Clinical Trials Register

Summary
EudraCT Number:	2016-000617-67
Sponsor's Protocol Code Number:	IRFMN-MPM-7109
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-10-02
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-000617-67

A.3

Full title of the trial

A phase II study to investigate the activity and safety of anti-PD-L1 antibody (Durvalumab) In ADvancEd pretreated malignant pleural Mesothelioma - DIADEM Study

A.3.1

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

Clinical study to investigate the activity and safety of anti-PD-L1 antibody (Durvalumab) in patients with advanced malignant pleural mesothelioma after a previous therapy

Studio clinico per valutare l’attività e la sicurezza dell’ anticorpo anti PD-L1 (Durvalumab) nei pazienti con mesotelioma pleurico maligno avanzato che hanno ricevuto un terapia precedente

A.3.2

Name or abbreviated title of the trial where available

DIADEM

A.4.1

Sponsor's protocol code number

IRFMN-MPM-7109

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	IRCCS- ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI
B.1.3.4	Country	Italy
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	AstraZeneca
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS - Istituto di Ricerche Farmacologiche Mario Negri
B.5.2	Functional name of contact point	Lital Hollander
B.5.3	Address:
B.5.3.1	Street Address	Via Giuseppe La Masa 19
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20156
B.5.3.4	Country	Italy
B.5.4	Telephone number	0239014640
B.5.5	Fax number	0233200231
B.5.6	E-mail	lital.hollander@marionegri.it

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	Durvalumab
D.3.2	Product code	1428935-60-7
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	DURVALUMAB
D.3.9.1	CAS number	1428935-60-7
D.3.9.4	EV Substance Code	SUB176342
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	1500
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	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	Yes
D.3.11.13.1	Other medicinal product type	Anticorpo monoclonale umano

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

Advanced malignant pleural mesothelioma

Mesotelioma pleurico maligno in stadio avanzato

E.1.1.1

Medical condition in easily understood language

Advanced malignant pleural mesothelioma

Mesotelioma pleurico maligno in stadio avanzato

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	PT
E.1.2	Classification code	10027406
E.1.2	Term	Mesothelioma
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of antiPD-L1 Ab Durvalumab in patients with MPM relapsing after first line treatment with pemetrexed plus platinum-based drugs.

Valutare l’attività dell’anticorpo antiPD-L1 durvalumab in pazienti con MPM in ricaduta dopo trattamento di prima linea con pemetrexed e derivati del platino.

E.2.2

Secondary objectives of the trial

- Progression Free Survival (PFS)
- Overall survival (OS)
- Objective Response rate (ORR)
- Safety
- Exploratory: PD-L1 IHC expression in tumour samples and tumour infiltrating lymphocytes (TIL).

Valutare :
- Sopravvivenza libera da progressione (PFS)
- Sopravvivenza globale (OS)
- Tasso di risposta oggettiva (ORR)
- Sicurezza del trattamento con Durvalumab
- Esplorativo: espressione di PD-L1 nel tessuto tumorale e nei linfociti infiltranti il tumore.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Cytological or histological diagnosis of
unresectable MPM (advanced or inoperable);
2. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or at least 15 unstained slides for central determination of PD-L1 expression;
3. Aged ≥ 18 years;
4. Performance status 0-2 (ECOG);
5. Measurable disease as defined by Modified RECIST v1.1 for MPM;
6. One previous chemotherapy line for MPM of pemetrexed plus platinum derivative;
7. Previous chemotherapy course concluded at least 4 weeks prior to recruitment;
8. Signed informed consent;
9. Negative pregnancy test. All patients in reproductive age or potential must agree to use effective contraception, as defined by the study protocol for the entire duration of treatment with study drug and for 3 months following its interruption;
10. Patients who have received palliative radiation are eligible if <30% of bone marrow was irradiated and normal hematological function was completely regained;
11. Adequate organ and marrow function as defined below: Haemoglobin ≥ 9.0 g/dL, Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3), Platelet count ≥ 100 x 109/L (>100,000 per mm3);
12. Adequate liver function: Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (except for patients confirmed Gilbert’s syndrome, who will be allowed only in consultation with their physician); AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN;
13. Adequate renal function: Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.

