Clinical Trials Register

Summary
EudraCT Number:	2018-003704-39
Sponsor's Protocol Code Number:	BAY88-8223/19781
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

2018-003704-39

A.3

Full title of the trial

An open-label, multicenter, Phase 1/2 study of radium-223 dichloride in combination with pembrolizumab in participants with stage IV non-small cell lung cancer

Estudio fase I/II abierto, multicéntrico con dicloruro de radio-223 en combinación con pembrolizumab en pacientes con cáncer de pulmón no microcítico en estadio IV

A.3.1

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

A study evaluating the safety and efficacy of radium-223 dichloride in combination with pembrolizumab in lung cancer patients

Un estudio para evaluar la seguridad y eficacia de dicloruro de radio-223 en combinación con pembrolizumab en pacientes con cáncer de pulmón

A.4.1

Sponsor's protocol code number

BAY88-8223/19781

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	Bayer Consumer Care AG
B.1.3.4	Country	Switzerland
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	Bayer Consumer Care 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	Bayer AG
B.5.2	Functional name of contact point	Bayer Clinical Trials Contact
B.5.3	Address:
B.5.3.1	Street Address	Müllerstraße 178
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13353
B.5.3.4	Country	Germany
B.5.4	Telephone number	0034900102372
B.5.6	E-mail	clinical-trials-contact@bayer.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	Xofigo
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer AG
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	Radium RA 223 dichloride
D.3.2	Product code	BAY88-8223
D.3.4	Pharmaceutical form	Solution for injection
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	Radium-223 dichloride
D.3.9.1	CAS number	444811-40-9
D.3.9.2	Current sponsor code	BAY 88-8223
D.3.9.3	Other descriptive name	RADIUM RA 223 DICHLORIDE
D.3.9.4	EV Substance Code	SUB129907
D.3.10	Strength
D.3.10.1	Concentration unit	kBq/ml kilobecquerel(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1100
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	Yes
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	Yes
D.2.1.1.1	Trade name	Keytruda
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme B.V.
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	Pembrolizumab
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	PEMBROLIZUMAB
D.3.9.1	CAS number	1374853-91-4
D.3.9.4	EV Substance Code	SUB167136
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	25
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	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

Stage IV non-small cell lung cancer (NSCLC)

Cancer de pulmón no microcítico (CPNM) en estadio IV

E.1.1.1

Medical condition in easily understood language

Lung cancer

Cáncer de pulmón

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	PT
E.1.2	Classification code	10029522
E.1.2	Term	Non-small cell lung cancer stage IV
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

Phase 1
- To assess the safety of the combination of radium-223 dichloride and pembrolizumab and to determine the recommended Phase 2 dose (RP2D)

Phase 2
- To assess the efficacy of the combination of radium-223 dichloride and pembrolizumab (for Cohort 1: compared to pembrolizumab alone)

Fase 1
- Analizar la seguridad de la combinación de dicloruro de radio-223 y pembrolizumab y determinar la dosis recomendada para la fase 2 (DRF2)

Fase 2
- Analizar la seguridad de la combinación de dicloruro de radio-223 y pembrolizumab (para la Cohorte 1: comparación con pembrolizumab en monoterapia)

E.2.2

Secondary objectives of the trial

Phase 1
- To assess the efficacy of the combination of radium-223 dichloride and pembrolizumab

Phase 2
- To assess the efficacy of the combination of radium-223 dichloride and pembrolizumab (for Cohort 1: compared to pembrolizumab alone)
- To evaluate the safety of the combination of radium-223 dichloride and pembrolizumab (for Cohort 1: compared to pembrolizumab alone)

Fase 1
- Evaluar la eficacia de la combinación de dicloruro de radio-223 y pembrolizumab

