Clinical Trials Register

Summary
EudraCT Number:	2018-003265-34
Sponsor's Protocol Code Number:	MS200647_0005
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-06-28
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

2018-003265-34

A.3

Full title of the trial

A Multicenter, Double Blind, Randomized, Controlled Study of M7824 with Concurrent Chemoradiation Followed by M7824 versus Concurrent Chemoradiation Plus Placebo Followed by Durvalumab in Participants with Unresectable Stage III Non-small Cell Lung Cancer

Estudio multicéntrico, doble ciego, aleatorizado y controlado de M7824 con quimiorradioterapia concurrente seguida de M7824 en comparación con quimiorradioterapia concurrente más placebo seguida de durvalumab en participantes con cáncer de pulmón no microcítico irresecable en estadio III

A.3.1

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

M7824 with cCRT in Unresectable Stage III NSCLC

M7824 con QRTc en el CPNM irresecable en estadio III

A.4.1

Sponsor's protocol code number

MS200647_0005

A.5.4

Other Identifiers

Name:

IND

Number:

124757

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	Merck KGaA
B.1.3.4	Country	Germany
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	Merck KGaA
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	Merck KGaA
B.5.2	Functional name of contact point	Communication Center Merck KGaA
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Strasse 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+34900810844
B.5.5	Fax number	+496151 72 2000
B.5.6	E-mail	service@merckgroup.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	M7824
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	bintrafusp alfa (proposed INN)
D.3.9.2	Current sponsor code	MSB0011359C
D.3.9.3	Other descriptive name	M7824
D.3.9.4	EV Substance Code	SUB179957
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	10
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	Comparator
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	IMFINZI 50 mg/mL concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
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.3.4	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	DURVALUMAB
D.3.9.3	Other descriptive name	IMFINZI
D.3.9.4	EV Substance Code	SUB176342
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	50
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Unresectable Stage III Non-small Cell Lung Cancer

cáncer de pulmón no microcítico irresecable en estadio III

E.1.1.1

Medical condition in easily understood language

Unresectable Stage III Non-small Cell Lung Cancer

cáncer de pulmón no microcítico irresecable en estadio III

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10029519
E.1.2	Term	Non-small cell lung cancer stage III
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 evaluate PFS in participants treated with cCRT plus M7824
followed by M7824 or cCRT plus placebo followed by
durvalumab

Evaluar la SSP en los participantes tratados con QRTc más
M7824 seguida de M7824 o QRTc más placebo seguida de
durvalumab

E.2.2

Secondary objectives of the trial

To evaluate the safety in participants treated with cCRT plus M7824 followed by M7824 or cCRT plus placebo followed by durvalumab
To evaluate OS in participants treated with cCRT plus M7824 followed by M7824 or cCRT plus placebo followed by durvalumab
To evaluate changes in lung function in participants treated with
cCRT plus M7824 followed by M7824 or cCRT plus placebo followed by durvalumab
To evaluate the association of PD-L1 expression at Baseline with efficacy in participants treated with cCRT plus M7824 followed by M7824 or cCRT plus placebo followed by durvalumab
To evaluate objective tumor response in participants treated with
cCRT plus M7824 followed by M7824 or cCRT plus placebo followed by durvalumab
To evaluate duration of response in participants treated with
cCRT plus M7824 followed by M7824 or cCRT plus placebo followed by durvalumab
To characterize PK profile of M7824 plus cCRT and after cCRT
To characterize the immunogenicity of M7824 plus cCRT and after cCRT

-Evaluar la seguridad en los participantes tratados con QRTc más M7824 seguida de M7824 o QRTc + placebo seguida de durvalumab
Evaluar la SG en los participantes tratados con QRTc más M7824 seguida de M7824 o QRTc + placebo seguida de durvalumab
Evaluar los cambios en la func. pulmonar en los participantes tratados con QRTc más M7824 seguida de
M7824 o QRTc + placebo seguida de durvalumab
Evaluar la asociación de la expresión de PD-L1 en el inicio con la eficacia en los participantes tratados con QRTc + M7824 seguida de M7824 o QRTc + placebo seguida de durvalumab
Evaluar la respuesta objetiva del tumor en los participantes tratados con QRTc + M7824 seguida de M7824 o QRTc +placebo seguida de durvalumab
Evaluar la duración de la respuesta en los participantes tratados con QRTc + M7824 seguida de M7824 o QRTc + placebo seguida de durvalumab
Caracterizar el perfil FC de M7824 + QRTc y después de la QRTc
Caracterizar la inmunogenicidad de M7824 + QRTc y después de la QRTc

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Investigator Participants must have histologically documented NSCLC who present with Stage III locally advanced, unresectable disease (International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology], v8).

2. Participants with tumor harboring an EGFR sensitizing (activating) mutation, ALK translocation, ROS-1 rearrangement are eligible. These tests are not required for enrollment in the study.

3. Participants must have adequate pulmonary function defined as a forced expiratory volume in 1 second (FEV1) ≥ 1.2 liters or ≥ 50% of predicted normal volume measured within 3 weeks prior to randomization. If participants do not meet the above criteria, treatment with inhaled steroids and bronchodilators can be initiated if clinically indicated and eligibility can be reassessed after 1-2 weeks.