1. Diagnosi citologica o istologica di MPM non resecabile (avanzato o non operabile)
2. Disponibilità di campioni di tumore rappresentativi per la determinazione centralizzata della espressione di PD-L1, fissati e inseriti in paraffina in blocchetti (preferibilmente), o almeno 5 vetrini
3. Età ≥ 18 anni
4. Performance status (ECOG) 0-1
5. Malattia misurabile secondo i criteri RECIST v1.1 modificati per mesotelioma
6. Una singola precedente linea di chemioterapia a base di pemetrexed più derivati del platino
7. precedente chemioterapia conclusa 4 settimane prima del reclutamento
8. Consenso informato firmato
9. Test di gravidanza negativo. Tutti i pazienti in età riproduttiva o con potenziale riproduttivo dovranno acconsentire ad utilizzare mezzi contracettivi efficaci, come definito dal protocollo di studio, per l’intera durata del trattamento con il farmaco in studio e per i tre mesi successivi alla fine del trattamento.
10. Pazienti che hanno ricevuto radioterapia palliativa sono eleggibili se è stato irradiato meno del 30% del midollo osseo ed è stata recuperata la normale funzionalità ematologica
11. Conservata funzionalità midollare e d’organo come definito di seguito: emoglobina ≥ 9.0 g/dL, conta neutrofila assoluta ≥ 1.5 x 109/L (> 1500 per mm3), conta piastrinica ≥ 100 x 109/L (>100,000 per mm3)
12. Adeguata funzionalità epatica: bilirubina sierica ≤ 1.5 x ULN (ad eccezione di pazienti con confermata sindrome di Gilbert, la cui partecipazione sarà confermata dopo consulto specialistico); AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN a meno che siano presenti metastasi nel quale caso deve essere ≤ 5x ULN
13. Adeguata funzionalità renale: creatinina sierica CL>40 mL/min secondo la formula di Cockcroft-Gault (Cockcroft and Gault 1976) attraverso la raccolta delle urine nelle 24 ore per la determinazione della clearance.

E.4

Principal exclusion criteria

Exclusion Criteria:
1. Radiotherapy with curative intent to thoracic wall (concomitant with or prior to chemotherapy);
2. Severe concomitant illness;
3. History of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis;
4. Enrolment in other trials;
5. Any other anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent);
6. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis);
7. History of primary immunodeficiency;
8. HIV, TB, HBV or HCV infection (HBsAg+; HCV-RNA+);
9. History of allogeneic organ transplant;
10. History of hypersensitivity to durvalumab or any excipient;
11. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving Durvalumab;
12. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results;
13. History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission for 5 years or more and judged of negligible potential of relapse;
14. Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within one year before enrolment, uncontrolled arterial hypertension or arrhythmias;
15. Brain / leptomeningeal involvement;
16. Any previous treatment with a PD-1 or PD-L1 inhibitor, including Durvalumab;
17. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
18. AEs from prior anticancer therapy that have not resolved to grade ≤ 1 except for alopecia

1. Radioterapia della parete toracica con intento curativo (prima o durante la chemioterapia)
2. Malattia concomitante di sufficiente gravità
3. Anamnesi positiva per malattie autoimmuni comprese, ma non limitatamente a: lupus reumatoide eritematoso; malattia infiammatoria intestinale: artride reumatoide, trombosi vascolare associata a sindrome antifosfolipidica, granulomatosi di Wegener, sindrome di Sjögren, sindrome di Guillain-Barré, sclerosi multipla, diabete mellito di tipo I, vasculite o glomerulonefrite;
4. Qualsiasi terapia antitumorale (chemioterapia, immunoterapia, terapia ormonale, terapia target, terapia biologica, embolizzazione tumorale, anticorpi monoclonali, altri agenti sperimentali);
5. Anamnesi positiva per immunodeficienza primaria;
6. Infezioni da HIV (Ab anti HIV+), infezione attiva TB, HBV o HCV infection;
7. Storia di trapianto d’organo allogenico,
8. Storia di ipersensibilità a durvalumab o ad uno dei suoi eccipienti;
9. Qualsiasi condizione che, a parere dell’investigatore, è in grado di interferire con la valutazione del trattamento in studio o l’interpretazione dei risultati di efficacia e sicurezza
10. Storia di altro tumore maligno (ad eccezione del del tumore delle cellule basali o del carcinoma della cervice uterina in situ, melanoma stadio uno, adenocarcinoma della prostata, carcinoma vescicale), a meno che sia in remissione da almeno cinque anni e considerato a potenziale di ricaduta trascurabile
11. Instabilità cardiaca, compresi: insufficienza cardiaca congestizia, angina pectoris, infarto miocardico a meno di un anno dall’arruolamento, ipertensione arteriosa incontrollata o aritmie;
12. Coinvolgimento cerebrale / delle leptomeningi;
13. Qualsiasi trattamento precedente con un inibitore del PD-1 o PD-L1, compreso durvalumab;
14. AEs di una precedente terapia anticancro che non ha risolto con un grado ≤ 1 eccetto per l’alopecia;

