Clinical Trials Register

Summary
EudraCT Number:	2019-002369-36
Sponsor's Protocol Code Number:	GECP19/01
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:	2020-01-14
Trial 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

2019-002369-36

A.3

Full title of the trial

Clinical Utility of Liquid Biopsy as a tool to assess the evolution of brigatinib treated patients with non-small cell lung cancer with EML4-ALK translocation: an exploratory study

Utilidad clínica de la biopsia líquida como herramienta para evaluar la evolución de pacientes tratados con brigatinib con cáncer de pulmón de células no pequeñas con translocación EML4-ALK: un estudio exploratorio

A.3.1

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

Utility of analysis in blood of the evolution of the drug brigatinib for patients with lung cancer with ALK mutations

Utilidad del análisis en sangre de la evolución del fármaco brigatinib para pacientes con cáncer de pulmón con mutaciones ALK

A.3.2

Name or abbreviated title of the trial where available

Clinical Utility of liquid biopsy in Brigatinib ALK+ patients_CUBIK

Utilidad clínica de la biopsia líquida en pacientes ALK + con Brigatinib_CUBIK

A.4.1

Sponsor's protocol code number

GECP19/01

A.5.4

Other Identifiers

Name:

Takeda code

Number:

CCR-GECP-Brig

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	Fundación GECP
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fundación GECP
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fundación GECP
B.5.2	Functional name of contact point	Eva Pereira
B.5.3	Address:
B.5.3.1	Street Address	Avenida Meridiana 358, 6ª planta
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08027
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34934302006205
B.5.5	Fax number	+34934302006
B.5.6	E-mail	epereira@gecp.org

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	Alunbrig
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Pharma
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	Brigatinib
D.3.2	Product code	AP26113
D.3.4	Pharmaceutical form	Film-coated tablet
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	BRIGATINIB
D.3.9.1	CAS number	1197953-54-0
D.3.9.2	Current sponsor code	AP26113
D.3.9.4	EV Substance Code	SUB184911
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	30
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

ALK+ non-small cell lung cancer

Cáncer de pulmón no microcítico ALK+

E.1.1.1

Medical condition in easily understood language

Lung cancer with ALK mutations in a gen

Cáncer de pulmón con mutaciones en el gen ALK

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	LLT
E.1.2	Classification code	10025055
E.1.2	Term	Lung cancer non-small cell stage IV
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 evaluate the Overall response rate (ORR) of brigatinib as measured by investigator. Overall response will be assessed per RECIST V1.1 criteria

Evaluar la tasa de respuesta (ORR) de brigatinib. La respuesta se evaluará según los criterios RECIST V1.1

E.2.2

Secondary objectives of the trial

•To evaluate the efficacy of brigatinib as measured by investigator. Assessed as duration of response (DOR) according to RECIST v1.1.
• To evaluate the efficacy of brigatinib as measured by investigator. Assessed as time on treatment according to RECIST v1.1.
• To evaluate the intracranial overall response rate (ORR) and the intracranial time to progression
• To evaluate the PFS rate at 1 year and 2 years of treatment with brigatinib by RECIST v1.1
• To evaluate the Overall Survival (OS) rate at 1 year and 2 years of treatment with brigatinib
• To evaluate the safety and tolerability of brigatinib.

• Evaluar la eficacia de brigatinib, evaluando la duración de la respuesta (DOR) según RECIST v1.1.
• Evaluar la eficacia de brigatinib evaluando el tiempo de tratamiento según RECIST v1.1.

• Evaluar la tasa de respuesta global intracraneal (ORR) y el tiempo de respuesta intracraneal hasta la progresión.
• Evaluar la tasa de SLP a 1 año y 2 años de tratamiento con brigatinib por RECIST v1.1
• Evaluar la tasa de supervivencia global (SG) a 1 año y 2 años de tratamiento con brigatinib
• Evaluar la seguridad y la tolerabilidad de brigatinib.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, aged ≥ 18 years old
2. ECOG performance status of 0-2
3. Histologically or cytologically confirmed, Stage IIIB or IV NSCLC
4. Patients who have documented locally ALK rearrangement
5. No prior treatment for Stage IIIB or IV non-squamous NSCLC.
6. Having a life expectancy ≥ 3 months
7. Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or chemo-radiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from enrollment since the last chemotherapy, radiotherapy, or chemo-radiotherapy.
8. Untreated or treated CNS metastases allowed, as long as asymptomatic and neurologically stable
9. Patients with at least 1 measurable lesion, as defined by RECIST v1.1
10. Normal QT interval (QT) on screening ECG evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤ 450 milliseconds (msec) in males of ≤ 470 msec in females
11. Adequate hematologic and organ function
12. All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention.
13. Willingness and ability to comply with scheduled visits and study procedures
14. For female patients of childbearing potential, a negative pregnancy test must have been documented prior to enrollment (within 14 days prior to enrollment)

1. Hombre o mujer, de edad ≥ 18 años.
2. ECOG de 0-2
3. Confirmado histológica o citológicamente, NSCLC en estadio IIIB o IV
4. Pacientes con reordenamiento de ALK
5. Pacientes que no hayan recibido tratamiento previo para el NSCLC no escamoso en estadio IIIB o IV.
6. Tener una esperanza de vida ≥ 3 meses
7. Los pacientes que hayan recibido quimioterapia neoadyuvante, adyuvante, radioterapia o quimioterapia con intención curativa para la enfermedad no metastásica deben haber experimentado un intervalo sin tratamiento de al menos 6 meses desde la última quimioterapia, radioterapia, o quimio-radioterapia.
8. Se pueden incluir pacientes con metástasis del SNC no tratadas o tratadas, siempre que sean asintomáticas y neurológicamente estables
9. Pacientes con al menos 1 lesión medible, según RECIST v1.1
10. Intervalo QT normal (QT) en la evaluación del ECG, definido como intervalo QT corregido (Fridericia) (QTcF) de ≤ 450 milisegundos (mseg) en hombres de ≤ 470 mseg en mujeres
11. Función hematológica y orgánica adecuada.
12. Todos los pacientes deben firmar un consentimiento informado por escrito de acuerdo con las directrices institucionales y nacionales, incluida la Declaración de Helsinki antes de cualquier intervención relacionada con el ensayo.
13. Voluntad y capacidad para cumplir con las visitas programadas y los procedimientos de estudio.
14. Para las pacientes de sexo femenino en edad fértil, debe haberse documentado una prueba de embarazo negativa antes de la inclusión (dentro de los 14 días anteriores a la inscripción)