Fase 2
- Analizar la seguridad de la combinación de dicloruro de radio-223 y pembrolizumab (para la Cohorte 1: comparación con pembrolizumab en monoterapia)
- Evaluar la seguridad de la combinación de dicloruro de radio-223 y pembrolizumab (para la Cohorte 1: comparación con
pembrolizumab en monoterapia)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histologically or cytologically confirmed diagnosis of stage IV NSCLC. Phase 2 Cohort 1: no Epidermal Growth Factor Receptor (EGFR) sensitization (activating) mutation or anaplastic lymphoma kinase (ALK)/ROS1 rearrangement. Treatment naïve (no prior systemic therapy) for their metastatic NSCLC. Phase 2 Cohort 2: progression on prior treatment with an immune checkpoint inhibitor. Phase 1 includes participants meeting either Cohort 1 or Cohort 2 criteria.
- Measurable disease per RECIST v1.1.
- At least 2 skeletal metastases.
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
- Adequate bone marrow and organ function.

- Tener una confirmación citológica o histológica del diagnóstico de CPNM en estadio IV. Cohorte 1 de la Fase II: Sin mutación de sensibilización (activación) del factor de crecimiento epidérmico (EGFR) o reordenación de la cinasa del linfoma anaplásico (ALK)/ROS1. Sin tratamiento previo (sin tratamiento sistémico previo) para su CPNM metastásico. Cohorte 2 de la Fase II: Progresión con tratamiento previo con un inhibidor del punto de control inmunitario. La Fase I incluye a los participantes que cumplan los criterios de inclusión de la Cohorte 1 o la Cohorte 2.
- Enfermedad medible de acuerdo con los criterios RECIST v1.1
- Al menos 2 metástasis óseas identificadas
- Estado funcional (EF) de 0 o 1, según el Grupo Oncológico Cooperativo del Este (ECOG)
- Función adecuada de la médula ósea y de los órganos.

E.4

Principal exclusion criteria

- Previous or concurrent cancer within 3 years prior to enrollment.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor. Phase 2 Cohort 2: was discontinued from that treatment due to a Grade 3 or higher immune-related AEs (irAEs).
- Known active central nervous system metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
- Active autoimmune disease that has required systemic treatment in the past 2 years.
- History of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
- Known history or presence of osteonecrosis of jaw.
- Ongoing infection >Grade 2 NCI-CTCAE v.5.0 requiring systemic therapy.
- Significant acute GI disorders with diarrhea as a major symptom e.g., Crohn’s disease, malabsorption, or ≥ NCI-CTCAE v.5.0 Grade 2 diarrhea of any etiology.
- Prior treatment with radium-223 dichloride or any therapeutic radiopharmaceutical.
- Prior radiotherapy within 21 days of planned start of study treatment.

- Cáncer previo o simultáneo en los 3 años anteriores a la inclusión
- Haber recibido tratamiento previo con un fármaco anti-PD-1, anti-PD-L1, anti-PD-L2 o con un fármaco dirigido a otro receptor estimulante o coinhibidor de linfocitos T. Cohorte 2 de la Fase II: haber interrumpido ese tratamiento debido a un AAir de grado 3 o superior.
- Metástasis activas conocidas en el sistema nervioso central o meningitis carcinomatosa. Los participantes con metástasis cerebrales tratadas previamente podrán participar siempre que sean radiológicamente estables clínicamente estables y sin necesidad de tratamiento con corticoesteroides durante al menos 14 días antes de la primera dosis del tratamiento del estudio.
- Presencia de enfermedad autoinmunitaria activa que haya requerido tratamiento sistémico en los 2 últimos años.
- Antecedentes de neumonitis (no infecciosa) que requiriera corticoesteroides o neumonitis en curso.
- Antecedentes conocidos o presencia de osteonecrosis de la mandíbula.
- Infección en curso de grado >2 según los CTCAE v5.0 del NCI que requiera tratamiento sistémico
- Trastornos GI agudos significativos con diarrea como un síntoma principal p. ej., enfermedad de Crohn, malabsorción, o diarrea de cualquier etiología de grado ≥2 según los CTCAE v5.0 del NCI.
- Tratamiento anterior con dicloruro de radio-223 o cualquier radiofármaco experimental.
- Radioterapia previa en el plazo de 21 días antes del comienzo previsto del tratamiento del estudio.

