Clinical Trials Register

Summary
EudraCT Number:	2018-004515-45
Sponsor's Protocol Code Number:	GECP18/02
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:	2019-04-11
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

2018-004515-45

A.3

Full title of the trial

A randomized phase II study of neo-adjuvant chemo/immunotherapy versus chemotherapy alone for the treatment of locally advanced and potentially resectable non-small cell lung cancer (NSCLC) patients

Ensayo clínico Fase II randomizado de quimioinmunoterapia neo-adyuvante versus quimioterapia sola para el tratamiento de pacientes con cáncer de pulmón no microcítico (CPNM) localmente avanzado y potencialmente resecable

A.3.1

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

Study of chemotherapy and immunotherapy for patients with lung cancer bounded in the thorax and potentially resectable

Estudio de quimioterapia e inmunoterapia para pacientes con cáncer de pulmón confinado en el tórax y que son candidatos a ser operados

A.4.1

Sponsor's protocol code number

GECP18/02

A.5.4

Other Identifiers

Name:

BMS Number

Number:

CA209-8W4

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	+34934302006
B.5.5	Fax number	+34934191768
B.5.6	E-mail	epereira@gecp.org

D. IMP Identification
D.IMP: 1
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	OPDIVO
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	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	NIVOLUMAB
D.3.9.2	Current sponsor code	BMS-936558
D.3.9.3	Other descriptive name	OPDIVO
D.3.9.4	EV Substance Code	SUB122750
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)	Yes
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

Non-small cell lung cancer

Cáncer de pulmón no microcítico

E.1.1.1

Medical condition in easily understood language

Non-small cell lung cancer

Cáncer de pulmón de células no pequeñas

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	10029514
E.1.2	Term	Non-small cell lung cancer NOS
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

The primary objective is pathological Complete Response (pCR) defined as the absence of residual tumor in lung and lymph nodes comparing patients treated with chemo-inmunotherapy versus chemotherapy alone

El objetivo principal es la Respuesta patológica completa (pCR), definida como la ausencia de tumor residual en los pulmones y los ganglios linfáticos entre los pacientes tratados con quimio-inmunoterapia versus los tratados con quimioterapia sola.

E.2.2

Secondary objectives of the trial

- Overall survival
- Progression-free survival
- Major pathological response rate
- Downstaging
- Portion of delayed/canceled surgeries, length of hospital stays, surgical ap-proach, incidence of AE/SAE related to surgery
- Mortality at 90 days after surgery
- Safety and tolerability: Adverse events graded according to CTCAE v5.0
- Biomarker endpoints

- Supervivencia global
- Supervivencia libre de progresión
- Mayor tasa de respuesta patológica.
- Retroceso quirúrgico
- Porción de cirugías retrasadas / canceladas, duración de las estadías en el hospital, abordaje quirúrgico, incidencia de AE / SAE relacionada con la cirugía
- Mortalidad a los 90 días de la cirugía.
- Seguridad y tolerabilidad: eventos adversos clasificados de acuerdo con CTCAE v5.0
- Marcadores moleculares

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Previously untreated patients with histologically- or cytologically- documented NSCLC who present stage IIIA disease (according to 8th version of the Interna-tional Association for the Study of Lung Cancer Staging Manual in Thoracic Oncol-ogy) and also, potentially resectable locally advanced NSCLC patients’ stage IIIB with T3N2 disease according to 8th edition can be included.
- PET/CT including IV contrast (CT of diagnostic quality) will be per-formed at baseline
2. Tumor should be considered resectable before study entry by a multidisciplinary team

3. ECOG (Performance status) 0-1

4. Screening laboratory values must meet the following criteria and should be ob-tained within 14 days prior to registration/inclusion
i. Neutrophils ≥ 1500×109/L
ii. Platelets ≥ 100 x×109/L
iii. Hemoglobin > 9.0 g/dL
iv. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):
a. Female CrCl = (140 - age in years) x weight in kg x 0.85/
72 x serum creatinine in mg/dL

b. Male CrCl = (140 - age in years) x weight in kg x 1.00/
72 x serum creatinine in mg/dL
v. AST/ALT ≤ 3 x ULN
vi. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
vii. The patients need to have a forced expiratory volume (FEV1) ≥ 1.2 liters or >40% predicted value
viii. INR/APTT within normal limits

5. 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

6. Patients aged > 18 years

7. Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before beginning of chemotherapy.

