Clinical Trials Register

Summary
EudraCT Number:	2014-003935-20
Sponsor's Protocol Code Number:	N14MPN
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-01-15
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

Netherlands - Competent Authority

A.2

EudraCT number

2014-003935-20

A.3

Full title of the trial

A single arm phase II study of Nivolumab in patients with progressive malignant pleural mesothelioma: interim biopsy analysis to determine efficacy. Acronym: NivoMes Study

Eenarmige fase II study met Nivolumab bij patiënten met een progressief maligne pleuraal mesothelioom: tussentijdse analyse door middel van een biopt om de werkzaamheid te bepalen. Acroniem: NivoMes studie.

A.3.1

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

Nivolumab in patients with progressive malignant pleural mesothelioma: NivoMes

Nivolumab behandeling bij een progressief maligne pleuraal mesothelioom: NivoMes

A.4.1

Sponsor's protocol code number

N14MPN

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	Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
B.1.3.4	Country	Netherlands
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	Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
B.5.2	Functional name of contact point	J.M.M.F. Quispel-Janssen
B.5.3	Address:
B.5.3.1	Street Address	Plesmanlaan 121
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1066 CX
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031205122958
B.5.5	Fax number	0031205122572
B.5.6	E-mail	jm.janssen@nki.nl

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	SUB32944
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

A single arm phase II study of Nivolumab in patients with progressive malignant pleural mesothelioma: interim biopsy analysis to determine efficacy. Acronym: NivoMes Study

E.1.1.1

Medical condition in easily understood language

Nivolumab in patients with progressive malignant pleural mesothelioma: NivoMes

Nivolumab behandeling bij een progressief maligne pleuraal mesothelioom: NivoMes

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10027408
E.1.2	Term	Mesothelioma malignant advanced
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 determine the DCR (disease control rate) at 12 weeks of nivolumab monotherapy in patients with progressive MPM.

Het bepalen van de DCR (ziekteaktiviteit) bij 12 weken nivolumab monotherapie bij patiënten met progressieve MPM.

E.2.2

Secondary objectives of the trial

Secondary Objectives
• To determine the safety of nivolumab monotherapy in patients with recurrent MPM
• To determine the PFS, OS and TTP of nivolumab monotherapy
• To determine the objective response rate (ORR) as defined by the modified RECIST criteria

Exploratory Objectives
• To determine the effects of nivolumab on tissue samples with respect to influx of immuno-modulating cells.
• To determine the PD-L1 status of tumors and other possible biomarkers and explore correlations between biomarkers and anti-tumor activity.

Secundaire doelstellingen
• Het bepalen van de veiligheid van nivolumab monotherapie bij patiënten met terugkerende MPM.
• Het bepalen van de PFS, OS en TTP van nivolumab monotherapie.
• Het bepalen van de objectieve respons rate (ORR).

Verkennende doelstellingen
• Het bepalen van de effecten van nivolumab op tumorweefsel samples met betrekking tot de toestroom van immuun-modulerende cellen.
• Het bepalen van de PD-L1 status van de tumoren en andere mogelijke biomarkers en het verkennen van de correlaties tussen de biomarkers en anti-tumor aktiviteit.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients with proven malignant pleural mesothelioma, who have progressive disease after chemotherapy in first or second line.
• Patients with histological or cytological diagnosed malignant pleural mesothelioma and age >18 years.
• Medically suitable for limited surgical intervention (pleural biopsies up to limited pleurectomy).
• Not considered candidates for trimodality treatment (as part of a study).
• Measurable or evaluable disease (see tumor response assessment).
• Ability to understand the study and give signed informed consent prior to beginning of protocol specific procedures including the approval of a second thoracoscopy or transthoracic pleural biopsy after the third course.
• Radiotherapy is allowed when this is given for palliation of painful sites, the interval is > 12 weeks, not more than 1/3 of the bone marrow capacity or all tumor is within the irradiation field.
• WHO performance status 0 or 1.
• Adequate organ function as evidenced by the following peripheral blood counts or serum chemistries at study entry:
• Hematology: Neutrophil count ≥ 1.5 x 109/l, Platelets ≥ 150 x 109/l, Hemoglobin ≥ 6,0 mmol/l.
• Chemistry: Total serum bilirubin within the upper normal limits; ASAT and ALAT ≤ 2.5 times the upper limits of normal (ULN), AP (alkaline phosphatases) < 5x ULN (unless bone metastases are present in the absence of any liver disease).

