Clinical Trials Register

Summary
EudraCT Number:	2019-001512-34
Sponsor's Protocol Code Number:	DS8201-A-U205
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-07-26
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

2019-001512-34

A.3

Full title of the trial

A PHASE 2, OPEN-LABEL, SINGLE-ARM TRIAL OF TRASTUZUMAB DERUXTECAN (DS-8201A) IN HER2-POSITIVE, UNRESECTABLE OR METASTATIC GASTRIC OR GASTROESOPHAGEAL JUNCTION (GEJ) ADENOCARCINOMA SUBJECTS WHO HAVE PROGRESSED ON OR AFTER A TRASTUZUMAB-CONTAINING REGIMEN

Estudio en fase II abierto de un único grupo de trastuzumab deruxtecán (DS-8201a) en sujetos con adenocarcinoma gástrico o de la unión gastroesofágica (UGE) positivo para HER2, no resecable o metastásico que han progresado durante o después de una pauta que contenía trastuzumab

A.3.1

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

DS-8201a in HER2-positive Gastric Cancer that cannot be surgically removed or has spread

(DS-8201a) en sujetos con adenocarcinoma gástrico que no se puede extirpar quirúrgicamente o que se ha diseminado

A.4.1

Sponsor's protocol code number

DS8201-A-U205

A.5.4

Other Identifiers

Name:

IND Number

Number:

136179

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	Daiichi Sankyo Inc.
B.1.3.4	Country	United States
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	DAIICHI SANKYO INC.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Daiichi Sankyo Inc.
B.5.2	Functional name of contact point	Not applicable
B.5.3	Address:
B.5.3.1	Street Address	211 Mt Airy Road
B.5.3.2	Town/ city	Basking Ridge
B.5.3.3	Post code	NJ 07920
B.5.3.4	Country	United States
B.5.4	Telephone number	+1908992 6400
B.5.6	E-mail	eu_cta@dsi.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.3.1	Product name	DS-8201a
D.3.2	Product code	DS-8201a
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	Trastuzumab deruxtecan
D.3.9.2	Current sponsor code	DS-8201A
D.3.9.3	Other descriptive name	Anti-HER2 antibody-drug conjugate
D.3.9.4	EV Substance Code	SUB188940
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

Unresectable or metastatic gastric or gastro-esophageal junction (GEJ)
adenocarcinoma that has progressed on or after a trastuzumab-containing
regimen

Adenocarcinoma gástrico o de la unión gastroesofágica (UGE) no resecable o metastásico que han progresado durante o después de una pauta que contenía trastuzumab

E.1.1.1

Medical condition in easily understood language

HER2-POSITIVE, UNRESECTABLE OR METASTATIC GASTRIC OR GASTROESOPHAGEAL JUNCTION (GEJ) ADENOCARCINOMA

Adenocarcinoma gástrico o de la unión gastroesofágica (UGE ) positivo para HER2, no resecable o metastásico

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10071114
E.1.2	Term	Metastatic gastric adenocarcinoma
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10066354
E.1.2	Term	Adenocarcinoma of the gastroesophageal junction
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

To investigate the efficacy of Trastuzumab Deruxtecan (DS-8201a) based on objective response rate (ORR) by independent central review based on Response Evaluation Criteria in Solid Tumors (RECIST), version (v)1.1

Investigar la eficacia de trastuzumab deruxtecan en base a la tasa de respuesta objetiva (TRO) mediante una revisión central independiente según la versión (v)1.1 de los Criterios de evaluación de la respuesta en tumores sólidos (RECIST)

E.2.2

Secondary objectives of the trial

- To evaluate the efficacy of Trastuzumab Deruxtecan on progression-free survival (PFS), based on independent central review using RECIST v1.1.

Other secondary objectives:
- To further evaluate the efficacy of Trastuzumab Deruxtecan using the endpoint of overall survival (OS)

- To further evaluate the efficacy of Trastuzumab Deruxtecan using RECIST v1.1 for endpoints of PFS and ORR based on Investigator assessment, and on duration of response (DoR) based on independent central review and Investigator assessment

- To determine the pharmacokinetics (PK) of Trastuzumab Deruxtecan in serum

- To further evaluate the safety of Trastuzumab Deruxtecan based on treatment-emergent adverse events (TEAEs) and anti-drug antibodies (ADAs)

- To evaluate Health Economics and Outcomes Research (HEOR) endpoints based on patient-reported outcomes (PROs)

