Clinical Trials Register

Summary
EudraCT Number:	2015-000442-39
Sponsor's Protocol Code Number:	Neo-Nivo
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-04-27
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

2015-000442-39

A.3

Full title of the trial

PHASE II STUDY OF NEOADJUVANT NIVOLUMAB IN PATIENTS WITH GLIOBLASTOMA MULTIFORME

Estudio fase II con nivolumab neoadyuvante en pacientes con glioblastoma multiforme

A.3.1

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

Nivolumab administered before surgery in patients with glioblastoma multiforme

A.4.1

Sponsor's protocol code number

Neo-Nivo

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	Clinica Universidad de Navarra/Universidad de Navarra
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	Clinica Universidad de Navarra
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	Clinica Universidad de Navarra
B.5.2	Functional name of contact point	UCEC
B.5.3	Address:
B.5.3.1	Street Address	Avda. Pio XII 36
B.5.3.2	Town/ city	Pamplona
B.5.3.3	Post code	31008
B.5.3.4	Country	Spain
B.5.4	Telephone number	349482554002723
B.5.5	Fax number	34948296667
B.5.6	E-mail	ucicec@unav.es

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	Nivolumab
D.3.2	Product code	BMS-936558
D.3.4	Pharmaceutical form	Solution for injection/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.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	BMS-936558-01
D.3.9.3	Other descriptive name	BMS936558
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)	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

Glioblastoma multiforme

Glioblastoma Multiforme

E.1.1.1

Medical condition in easily understood language

Glioblastoma multiforme (malignant brain tumor)

Glioblastoma Multiforme (tumor cerebral maligno)

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10018337
E.1.2	Term	Glioblastoma multiforme
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10018336
E.1.2	Term	Glioblastoma
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

2.1 Main objective.
To assess changes in PD-L1 and CD8 expression induced by neoadjuvant nivolumab in GBM. For that purpose we will compare GBM tissue of patients before and after treatment with neoadjuvant nivolumab.

Determinar cambios en la expresión de PD-L1 y CD8 inducidos por nivolumab neo adyuvante en GBM. Para ello compararemos tejido de pacientes con GBM antes y después de nivolumab neoadyuvante

E.2.2

Secondary objectives of the trial

2.2 Secondary objectives.
To determine:
- Progression-free survival (PFS) and overall survival (OS) in all patients.
- Safety of neoadjuvant nivolumab in patients with GBM.
- Tumor and peripheral blood biomarkers with potential predictive of pharmacodynamic effects and clinical activity.
- Early tumor response to the neoadjuvant dose

Determinar:
- Supervivencia libre de progresión (SLP) y supervivencia global en todos los pacientes.
- Seguridad de nivolumab neoadyuvante en pacientes con GBM.
- Biomarcadores en tumor y en sangre periférica con valor potencial predictivo de eficacia y de efectos farmacodinámicos.
- Respuesta tumoral precoz al tratamiento neoadyuvante.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent.
2. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing and other requirements of the study.
3. Patients with GBM that are candidates to primary or salvage resection surgery, according to the following criteria:
a. in patients undergoing primary surgery, diagnosis of GBM should be confirmed by previous biopsy or previous partial resection.
b. in patients with recurrent GBM, diagnosis of progression will be confirmed either by previous biopsy or by the Revised Assessment in Neuro-Oncology (RANO) criteria, as assessed by the investigator (appendix 1).
4. Patients may have received previous treatments for GBM. There is no limit on previous treatment lines, as long as the other inclusion criteria are met.
5. Patients in whom surgery can be safely delayed for a minimum period of 2 weeks following the administration of the first dose of nivolumab, in the opinion of the investigator.
6. ECOG performance status of 0-1. Patients with ECOG>1 due to neurological symptoms considered to be reversible following surgery, according to investigator´s criteria will be eligible.
7. Life expectancy >12 weeks.
8. Steroids should be ideally discontinued or reduced to a dose <10 mg of prednisone or its equivalence at inclusion and during treatment with nivolumab. Nevertheless, greater doses of systemic steroids are allowed for the control of cerebral edema.
9. Adequate organ function defined by:
a. Bone Marrow Reserve: white blood cells (WBC): ?2000/ mm3 absolute neutrophil count (ANC) ?1500x 109/L; platelet count ?100000/ mm3 100 x 109/L; hemoglobin ?9.0 g/dL).
b. Hepatic: bilirubin <1.5 times the upper limit of normality (ULN), AST and ALT <3.0 ? ULN (BR< 3 x ULN for patients with Gilbert´s Syndrome).
c. Renal: creatinine < 1.5 x ULN or estimated creatinine clearance > 40 ml/min, using the Cokcroft-Gault formula.
10. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
11. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab
12. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception.
13. Patients must be at least 18 years old.