E.5 End points

E.5.1

Primary end point(s)

1. Number of participants with adverse events (AEs) in Phase 1
2. Number of participants with dose limiting toxicities (DLTs) in Phase 1
3. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in Phase 2

1. Número de participantes con acontecimientos adversos en la Fase 1.
2. Número de participantes con incidencias de toxicidades limitantes de las dosis (TLD) en la Fase 1.
3. Tasa de respuesta objetiva (TRO) según los Criterios de evaluación de la respuesta en tumores sólidos (RECIST) v1.1 en Fase 2.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Until 30 days after the last dose of the study intervention (up to 4 years)
2. Up to 6 weeks
3. Up to 36 weeks

1. 30 días después de la última dosis de intervención del estudio (hasta 4 años).
2. Hasta 6 semanas
3. Hasta 36 semanas

E.5.2

Secondary end point(s)

1. ORR per RECIST v1.1 in Phase 1
2. ORR per iRECIST in Phase 1
3. Duration of response (DOR) per RECIST v1.1 in Phase 1
4. DOR per iRECIST in Phase 1
5. Disease control rate (DCR) per RECIST v1.1 in Phase 1
6. DCR per iRECIST in Phase 1
7. ORR per iRECIST in Phase 2
8. DOR per RECIST v1.1 in Phase 2
9. DOR per iRECIST in Phase 2
10. DCR per RECIST v1.1 in Phase 2
11. DCR per iRECIST in Phase 2
12. Progression free survival (PFS) per RECIST v1.1 in Phase 2
13. PFS per iRECIST in Phase 2
14. Overall survival (OS) in Phase 2
15. Number of participants with AE in Phase 2

1. TRO según RECIST v 1.1
2. TRO según iRECIST en la Fase 1
3. Duración de la respuesta (DR) según RECIST v1.1 en la Fase 1
4. DR según iRECIST en la Fase 1
5. Tasa de control de la enfermedad (TCE) según los criterios RECIST v1.1 en la Fase 1
6. TCE según iRECIST en la Fase 1
7. TRO según iRECIST en la Fase 2
8. DR según RECIST v1.1 en la Fase 2
9. DR según iRECIST en la Fase 2
10. TCE según RECIST en la Fase 2
11. TCE según iRECIST en la Fase 2
12. Supervivencia sin progresión (SSP) según RECIST v1.1 en la Fase 2
13. SSP según iRECIST v1.1 en la Fase 2
14. Supervivencia general (SG) en la Fase 2
15. Número de participantes con acontecimientos adversos en la Fase 2

E.5.2.1

Timepoint(s) of evaluation of this end point

Points 1-14: Up to 5 years
Point 15: Until 30 days after the last dose of the study intervention (up to 5 years)

Puntos 1-14: Hasta 5 años
Punto 15: 30 días después de la última dosis de intervención del estudio (hasta 5 años)

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

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

Inmunogenicidad

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

To determine the Recommended Phase 2 Dose of radium-223 dichloride in combination with pembrolizumab

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

Sequential Assignment

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

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

Germany

Israel

Italy

Japan

Netherlands

Poland

Spain

United Kingdom

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 date when the last participant has been followed for at least 2 years after the last dose of radium-223 dichloride or died or withdrew consent.

La fecha de la última visita de seguimiento del último paciente después de al menos 2 años de la última dosis de dicloridio de radio-223 o la muerte o retirada del consentimiento.

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:

108

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

154

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 the end of study, further therapy is at the discretion of the investigator.

Tras el final del estudio, la terapia adicional será a discreción del investigador.

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

2019-10-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-10

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

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