8. All sexually active men and women of childbearing potential must use an effective contraceptive method (two barrier methods or a barrier method plus a hormonal method) during the study treatment and for a period of at least 12 months follow-ing the last administration of trial drugs

9. Patient capable of proper therapeutic compliance and accessible for correct fol-low-up

10. Measurable or evaluable disease (according to RECIST 1.1 criteria)

1. Pacientes no tratados previamente con cáncer de pulmón no microcítico documentado histológicamente o citológicamente que presenten enfermedad en estadio IIIA (de acuerdo con la octava versión de la Asociación Internacional para el Estudio de la Estadificación del Cáncer de Pulmón en Oncología Torácica) y también, potencialmente resecable localmente avanzado. Se puede incluir pacientes en estadio IIIB con enfermedad T3N2 según la 8ª edición.
2. PET / TAC, incluido el contraste IV (TC de calidad diagnóstica) se realizará en el momento basal
El tumor debe considerarse resecable por un equipo multidisciplinar
3. ECOG (Estado de rendimiento) 0-1

4. Los valores de laboratorio de detección deben cumplir con los siguientes criterios y deben obtenerse dentro de los 14 días anteriores al registro / inclusión
yo. Neutrófilos ≥ 1500 × 109 / L
ii. Plaquetas ≥ 100 x × 109 / L
iii. Hemoglobina> 9.0 g / dL
iv. Creatinina sérica ≤ 1,5 x ULN o aclaramiento de creatinina (CrCl) ≥ 40 ml / min (si se utiliza la siguiente fórmula de Cockcroft-Gault):
a. CrCl femenino = (140 - edad en años) x peso en kg x 0,85 /
72 x creatinina sérica en mg / dL segundo. CrCl masculino = (140 - edad en años) x peso en kg x 1.00 / 72 x creatinina sérica en mg / dL
v. AST / ALT ≤ 3 x ULN
vi. Bilirrubina total ≤ 1.5 x ULN (excepto los sujetos con síndrome de Gilbert, que pueden tener bilirrubina total <3.0 mg / dL)
vii Los pacientes deben tener un volumen espiratorio forzado (FEV1) ≥ 1.2 litros o> 40% del valor predicho
viii. INR / APTT dentro de los límites normales

5. Se notificará a todos los pacientes la naturaleza de este estudio y se firmará 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.

6. Pacientes de edad> 18 años.

7. Las mujeres en edad fértil, incluidas las que tuvieron su último período menstrual en los últimos 2 años, deben tener una prueba de embarazo negativa en suero u orina dentro de los 7 días antes de comenzar la quimioterapia.

8. Todos los hombres sexualmente activos y las mujeres en edad fértil deben usar un método anticonceptivo eficaz (dos métodos de barrera o un método de barrera más un método hormonal) durante el tratamiento del estudio y durante un período de al menos 12 meses después de la última administración de drogas de prueba

9. Paciente con capacidad terapéutica adecuada y accesible para un seguimiento correcto.

10. Enfermedad medible o evaluable (según criterios RECIST 1.1)

E.4

Principal exclusion criteria

1. All patients carrying activating mutations in the TK domain of EGFR or any variety of alterations in the ALK gene.

2. Patients with active, known or suspected autoimmune disease. Subjects with viti-ligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thy-roiditis only requiring hormone replacement or unexpected conditions of recur-rence in the absence of an external trigger are allowed to be included.

3. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids, and adrenal replace-ment steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

4. Patients with a history of interstitial lung disease cannot be included if they have sympthomatic ILD (Grade 3-4) and/or poor lung function. In case of doubt please contact trial team.

5. Patients with other active malignancy requiring concurrent intervention and/or concurrent treatment with other investigational drugs or anti-cancer therapy

6. Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period.