• Patiënten met bewezen maligne mesothelioom van de pleura, die progressieve ziekte hebben na eerste- of tweedelijns chemotherapie.
• Patiënten met histologische of cytologische bewezen maligne mesothelioom van de pleura en leeftijd > 18 jaar.
• Medisch geschikt voor beperkte chirurgische ingreep (pleurale biopsieën tot beperkte pleurectomie).
• Niet beschouwd als kandidaten voor trimodality behandeling (als onderdeel van een studie).
• Meetbare of evalueerbare ziekte (zie tumorrespons beoordeling).
• Mogelijkheid om de studie te begrijpen en informed consent te ondertekenen vóórdat er met protocol specifieke procedures wordt gestart met inbegrip van de goedkeuring van een tweede thoracoscopie of transthoracale pleurale biopsie na de derde kuur.
• Radiotherapie is toegestaan wanneer dit wordt gegeven voor palliatie van pijnlijke sites, het interval > 12 weken is, niet meer dan 1/3 van de capaciteit van het beenmerg of alle tumor zich in het bestralingsveld bevindt.
• WHO performance status 0-1
• Adequaat orgaan functioneren zoals blijkt uit de volgende perifere bloedwaarden of serum chemie voor studie start:
• Hematologie: Neutrofielen ≥ 1.5 x 109/l, Bloedplaatjes ≥ 150 x 109/l, Hemoglobine ≥ 6,0 mmol/l.
• Chemie: Total serum bilirubin binnen de normale bovengrens; ASAT and ALAT ≤ 2.5 x ULN, AP (alkaline phosphatases) < 5x ULN (tenzij er botmetastases aanwezig zijn in de afwezigheid van elke leverziekte).

E.4

Principal exclusion criteria

• Active uncontrolled infection, severe cardiac dysfunction or uncorrectable bleeding tendency.
• Inability to perform biopsies of the pleural lesions.
• Symptomatic peripheral neuropathy ≥ grade 2 according to NCI CTC, version 4.0.
• Presence of symptomatic CNS metastases.
• Unstable peptic ulcer, unstable diabetes mellitus or other serious disabling condition.
• Impaired renal function: creatinine clearance less than 50ml/min.
• Concomitant administration to any other experimental drugs under investigation.
• Patients are excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have 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
• Patients are excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immuno-suppressive 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.
• Patients are excluded if they 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 co-stimulation or immune checkpoint pathways

• Actieve ongecontroleerde infectie, ernstige cardiale dysfunctie of niet corrigeerbare bloedingsneiging.
• Onvermogen om bioptin van pleurale lesies te nemen.
• Symptomatische perifere neuropathie ≥ graad 2 volgens NCI CTC, versie 4.0.
• Aanwezigheid van symptomatische hersenmetastasen.
• Instabiele maagzweer, instabiele diabetes mellitus of andere ernstige invaliderende aandoening.
• Verminderde nierfunctie: creatinine klaring van minder dan 50ml/min.
• Gelijktijdige toediening van elk ander experimenteel middel dat onderzocht wordt.
• Patiënten mogen niet deelnemen als zij een actieve, bekende of vermoedelijke auto-immuun ziekte hebben. Patiënten mogen wel deelnemen als zij de volgende aandoeningen hebben: vitiligo; type I diabetes mellitus; residuele hypothyreodie die te wijten is aan een auto-immuun aandoening waarbij alleen hormoon vervanging wordt gegeven; psoriasis, die geen systemische behandeling vereist; of condities, die niet verwacht worden terug te keren in de afwezigheid van een externe trigger.
• Patiënten mogen niet deelnemen als zij een aandoening hebben waarvoor systemische behandeling met corticosteroiden (>10mg dagelijks prednison equivalenten) of andere immuun-onderdrukkende medicijnen binnen 14 dagen voor inname van de studiemedicatie vereist zijn. Inhalatie of topische steroiden en een dagelijkse dosis prednison < 10 mg of equivalent hiervan voor suppletie bij bijnierinsufficiëntie, zijn toegestaan als er geen actieve auto-immuunziekte aanwezig is.
• Patiënten mogen niet deelnemen als zij eerder behandeld zijn met anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antilichaam, of elke andere antilichaam of medicijnen die specifiek gericht zijn op T-cel co-stimulatie of 'immuun checkpoint pathways'.

E.5 End points

E.5.1

Primary end point(s)

DCR at 12 weeks.

DCR (disease control rate) bij 12 weken

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks

12 weken

E.5.2

Secondary end point(s)

Safety, PFS, OS, TTP, ORR

Veiligheid, progressievrije overleving, algehele overleving, tijd tot progressie, algehele respons rate.

E.5.2.1

Timepoint(s) of evaluation of this end point

Safety: 2 weekly during treatment, thereafter every 6 weekly until week 24. Thereafter 8 weekly.
PFS, TTP and ORR: 6 weekly until week 24. Thereafter 8 weekly
OS: 8 weekly

Veiligheid: elke 2 weken tijdens de behandeling, daarna elke 6 weken tot week 24. Daarna elke 8 weken.
Progressievrije overleving, tijd tot progressie en algehele respons rate: elke 6 weken tot week 24. Daarna elke 8 weken.
Algehele overleving: elke 8 weken

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

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.8.3

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

Laatste visite van de laatste patient

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

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.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)

Once patients have been discontinued from study treatment, other treatment options will be at the discretion of the investigator

Zodra patienten de studiebehandeling hebben beeindigd, zullen andere behandelingsopties besproken worden door de onderzoeker

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

2015-01-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-02

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

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