4. Adequate hematological, hepatic and renal function as defined in the protocol
Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies

5. Other protocol defined inclusion criteria could apply

1. Los participantes en el estudio de investigación deben presentar CPNM localmente avanzado irresecable en estadio III histológicamente documentado (versión 8 del Manual de Estadificación en Oncología Torácica de la Asociación Internacional para el Estudio del Cáncer de Pulmón [International Association for the Study of Lung Cancer, IASLC]).
2. Los participantes con tumores que alberguen una mutación sensibilizante (activadora) del EGFR, translocación de ALK, reordenación de ROS-1, son aptos. Estas pruebas no son necesarias para la inclusión en el estudio.
3. Los participantes deben presentar una función pulmonar adecuada definida como un volumen espiratorio forzado en 1 segundo (FEV1) ≥ 1,2 litros o ≥ 50 % del volumen normal previsto medido en un plazo de 3 semanas antes de la aleatorización. Si los participantes no cumplen los criterios anteriores, puede iniciarse el tratamiento con esteroides inhalados y broncodilatadores, si está clínicamente indicado, y se puede evaluar de nuevo la idoneidad después de 1-2 semanas.
4. Funciones hematológica, hepática y renal adecuadas según se define en el protocolo.
El uso de anticonceptivos por hombres o mujeres debe ser coherente con las normativas locales relativas a los métodos anticonceptivos para los participantes en estudios clínicos.
5. Podrán aplicarse otros criterios de inclusión definidos en el protocolo.

E.4

Principal exclusion criteria

1. Participants with Mixed small cell with non-small cell lung cancer histology

2. Recent major surgery within 4 weeks prior to entry into the study

3. Significant acute or chronic infections

4. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization

5. Active autoimmune disease that has required systemic treatment in past 1 year (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs)
Other protocol defined exclusion criteria could apply

1. Participantes con histología de cáncer de pulmón mixto microcítico y no microcítico.
2. Cirugía mayor reciente en las 4 semanas anteriores a la inclusión en el estudio.
3. Infecciones agudas o crónicas significativas.
4. Exacerbación de la enfermedad pulmonar obstructiva crónica o de otra enfermedad respiratoria que requiera hospitalización.
5. Enfermedad autoinmune activa que ha necesitado tratamiento sistémico en el último año (es decir, con agentes modificadores de la enfermedad, corticosteroides o fármacos inmunodepresores).
Podrían aplicarse otros criterios de exclusión definidos en el protocolo.

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) assessed by Independent Review Committee (IRC)

Supervivencia sin progresión (SSP) según los criterios de evaluación de la respuesta en tumores sólidos, versión 1.1 (RECIST 1.1) evaluada por un Comité de revisión independiente (CRI)

E.5.1.1

Timepoint(s) of evaluation of this end point

Time from randomization to final assessment at 8 years and 10 months

Tiempo desde la aleatorización hasta la evaluación final a los 8 años y 10 meses

E.5.2

Secondary end point(s)

1. Occurrence of Treatment-emergent Adverse Events (TEAEs) and treatment-related Adverse Events (AEs)

2. Overall Survival

3. Changes from Baseline in pulmonary function

4. Programmed death-ligand 1 (PD-L1) expression in tumors at Baseline

5. Objective response according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

6. Duration of response

7. Pharmacokinetics profile of M7824 in terms of Ceoi and Ctrough

8. Immunogenicity of M7824

1. Aparición de acontecimientos adversos surgidos durante el tratamiento (AAST) y acontecimientos adversos graves surgidos durante el tratamiento (AAGST).
2. Supervivencia general
3. Los cambios desde el inicio en la función pulmonar.
4. Expresión del ligando 1 de muerte programada (PD-L1) en los tumores en el inicio.
5. Respuesta objetiva según los criterios de evaluación de la respuesta en tumores sólidos (RECIST), versión 1.1.
6. Duración de la respuesta
7. Perfil FC de M7824 en términos de Cfdi y Cmín
8. Inmunogenicidad de M7824

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Time from randomization to final assessment at 8 years and 10 months

2. Time from randomization to final assessment at 8 years and 10 months

3. Time from randomization to final assessment at 14 months

4. Randomization

5. Time from randomization to final assessment at 8 years and 10 months

6. Time from randomization to final assessment at 8 years and 10 months

7. Time from randomization to final assessment at 17 months

8. Time from randomization to final assessment at 17 months

1. Tiempo desde la aleatorización hasta la evaluación final a los 8 años y 10 meses
2. Tiempo desde la aleatorización hasta la evaluación final a los 8 años y 10 meses
3. Tiempo desde la aleatorización hasta la evaluación final a los 14 meses
4. Aleatorización
5. Tiempo desde la aleatorización hasta la evaluación final a los 8 años y 10 meses
6. Tiempo desde la aleatorización hasta la evaluación final a los 8 años y 10 meses
7. Tiempo desde la aleatorización hasta la evaluación final a los 17meses
8. Tiempo desde la aleatorización hasta la evaluación final a los 17 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

Yes

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

Yes

E.6.11

Pharmacogenomic

Yes

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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)

Yes

E.8.2.2

Placebo

Yes

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

Argentina

Australia

Brazil

Canada

China

European Union

Japan

Korea, Republic of

Russian Federation

Taiwan

Turkey

United States

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

The end of the study is defined as the date of primary OS analysis when 254 participants have died.

El final del estudio se define como la fecha del análisis principal de la SG cuando 254 los participantes han muerto.

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:

175

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

175

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

142

F.4.2.2

In the whole clinical trial

350

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)

After a participant has completed the study or has withdrawn early,
participants may receive the care they and their physicians agree upon.
Participants will be followed for survival and AEs as specified in the
protocol

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

2019-06-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-03

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2021-09-15

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IMP with orphan designation in the indication
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