7. Any medical, mental or psychological condition which in the opinion of the inves-tigator would not permit the patient to complete the study or understand the pa-tient information

8. Patients who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways

9. Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or hep-atitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
10. Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
11. Patients with history of allergy to study drug components excipients
12. Women who are pregnant or in the period of breastfeeding
13. Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study

1. Todos los pacientes portadores de mutaciones activadoras en el dominio tirosin quinasa de EGFR o cualquier variedad de alteraciones en el gen ALK.

2. Pacientes con enfermedad autoinmune activa, conocida o sospechada. Se pueden incluir sujetos con vitiligo, diabetes mellitus tipo I, hipotiroidismo residual debido a la tiroiditis autoinmune que solo requiere reemplazo hormonal o afecciones inesperadas de recurrencia en ausencia de un activador externo.

3. Pacientes con una condición que requiera tratamiento sistémico con corticosteroides (> 10 mg equivalentes diarios de prednisona) u otros medicamentos inmunosupresores dentro de los 14 días de la inscripción. Se permiten los esteroides inhalados o tópicos, y las dosis de esteroides de reemplazo suprarrenal> 10 mg de prednisona equivalente diaria, en ausencia de enfermedad autoinmune activa.

4. Los pacientes con antecedentes de enfermedad pulmonar intersticial no pueden ser incluidos si tienen enfermedad intersticial pulmonar sintomática (grado 3-4) y / o mala función pulmonar. En caso de duda contacte con el equipo de prueba.

5. Pacientes con otros tumores malignos activos que requieren intervención concurrente y / o tratamiento concomitante con otros fármacos en investigación o terapia anticancerosa

6. Se excluyen los pacientes con neoplasias malignas anteriores (excepto los cánceres de piel no melanoma y los siguientes cánceres in situ: vejiga, estómago, colon, endometrio, displasia cervical, melanoma o mama) a menos que se logre una remisión completa al menos 2 años. antes de ingresar al estudio Y no se requiere terapia adicional durante el período de estudio.

7. Cualquier condición médica, mental o psicológica que, en opinión del investigador, no permita que el paciente complete el estudio o entienda la información del paciente.

8. Pacientes que han recibido tratamiento previo con un anticuerpo anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 o cualquier otro anticuerpo o medicamento que se dirija específicamente a la estimulación de células T o al punto de control inmunológico. caminos

9. Pacientes con prueba positiva para el antígeno de superficie del virus de la hepatitis B (sAg del VHB) o el ácido ribonucleico del virus de la hepatitis C (hepatitis C) que indiquen una infección aguda o crónica

10. Pacientes con antecedentes conocidos de pruebas positivas para el virus de inmunodeficiencia humana (VIH) o el síndrome de inmunodeficiencia adquirida conocido (SIDA)
11. Pacientes con antecedentes de alergia al estudio de componentes de fármacos excipientes.
12. Mujeres embarazadas o en período de lactancia.
13. Hombres y mujeres sexualmente activos en edad fértil que no estén dispuestos a usar un método anticonceptivo eficaz durante el estudio.

E.5 End points

E.5.1

Primary end point(s)

pathological Complete Response (pCR)

Respuesta Patológica completa

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after start the treatment

6 meses después de iniciar el tratamiento

E.5.2

Secondary end point(s)

- Supervivencia global
- Supervivencia libre de progresión
- Mayor tasa de respuesta patológica.
- regresión quirúrgica
- Parte de cirugías retrasadas / canceladas, duración de las estadías en el hospital, abordaje quirúrgico, incidencia de AE / SAE relacionada con la cirugía
- Mortalidad a los 90 días.
- Seguridad y tolerabilidad
- Marcadores moleculares

E.5.2.1

Timepoint(s) of evaluation of this end point

at the end of the follow up

al final del periodo de seguimiento

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

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

Yes

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

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

Yes

E.8.2.3.1

Comparator description

Quimioterapia aprovada para esta indicación (Carboplatino y Paclitaxel)

Approved chemotherapy for the adjuvant treatment (Carboplatin and Paclitaxel)

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

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

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

LVLS

Ultima visita del último paciente

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

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.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

2019-04-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-03-11

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

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