1. Consentimiento informado por escrito.
2. Capacidad de cumplir los procedimientos del estudio.
3. Pacientes con GBM candidatos a resección primaria o de rescate, según los siguientes criterios:
a. En los pacientes con tumores primarios el diagnostico de GBM debe estar confirmado por biopsia o resección parcial previa. El material previo debe estar disponible y debe ser suficiente para cumplir el objetivo principal del estudio, según el criterio de los investigadores.
b. En los pacientes con GBM recurrente, el diagnostico de progresión se confirmará por biopsia o por los criterios RANO (Revised Assessment in Neuro-Oncology) Será necesario obtener tejido tumoral previo en cantidad suficiente para cumplir el objetivo principal, según el criterio de los investigadores.
4. Los pacientes pueden haber recibido tratamientos previos sin límite para el GBM.
5. Pacientes en los que se pueda retrasar 2 semanas la cirugía con seguridad para ellos, según el criterio del investigador.
6. ECOG 0-1. Los pacientes con ECOG>1 por deficit neurológico, que se considere reversible tras la intervención, según el criterio de los investigadores, podrán ser incluidos.
7. Esperanza de vida >12 semanas.
8. Se deberán discontinuar los esteroides o reducirlos a dosis <10 mg de prednisona o equivalente en el momento de la inclusión o durante el tratamiento con nivolumab. No obstante, se permitirán dosis mayores de esteroides para el control del edema cerebral.
9. Función orgánica adecuada, definida por:
a. Hematológica: leucocitos: 2000/ mm3; neutrófilos 1500x 109/L; plaquetas100000/ mm3 100 x 109/L; hemoglobina 9.0 g/dL).
b. Hepática: bilirrubina <1.5 x límite superior de la normalidad (LSN), AST y ALT <3.0  LSN (BR< 3 x LSN para pacientes con síndrome de Gilbert).
c. Renal: creatinina < 1.5 x LSN o aclaramiento estimado de creatinina > 40 ml/min (Cokcroft-Gault).
10. Las mujeres con capacidad reproductiva deberán utilizar métodos adecuados para evitar la concepción durante el tratamiento hasta al menos 23 semanas después de la última dosis de nivolumab.
11. Las mujeres en capacidad reproductiva deberán tener una prueba negativa de embarazo en suero u orina 24 horas antes del comienzo del tratamiento con nivolumab.
12. Los hombres sexualmente activos deberán usar un método anticonceptivo con una tasa de fallos <1% al año, durante el tratamiento hasta al menos 31 semanas después de la última dosis de nivolumab. Las mujeres u hombres sin capacidad reproductiva no requieren medidas anticonceptivas.
13. Edad mayor o igual a 18 años

E.4

Principal exclusion criteria

1. Presence of extracranial disease.
2. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive the planned therapy (including brain surgery), or interfere with the interpretation of study results.
3. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
4. Previous treatment with a PD-1, PDL1 or CTLA-4 targeted therapy
5. Treatment with any anti-cancer drug or radiation therapy within the last 14 days. A shorter interval can be approved by the principal investigator, if deemed appropriate.
6. Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents), with the exception of control of cerebral edema, or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
7. Pregnant or breastfeeding patients.
8. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Routine testing is not required.
9. Positive tests for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating active or chronic infection.
10. History of allergy to study drug components or of severe hypersensitivity reactions to any monoclonal antibodies.
11. Prisoners or subjects who are involuntarily incarcerated or who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
12. Subjects unable (due to existent medical condition, e.g, pacemaker or implantable cardioverter defibrillator device) or unwilling to have a head contrast enhanced MRI and/or a CT scan of the brain.
13. Concomitant or prior malignancy that, in the opinion of the investigator contraindicates GBM surgery or can interfere with the results of the study, in the opinion of the investigator.
14. Known drug or alcohol abuse.

1. Enfermedad extracraneal.
2. Alteraciones médicas serias o no controladas que en opinión de los investigadores aumenten el riesgo del sujeto al participar en el estudio, impidan que reciba el tratamiento del estudio (incluyendo la cirugía) o interfiera con la interpretación de los resultados.
3. Enfermedad autoinmune activa, con la excepción de vitiligo, diabetes mellitus tipo I, hipotiroidismo residual autoinmune que solo precise tratamiento hormonal sustitutivo, psoriasis que no requiera tratamiento sistémico o enfermedades que no se sospeche que recurran.
4. Tratamiento previo con anti PD-1, PDL1 o CTLA-4.
5. Tratamiento con fármacos antitumorales o radioterapia en los 15 días previos.
6. Necesidad de recibir tratamiento con esteroides (>10 mg de prednisona diaria o equivalentes), con la excepción del control del edema cerebral
7. Lactancia o embarazo.
8. Positividad conocida para VIH. No es obligatorio realizar la prueba.
9. Positividad conocida para HBsAg o HCV RNA que indique infección activa o crónica.
10. Historia de alergias al fármaco del estudio o hipersensibilidad grave a los anticuerpos monoclonales.
11. Presos o sujetos recluidos para el tratamiento de una enfermedad psiquiátrica o física.
12. Incapacidad de realizar RNM o TAC del cerebro.
13. Enfermedad tumoral concomitante que pueda interferir con el resultado del estudio o impedir la cirugía.
14. Abuso conocido de alcohol o drogas.

E.5 End points

E.5.1

Primary end point(s)

Changes in CD8 and PDL1 expression after one dose of nivolumab

Cambios en expresión de CD8 y PDL1 tras una dosis de nivolumab

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 15 of the trial (after one neoadjuvant dose)

Dia 15 del ensayo (tras una dosis neoadyuvante)

E.5.2

Secondary end point(s)

Progression-free survival (PFS) and overall survival (OS) in all patients.
- Safety of neoadjuvant nivolumab in patients with GBM.
- Tumor and peripheral blood biomarkers with potential predictive of pharmacodynamic effects and clinical activity.
- Early tumor response to the neoadjuvant dose

- Supervivencia libre de progresión (SLP) y supervivencia global en todos los pacientes.
- Seguridad de nivolumab neoadyuvante en pacientes con GBM.
- Biomarcadores en tumor y en sangre periférica con valor potencial predictivo de eficacia y de efectos farmacodinámicos.
- Respuesta tumoral precoz al tratamiento neoadyuvante.

E.5.2.1

Timepoint(s) of evaluation of this end point

All throughout the trial

Durante toda la duración 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

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

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

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.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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

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. Patients may undergo any treatment they need.

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

2015-08-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-03-01

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