E.4

Principal exclusion criteria

1. Patients with a known sensitizing mutation in the epidermal growth factor receptor (EGFR) gene, STK-1 Ligand alteration, MDM2 amplification or ROS1 translocations.
2. Patients that received any prior TKI, including ALK-targeted TKIs or any systemic anticancer therapy for locally advanced or metastasic disease
3. Patients that have received chemotherapy or radiation within 14 days of first dose of study drug.
4. Symptomatic CNS metastases (parenchymal or leptomeningeal) that are neurologically unstable or required an increasing dose of corticosteroids within 7 days prior to first dose of study drug
5. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression is allowed.
6. Malignancies other than NSCLC within 3 years prior to enrollment
7. Women who are pregnant, lactating, or intending to become pregnant during the study.
8. Patients that received monoclonal antibodies or had major surgery within 30 days of the first dose of brigatinib
9. History of idiopathic pulmonary fibrosis, pulmonary interstitial disease, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
10. Have uncontrolled hypertension
11. Positive test for HIV. A and patients with active hepatitis B or active tuberculosis
12. Severe infections within 2 weeks prior to be included in the study
13. Have significant, uncontrolled or active cardiovascular disease
14. Patients with illnesses or conditions that interfere with their capacity to understand follow and/or comply with study procedures

1. Pacientes con una mutación sensibilizante conocida en el gen del receptor del factor de crecimiento epidérmico (EGFR), alteración del ligando STK-1, amplificación de MDM2 o translocaciones ROS1.
2. Pacientes que recibieron cualquier TKI previo, incluidos los TKI dirigidos a ALK o cualquier terapia anticancerígena sistémica para la enfermedad localmente avanzada o metastásica
3. Pacientes que hayan recibido quimioterapia o radiación dentro de los 14 días antes de la primera dosis del fármaco del estudio.
4. Metástasis sintomáticas del SNC (parenquimatosas o leptomeníngeas) que son neurológicamente inestables o requieren una dosis creciente de corticosteroides dentro de los 7 días previos a la primera dosis del fármaco del estudio
5. Tener compresión medular en el momento de la inclusión (sintomática o asintomática y detectada por imagen radiográfica). Se permiten pacientes con enfermedad leptomeníngea y sin compresión medular.
6. Malignidades que no sean NSCLC dentro de los 3 años anteriores a la inclusión
7. Mujeres embarazadas, en periodo de lactancia o que pretenden quedarse embarazadas durante el estudio.
8. Pacientes que recibieron anticuerpos monoclonales o se sometieron a una cirugía mayor dentro de los 30 días posteriores a la primera dosis de brigatinib
9. Antecedentes de fibrosis pulmonar idiopática, enfermedad intersticial pulmonar, neumonía organizada (p. Ej., Bronquiolitis obliterante), neumonitis inducida por fármacos, neumonitis idiopática o evidencia de neumonitis activa en la exploración de TC de tórax.
10. Pacientes con hipertensión no controlada
11. Prueba positiva de VIH. Pacientes con hepatitis B activa o tuberculosis activa
12. Infecciones graves dentro de las 2 semanas previas a ser incluidos en el estudio
13.Pacientes con enfermedad cardiovascular significativa, no controlada o activa
14. Los pacientes con enfermedades o afecciones que interfieren con su capacidad de comprender seguir o cumplir con los procedimientos del estudio.

E.5 End points

E.5.1

Primary end point(s)

Overall response rate

Tasa de respuesta global

E.5.1.1

Timepoint(s) of evaluation of this end point

To evaluate the Overall response rate (ORR) RECIST V1.1 criteria will be used. CT-SCANs will be done every 12 weeks during the treatment to evaluate the response to the treatment.

Para evaluar la tasa de respuesta general (ORR) se utilizará el criterio RECIST V1.1. Los TAC se realizarán cada 12 semanas durante el tratamiento para evaluar la respuesta al tratamiento.

E.5.2

Secondary end point(s)

- Duration of response (DOR)
- Intracranial overall response rate
- PFS rate at 1 year and 2 years
- Overall Survival (OS) rate at 1 year and 2 years
- Safety and tolerability of brigatinib

- Duración de la respuesta (DOR)
- Tasa de respuesta global intracraneal
- Tasa de supervivencia libre de progresión (SLP) a 1 año y 2 años
- Tasa de supervivencia global (SG) a 1 año y 2 años
- Seguridad y tolerabilidad de brigatinib

E.5.2.1

Timepoint(s) of evaluation of this end point

DOR, PFS: from the start of the treatment to date of progression
OS: from the start of the treatment to date of death or last follow up
Safety and tolerability of brigatinib: at the end of the trial

DOR, PFS: desde el inicio del tratamiento hasta la fecha de progresión
OS: desde el inicio del tratamiento hasta la fecha de fallecimiento o el último seguimiento
Seguridad y tolerabilidad de brigatinib: al final del ensayo

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

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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 (LVLS)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

None

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

2020-04-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-12

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

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