Clinical Trials Register

Summary
EudraCT Number:	2014-002876-10
Sponsor's Protocol Code Number:	ONC-2014-002
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-09-11
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-002876-10

A.3

Full title of the trial

A PHASE II STUDY OF THE COMBINATION OF GEMCITABINE AND IMATINIB
MESYLATE IN PEMETREXED-PRETREATED PATIENTS WITH MALIGNANT
PLEURAL MESOTHELIOMA

STUDIO DI FASE II DELLA COMBINAZIONE DI GEMCITABINA E IMANTINIB MESILATO IN PAZIENTI CON MESOTELIOMA PLEURICO MALIGNO PRETRATTATI CON PEMETREXED

A.3.1

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

A PHASE II STUDY OF THE COMBINATION OF GEMCITABINE AND IMATINIB
MESYLATE IN PRETREATED PATIENTS WITH MALIGNANT
PLEURAL MESOTHELIOMA

STUDIO DI FASE II DELLA COMBINAZIONE DI GEMCITABINA E IMANTINIB MESILATO IN PAZIENTI CON MESOTELIOMA PLEURICO MALIGNO PRETRATTATI

A.4.1

Sponsor's protocol code number

ONC-2014-002

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	Istituto Clinico Humanitas
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	Istituto Clinico Humanitas
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	EMMEDI Srl Divisione Solaris
B.5.2	Functional name of contact point	CRO
B.5.3	Address:
B.5.3.1	Street Address	Via C. Poma 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20129
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390276114280
B.5.5	Fax number	00390276118026
B.5.6	E-mail	solaris@solariscro.com

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	Glivec
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	imatinib mesylate
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Buccal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IMATINIB MESYLATE
D.3.9.1	CAS number	220127-57-1
D.3.9.4	EV Substance Code	SUB12517MIG
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	100
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.IMP: 2
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	Gemzar
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli-Lilly
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Gemcitabine
D.3.4	Pharmaceutical form	Powder 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	GEMCITABINE
D.3.9.1	CAS number	95058-81-4
D.3.9.4	EV Substance Code	SUB07892MIG
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	1000
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

Malignant Pleural Mesothelioma

Mesotelioma Pleurico Maligno

E.1.1.1

Medical condition in easily understood language

Malignant Pleural Mesothelioma

Mesotelioma Pleurico 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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10059518
E.1.2	Term	Pleural mesothelioma malignant
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

- To assess the anti-tumor activity of IM in combination
with GEM, in terms of 3-months progression-free
survival (PFS) rate.

-Valutare l'attività anti-tumorale della combinazione
IM/GEM, in termini di tasso di sopravvivenza libera da
progressione a 3 mesi.

E.2.2

Secondary objectives of the trial

- To assess anti-tumor activity of IM in combination Protocol ONC-2014-002
Version/Date: 1.0/ 03 Sep 2014 11
with GEM, in terms of objective response rate
according to RECIST criteria (Modified RECIST
criteria for Malignant Pleural Mesothelioma), and
duration of response.
- To assess anti-tumor activity of IM in combination
with GEM, in terms of PFS and overall survival (OS)
- To determine the safety profile of IM in combination
with GEM.
- To evaluate the molecular profile of patients enrolled
with Ion PGM Torrent Next-generation Sequencing
platform correlating the molecular profiles identified
with clinical characteristics and survival data of
patients.

-Valutare l'attività antitumorale di IM in combinazione
con GEM in termini di tasso di risposta obiettiva
secondo i criteri RECIST (criteri RECIST modificati per
mesotelioma pleurico maligno) ed in termini di durata
della risposta.
-Valutare l'attività antitumorale di IM in combinazione
con GEM in termini di sopravvivenza globale (OS)
- Valutare il profile di sicurezza della combinazione
IM/GEM.
-Valutare il profilo molecolare dei pazienti arruolati con
la piattaforma di sequenziamento di nuova
generazione Ion PGM Torrent correlando I profile
identificati con le caratteristiche cliniche ed i dati di
risposta e sopravvivenza dei pazienti.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Age of > 18 years.
2) Patients with a histologically proven malignant
mesothelioma of the pleura, expressing PDFGR-beta
and/or C-Kit by immunochemistry (ICH).
3) Locally advanced disease, unsuitable for curative surgical
resection, or metastatic disease.
4) Confirmed progression of the disease according to
modified RECIST-criteria, documented after a
pemetrexed-based chemotherapy.
5) ECOG Performance Status of 0, 1 or 2.
6) Life expectancy of at least 3 months.
7) Written informed consent.

1) Età > 18 anni.
2) Pazienti con diagnosi di mesotelioma pleurico maligno
confermato istologicamente, che esprime PDGFR-beta
e/o C-kit in immunoistochimica (ICH).
3) Malattia localmente avanzata, non suscettibile di
resezione chirurgica completa, o malattia metastatica
4) Malattia in progressione secondo i criteri RECIST
modificati, documentati dopo una chemioterapia a base
di pemetrexed.
5) ECOG Performance Status 0-2.
6) Aspettativa di vita di almeno 3 mesi.
7) Consenso informato scritto.

