar pruebas para el estado de VHB o VHC salvo que esté clínicamente indicado o si el paciente presenta antecedentes de infección por VHB o VHC.
9. Enfermedad maligna distinta a la tratada en este estudio.

Se pueden aplicar otros criterios de exclusión definidos en el protocolo.

E.5 End points

E.5.1

Primary end point(s)

Phase I part:
- The incidence of dose limiting toxicities ( DLTs) with single agent LAG525 & for the combination treatment of LAG525 and PDR001

Phase II part: Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. of single agent LAG525 & the combination of LAG525 and PDR001.

Fase I:
Incidencia de toxicidades limitantes de dosis (DLT) durante el primer ciclo de tratamiento con LAG525 en monoterapia. Para el tratamiento en combinación de LAG525 y PDR001, la ventana de DLT será de 2 ciclos de tratamiento.
Fase II:
Tasa de respuesta global según los criterios de evaluación de respuesta en tumores sólidos (RECIST) v1.1.

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I:
- the incidence of DLTs continously: during the first cycle of treatment with single agent LAG525; for the combination treatment of LAG525 and PDR001, the DLT window will be 2 cycles of the treatment.

Phase II:
- Every 2 Cycles ± 1 week from Cycle 3 Day 1 to Cycle 11 Day 1, then every 3 cycles until progression of disease per irRC or patient withdrawal.

La incidencia de DLTs continuamente: durante el primer ciclo de tratamiento con un solo agente LAG525;
a el tratamiento de combinación de LAG525 y PDR001, la ventana de DLT será de 2 ciclos de tratamiento.

E.5.2

Secondary end point(s)

1. a) Safety incidence and severity if adverse events (AEs) and serious adverse events (SAEs) including changes in laboratory parameters, vital signs and ECGs; b) Tolerability: Dose interruptions, reductions and dose intensity.
2. Serum PK parameters (e.g. AUC, Cmax, Tmax, t1/2 half-life))
3. Presence and/ or concentration of anti-LAG525 and anti-PDR001 antibodies
4. Phase I Part: ORR, progression free survival (PFS), duration of response (DOR) and disease control rate (DCR); Phase II Part: ORR per immune related Response Criteria (irRC), PFS, DOR, DCR per RECIST V1.1 and per irRC

? Incidencia en la seguridad y gravedad en el caso de que se produzcan acontecimientos adversos (AA) y acontecimientos adversos graves (AAG), incluidos los cambios en los parámetros de laboratorio, las constantes vitales y los ECG
? Tolerabilidad: Interrupciones, reducciones e intensidad de la dosis.
? Parámetros de PK sérica (p. ej. AUC, Cmax, Tmax, vida media t1/2)
? Presencia y/o concentración de anticuerpos anti-LAG525 y anti-PDR001
Fase I:
ORR, supervivencia libre de progresión (PFS), duración de respuesta (DOR) y tasa de control de la enfermedad (DCR)
? Expresión de genes relacionados con la inmunidad de IFN-? según el perfil de ARNm
Fase II:
? ORR según los criterios de respuesta relacionados con la inmunidad (irRC), PFS, DOR, DCR según RECIST V1.1 e irRC

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Assessed continuously
2. Every Cycle until Cycle 6
3. Every Cycle until Cycle 6
4. Every 2 Cycles ± 1 week from Cycle 3 Day 1 to Cycle 11 Day 1, then every 3 cycles until progression of disease per irRC or patient withdrawal.

1. evaluar permanentemente
2. Cada ciclo hasta 6º Ciclo
3. Cada ciclo hasta 6º Ciclo
4. Cada 2 ciclos ± 1 semana desde Ciclo 3 Día 1 a Ciclo 11 Día 1, luego cada 3 ciclos hasta la progresión de la enfermedad por IRRC o revocación del paciente.

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

Yes

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)

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.8.2.4

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

Australia

Belgium

Canada

France

Germany

Hong Kong

Italy

Japan

Korea, Republic of

Singapore

Spain

Taiwan

United States

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

The end of the study will be when 80% of the patients per disease
group in the phase II part have completed the follow-up for disease
progression or discontinued the study for any reason, and all patients
have completed treatment and the 30 day safety follow-up period, or if
the study is terminated early.

El final del estudio se producirá cuando el 80 % de los pacientes por cada grupo de enfermedad de la fase II haya finalizado el seguimiento de la progresión de la enfermedad o haya abandonado el estudio por cualquier motivo y todos los pacientes hayan finalizado el tratamiento y el periodo de seguimiento de seguridad de 30 días, o si el estudio finaliza prematuramente.

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 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:

180

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

F.4.2.2

In the whole clinical trial

240

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

2015-09-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-12-31

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