•Evaluar la eficacia de trastuzumab deruxtecan en la supervivencia sin progresión (SSP), en base a una revisión central independiente usando los criterios RECIST v1.1
•Evaluar más la eficacia de trastuzumab deruxtecán usando el criterio de valoración de supervivencia general (SG)
•Evaluar aún más la eficacia de trastuzumab deruxtecán usando los criterios RECIST v1.1 para criterios de valoración de SSP y TRO según la evaluación del investigador, y en la duración de la respuesta (DR) en base a revisión central independiente y la evaluación del investigador
•Determinar la farmacocinética (FC) de trastuzumab deruxtecán en suero
• Evaluar aún más la seguridad de trastuzumab deruxtecán en base a acontecimientos adversos surgidos durante el tratamiento (AAST) y anticuerpos antifármaco (AAF)
• Evaluar los criterios de valoración de economía sanitaria e investigación de resultados (Health Economics and Outcomes Research, HEOR) en base a los resultados notificados por el paciente (RNP)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Key Inclusion Criteria:

- Men or women ≥18 years old (Please follow local regulatory requirements if the legal age of consent for study participation is >18 years old.)
- Has pathologically documented gastric or GEJ cancer that is:
- Unresectable or metastatic
- Centrally confirmed HER2-positive disease (immunohistochemistry [IHC]3+, IHC2+/in-situ hybridization [ISH]+) as determined according to American Society of Clinical Oncology – College of American Pathologists (ASCO-CAP) guidelines based on a new tissue sample obtained after progression on or after a trastuzumabcontaining regimen. If a tissue sample was already collected after discontinuation of first-line treatment with a trastuzumab-containing regimen, it is acceptable to consider this a new biopsy for the purpose of this study.

- Experienced disease progression during or after first-line therapy with a trastuzumab-containing regimen (brand or approved biosimilar). Note: Prior adjuvant therapy with a trastuzumab-containing regimen can be counted as a line of therapy if the subject progressed on or within 6 months of completing adjuvant therapy.

- Has at least 1 measurable lesion per RECIST v1.1 as confirmed by independent central review.

- Has left ventricular ejection fraction (LVEF) ≥50% within 28 days before enrollment per echocardiogram
(ECHO)/multigated acquisition (MUGA) scan.

- Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 4.5 months after the last dose of study drug.

- Adequate renal function, defined as creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation.

- Adequate hepatic function, defined as total bilirubin ≤1.5 × upper limit of normal (ULN); serum albumin ≥2.8 g/dL; aspartate transaminase (AST)/alanine transaminase (ALT) ≤3 × ULN in the absence of liver metastases or ≤5 × ULN in the presence of liver metastases.

• Hombres o mujeres ≥18 años de edad (siga las disposiciones reglamentarias locales si la edad legal de consentimiento para la participación en el estudio es de >18 años)
• Tener cáncer gástrico o de la UGE documentado por anatomía patológica que sea:
No resecable o metastásico
Enfermedad positiva para HER2 centralmente confirmada (inmunohistoquímica [IHQ]3+, IHQ2+/hibridación in situ [ISH]+) determinada de acuerdo con las directrices de la Sociedad Estadounidense de Oncología Clínica/Colegio de Anatomopatólogos Estadounidenses (American Society of Clinical Oncology – College of American Pathologists, ASCO-CAP) en base a una muestra de tejido nueva obtenida tras la progresión durante o después de una pauta que contenga trastuzumab. Si ya se recogió una muestra de tejido después de la interrupción del tratamiento de primera línea con una pauta que contenía trastuzumab, es aceptable considerarla como una nueva biopsia para el propósito de este estudio.
• Haber sufrido progresión de la enfermedad durante o después del tratamiento de primera línea con una pauta que contuviera trastuzumab (de marca comercial o biosimilar aprobado). Nota: el tratamiento adyuvante previo con una pauta que contuviera trastuzumab se puede contar como una línea de tratamiento si el paciente progresó durante o en el plazo de 6 meses desde la finalización del tratamiento adyuvante.
• Tener al menos 1 lesión medible de acuerdo con los criterios RECIST v1.1 según lo confirmado por una revisión central independiente.
• Tener una fracción de eyección ventricular izquierda (FEVI) ≥50 % en los 28 días anteriores a la inscripción mediante exploración por ecocardiograma (ECO)/ventriculografía isotópica (MUGA).
• Los sujetos de sexo masculino y femenino en edad fértil/con capacidad de concebir deben aceptar usar un método anticonceptivo altamente eficaz o evitar las relaciones sexuales durante y hasta la finalización del estudio y durante al menos 4,5 meses después de la última dosis del fármaco del estudio.
• Función renal adecuada, definida como un aclaramiento de creatinina ≥30 ml/min, calculado con la ecuación de Cockcroft-Gault.
• Función hepática adecuada, definida como bilirrubina total ≤1,5 × límite superior de la normalidad (LSN); albúmina sérica ≥2,8 g/dl; aspartato transaminasa (AST)/alanina transaminasa (ALT) ≤3 × LSN en ausencia de metástasis hepáticas o ≤5 × LSN en presencia de metástasis hepáticas.

E.4

Principal exclusion criteria

Key Exclusion Criteria:

- Use of anticancer therapy after first-line treatment with a trastuzumab-containing regimen.