E.4

Principal exclusion criteria

1) Co-existing tumors of different histologic origin, except
non melanomatous localized skin cancer and/or in situ
cervical carcinoma.
2) A history of earlier tumors of different histologic origin
being in complete remission since less than 5 years.
3) Unresolved toxicity from prior antitumor treatment(s).
4) Primary peritoneal mesothelioma.
5) Any of the following abnormal baseline hematological
values:
a. Hb < 9 g/dL
b. WBC < 3 x 10^9/L
c. Neutrophils < 1.5 x 10^9/L
d. Platelets < 100 x 10^9/L
e. Serum bilirubin > 2.5 mg/dL
f. ALAT and ASAT > 3 x UNL (unless due to liver
metastases)
g. Serum creatinine > 1.5 mg/dL.
6) Symptomatic and/or unstable pre-existing brain
metastases. To be enrolled in the study, subjects must
have confirmation of stable disease by MRI or computer tomography (CT) scan within 4 weeks from day 1 of cycle 1 of treatment and have CNS metastases well controlled by steroids, anti – epileptics or other symtom-relieving medications.
7) Clinically relevant cardiovascular disease, i.e., myocardial infarction or other severe coronary artery diseases within the prior 6 months, cardiac arrythmia requiring medication, uncontrolled hypertension, overt cardiac failure or non compensated chronic heart disease in NYHA class II or more.
8) History of psychiatric disabilities, potentially interfering with the capability of giving adequate informed consent.
9) Pregnant or lactating women or inability/unwillingness to practice a medically approved method of contraception during study period (including 3 months following the end of treatment)
10) Uncontrolled active infections.
11) Any condition which, in the judgement of the Investigator, would place the patient at undue risk or interfere with the results of the study.

1) Tumori co-esistenti di diversa origine istologica, ad
eccezione di tumore localizzato della pelle non
melanomatoso e/o di carcinoma cervicale in situ.
2) Una storia di tumori precedenti di diversa origine
istologica in remissione completa da meno di 5 anni.
3) Tossicità non risolta di un trattamento precedente.
4) Mesotelioma primitivo del peritoneo.
5) Uno dei seguenti valori ematologici basali anomali:
a. Hb < 9 g/dL
b. WBC < 3 x 10^9/L
c. Neutrofili < 1.5 x 10^9/L
d. Piastrine < 100 x 10^9/L
e. Bilirubina sierica > 2.5 mg/dL
f. ALT e AST > 3x (in assenza di metastasi epatiche)
g. Creatinina sierica > 1.5 mg/dL.
6) Metastasi cerebrali preesistenti sintomatiche e / o
instabili. Per essere arruolati nello studio, i soggetti
devono avere la conferma di malattia cerebrale stabile
alla risonanza magnetica o alla tomografia
computerizzata (TC) entro 4 settimane dal giorno 1 del
ciclo 1 del trattamento e devono avere la conferma che
le metastasi del sistema nervoso centrale siano ben
controllate dagli steroidi e/o dagli anti - epilettici e/o da
altri farmaci sintomatici.
7) Malattia cardiovascolare clinicamente rilevante, vale a
dire, infarto del miocardio o altre gravi malattie
coronariche nei precedenti sei mesi, aritmia cardiaca che
richiede farmaci, ipertensione non controllata,
insufficienza cardiaca manifesta o malattia cardiaca
cronica non compensata in classe NYHA II o superiore.
8) Storia di disabilità psichiatrica, potenzialmente
interferente con la capacità di dare adeguato consenso
informato.
9) Donne in gravidanza o in fase di allattamento o con
l'incapacità / non volontà di praticare un metodo
contraccettivo clinicamente approvato durante il periodo
di studio (compresi i tre mesi successivi alla fine del
trattamento).
10) Infezioni attive non controllate.
11) Qualsiasi condizione che, a giudizio dello
sperimentatore, potrebbe esporre il paziente a rischi
inutili o che potrebbe interferire con i risultati dello studio.

E.5 End points

E.5.1

Primary end point(s)

- To assess the anti-tumor activity of IM in combination
with GEM, in terms of 3-months progression-free
survival (PFS) rate.

-Valutare l'attività anti-tumorale della combinazione
IM/GEM, in termini di tasso di sopravvivenza libera da
progressione a 3 mesi.

E.5.1.1

Timepoint(s) of evaluation of this end point

March 2018

Marzo 2018

E.5.2

Secondary end point(s)

•- To assess anti-tumor activity of IM in combination with GEM, in terms of objective response rate according to RECIST criteria (Modified RECIST criteria for Malignant Pleural Mesothelioma), and duration of response.
•- To assess anti-tumor activity of IM in combination with GEM, in terms of PFS and overall survival (OS)
•- To determine the safety profile of IM in combination with GEM.
•- To evaluate the molecular profile of patients enrolled with Ion PGM Torrent Next-generation Sequencing platform correlating the molecular profiles identified with clinical characteristics and survival data of patients.

E.5.2.1

Timepoint(s) of evaluation of this end point

November 2018

Novembre 2018

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

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)

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)

Treated until disease progression

Trattamento fino a progressione della malattia

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

2014-10-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-09-17

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

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