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients alive and free from progression or death at 16 weeks (PFS 16 w) calculated from the start of treatment (Durvalumab).

Proporzione di pazienti vivi e liberi da progressione a 16 settimane (PFS16 W) calcolate dal primo giorno di trattamento con durvalumab.

E.5.1.1

Timepoint(s) of evaluation of this end point

16 weeks from the start of Durvalumab administration

16 settimane dall'inzio del trattamento con Durvalumab

E.5.2

Secondary end point(s)

Secondary:
Progression Free Survival (PFS): defined as the time from treatment start to progression of disease or death from any cause; in absence of an event, patients will be censored at the time of the latest date of assessment. If the patient has no evaluable visits or does not have baseline data they will be censored at 1 day.
Overall survival (OS): defined as the time from treatment start to death from any cause; in absence of an event, patients will be censored at the time of the latest date of assessment. If the patient has no evaluable visits or does not have baseline data they will be censored at 1 day.
Objective Response rate (ORR): defined as the proportion of patients with complete response (CR) or partial response (PR) according to CT assessment using the RECIST v1.1 criteria modified for MPM (Modified RECIST). Independent central review will be used to confirm investigator ORR.
Safety:
Evaluated based on frequency, type and severity of reported AEs, immune related irAE, clinical laboratory assessments, vital signs and physical examination. Adverse events will be encoded and graded using NCI-CTCAE version 4.03.

Sopravvivenza libera da progressione (PFS): definita come il tempo da inizio trattamento fino alla progressione di malattia o morte per qualsiasi causa. In assenza dell’evento, i pazienti saranno censorizzati alla data dell’ultima valutazione. I pazienti che non hanno il dato relativo alle valutazioni o non hanno i dati basali saranno censorizzati al giorno 1.
Sopravvivenza globale (OS): definita come il tempo dall’inizio del trattamento fino alla morte per qualsiasi causa. In assenza dell’evento, i pazienti saranno censorizzati alla data dell’ultima informazione sullo stato vitale. I pazienti che non hanno il dato relativo alle valutazioni o non hanno i dati basali saranno censorizzati al giorno 1.
Tasso di risposta oggettiva (ORR): definito come la proporzione di pazienti con risposta completa (CR) o parziale (PR) in base alla valutazione radiologica con TAC spirale valutata in accordo ai criteri RECIST versione 1.1 modificati per MPM (RECIST modificato). La valutazione dell’investigatore sarà confermata mediante una revisione centralizzata indipendente.
Sicurezza: sarà valutata considerando la frequenza, il tipo e la severità di tutti gli eventi avversi, gli eventi avversi immuno-mediati, i referti di laboratorio, gli esami obiettivi e i parametri vitali. Gli eventi avversi saranno codificati e graduati secondo il sistema NCI-CTCAE versione 4.03.

E.5.2.1

Timepoint(s) of evaluation of this end point

PFS: at progression
Overall Survival: at death from any cause
ORR: at 16 weeks form start of durvalumab administration
Treatment safety: throughout the study

PFS: alla progressione di malattia
OSS: Morte per ogni causa
ORR: A 16 settimane dall'inizio del trattamento
Sicurezza: durante tutto lo studio

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

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

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

A braccio singolo

Single arm

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

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

Information not present in EudraCT

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

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

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

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)

Patients will be followed as per clinical practice

I pazienti verranno seguiti secondo pratica clinica

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

2018-07-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-10

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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