- Uncontrolled or significant cardiovascular disease, including any of the following:
- History of myocardial infarction (MI) within 6 months before enrollment
- History of symptomatic congestive heart failure (New York Heart Association Class II to IV)
- Troponin levels consistent with MI as defined according to the manufacturer within 28 days prior to enrollment
- History of unstable angina or serious cardiac arrhythmia requiring treatment
- Corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (male) based on Screening triplicate 12-lead electrocardiogram (ECG)

- History of (non-infectious) interstitial lung disease (ILD) or pneumonitis that required corticosteroid therapy or has current ILD/pneumonitis or is suspected to have such diseases by imaging during Screening.

- Clinically significant corneal disease, in the opinion of the Investigator.

- Pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to or during Screening.)

- Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
- Subjects with clinically inactive brain metastases may be included in the study.
- Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy).

•Uso de tratamientos antineoplásicos después del tratamiento de primera línea con una pauta que contuviera trastuzumab.
•Enfermedad cardiovascular no controlada o significativa, incluidas cualquiera de las siguientes:
Antecedentes de infarto de miocardio (IM) en los 6 meses anteriores a la inscripción.
Antecedentes de insuficiencia cardíaca congestiva sintomática (clases II a IV según la Asociación Neoyorquina de Cardiología [New York Heart Association]).
Niveles de troponina coherentes con IM según la definición del fabricante en los 28 días anteriores a la inscripción.
Antecedentes de angina de pecho inestable o arritmia cardíaca grave que requiere tratamiento.
Prolongación del intervalo QT corregido (QTc) a >470 ms (mujeres) o >450 ms (hombres) en base al electrocardiograma (ECG) de 12 derivaciones por triplicado de la selección.
•Antecedentes de enfermedad pulmonar intersticial (EPI) (no infecciosa) o neumonitis que requirió tratamiento con corticoesteroides o presencia actual de EPI/neumonitis, o sospecha de la presencia de estas enfermedades según la exploración por imágenes durante la selección.
•Enfermedad corneal clínicamente significativa, en opinión del investigador.
•Derrame pleural, ascitis o derrame pericárdico que requiere drenaje, derivación peritoneal, o tratamiento de reperfusión acelular y concentrado de la ascitis (CART). (El drenaje y el CART no están permitidos en las 2 semanas previas a o durante la selección).
•Compresión de la médula espinal o metástasis en el sistema nervioso central clínicamente activas, definidas como no tratadas y sintomáticas o que requieran tratamiento con corticoesteroides o anticonvulsivos para controlar los síntomas asociados.
Los sujetos con metástasis cerebrales clínicamente inactivas pueden ser incluidos en el estudio.
Los sujetos con metástasis cerebrales tratadas que ya no son sintomáticas y que no requieren tratamiento con corticoesteroides o anticonvulsivos pueden ser incluidos en el estudio si se han recuperado del efecto tóxico agudo de la radioterapia. Debe haber transcurrido un mínimo de 2 semanas entre el final de la radioterapia cerebral total y la inscripción en el estudio (1 semana para la radioterapia estereotáctica)

E.5 End points

E.5.1

Primary end point(s)

Confirmed ORR (objective response rate) based on independent central review

TRO (tasa de respuesta objetiva) confirmada, en base a una revisión central independiente

E.5.1.1

Timepoint(s) of evaluation of this end point

Analysis of ORR will be performed for all enrolled subjects at the 18-week tumor assessment.

Analisis de la TRO se realizará para todos los sujetos inscritos en la evaluación del tumor de 18 semanas

E.5.2

Secondary end point(s)

Progression-Free Survival (PFS) , based on independent central review using RECIST v1.1.

Other Secondary Endpoints:
- PFS, based on Investigator assessment
- Objective response rate (ORR), based on Investigator assessment
- Overall survival (OS)
- Duration of Response (DoR), based on independent central review and Investigator assessment

Supervivencia sin progresión (SSP), basada en una revisión central independiente mediante RECIST v1.1.

• SSP, en base a la evaluación del investigador
• TRO, en base a la evaluación del investigador
• SG (supervivencia general)
•DR, en base a una revisión central independiente y la evaluación del investigador

E.5.2.1

Timepoint(s) of evaluation of this end point

Along the study. Based on independent central review

A lo largo del estudio. Basado en revisión central independiente

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

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.8.2.4

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

Belgium

Italy

Spain

United Kingdom

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 occur when all enrolled subjects have either completed their last scheduled visit or died or withdrawn from study participation, which is anticipated to occur approximately 12 months after the last subject is enrolled

El final del estudio se producirá cuando todos los sujetos reclutados hayan completado su última visita programada o hayan fallecido o hayan abandonado la participación en el estudio, lo que se prevé que ocurra aproximadamente 12 meses después de que se reclute el último sujeto

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

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

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)

See protocol

Ver protocolo

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

2019-10-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-19

P. End of Trial
P.	End of Trial Status	Ongoing

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