Clinical Trials Register

Summary
EudraCT Number:	2012-005745-20
Sponsor's Protocol Code Number:	IPR/26
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:	2013-02-07
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

2012-005745-20

A.3

Full title of the trial

NGR018: Randomized phase II study of NGR-hTNF plus an anthracycline versus an anthracycline alone in platinum-resistant ovarian cancer

NGR018: studio randomizzato di fase II sulla somministrazione di NGR hTNF in combinazione con una antraciclina confrontato con la somministrazione della sola antraciclina in pazienti affette da tumore ovarico resistenti al
platino

A.3.1

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

NGR018: Randomized study based on administration of NGR-hTNF plus an anthracycline versus an anthracycline alone in platinum-resistant ovarian cancer

NGR018: studio basato sull'assegnazione casuale a uno dei due trattamenti che prevedono rispettivamente la somministrazione di NGR-hTNF in combinazione con una antraciclica oppure la sola somministrazione della sola antraciclina in pazienti affette da tumore ovarico resistente al platino

A.3.2

Name or abbreviated title of the trial where available

NGR018

A.4.1

Sponsor's protocol code number

IPR/26

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	MolMed S.p.A.
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MolMed S.p.A.
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	MolMed S.p.A.
B.5.2	Functional name of contact point	Clinical Development
B.5.3	Address:
B.5.3.1	Street Address	Centro Direzionale Milano 2, Palazzo Canova, via Fratelli Cervi
B.5.3.2	Town/ city	Segrate
B.5.3.3	Post code	20090
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390221277234
B.5.5	Fax number	+360221277239
B.5.6	E-mail	clinical.operations@molmed.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	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	NGR-hTNF
D.3.2	Product code	MM102
D.3.4	Pharmaceutical form	Concentrate for 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	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	MM102
D.3.9.3	Other descriptive name	NGR-hTNF
D.3.9.4	EV Substance Code	SUB32556
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	180 to 220
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.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.2.1.2	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.3.4	Pharmaceutical form	Concentrate for 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	DOXORUBICIN
D.3.9.1	CAS number	23214-92-8
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB06391MIG
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	2
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	Yes
D.3.11.13.1	Other medicinal product type	Anthracycline

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 or metastatic platinum-resistant ovarian cancer patients

Pazienti affette da tumore ovarico
avanzato o metastatico e resistenti al platino

E.1.1.1

Medical condition in easily understood language

Advanced or metastatic platinum-resistant ovarian cancer patients

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 early safety of NGR-hTNF given every week (instead of every 3 or 4 weeks such as
in IPR/24 study) plus an anthracycline in 12
patients randomized to experimental arm A, as
compared to 12 patients randomized to control arm B and treated with an anthracycline alone

Valutare la sicurezza preliminare di NGR-hTNF somministrato ogni settimana (invece di ogni 3 o 4 settimane come nello studio IPR/24) in combinazione con una antraciclina in 12 pazienti randomizzate nel braccio sperimentale A, in confronto alle 12 pazienti randomizzate nel braccio di controllo B e trattate con la sola antraciclina

E.2.2

Secondary objectives of the trial

To document the preliminary efficacy in terms of progression-free and overall survival, response rate, disease control rate, and duration of disease control in patients randomized to NGR-hTNF plus an anthracycline versus patients randomized to an
anthracycline alone

Documentare l’efficacia preliminare in termini di sopravvivenza libera da progressione di malattia, sopravvivenza globale, tasso di risposta, percentuale e durata del controllo della malattia nelle pazienti randomizzate a ricevere NGR-hTNF in combinazione con una antraciclina , in confronto alle pazienti randomizzate a ricevere la sola antraciclina

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years
2. Histologically-proven ovarian cancer, fallopian tube and primary peritoneal cancer in advanced or metastatic stage
3. Patients previously treated with a maximum of two platinum-based regimen (cisplatin or carboplatin) plus paclitaxel and with documented progressive disease on treatment (refractory patient population) or within 6
months from last chemotherapy cycle (resistant patient population)
4. ECOG Performance status 0 - 2 (Appendix A)
5. Life expectancy of 12 weeks or more
6. Normal cardiac function (LVEF ≥ 50%) and absence of uncontrolled hypertension
7. Adequate baseline bone marrow, hepatic and renal function
8. At least one (not previously irradiated) target lesion
that could be measured in one dimension, or nonmeasurable
disease only, according to RECIST criteria
9. Patients may have had prior therapy providing the following conditions are met:
a. Surgery and radiation therapy: wash-out
period of 14 days
b. Systemic anti-tumor therapy: wash-out period of 21 days
10. Patients must give written informed consent to participate in the study

1. Eta` 18 anni
2. Tumore ovarico, tumore alle tube di fallopio o tumore peritoneale primario in stadio avanzato o metastatico confermati da esami istologici
3. Pazienti precedentemente trattate con massimo due regimi a base di platino (cisplatino o carboplatino) piu` paclitaxel
con documentata progressione di malattia durante il trattamento (popolazione refrattaria) o entro 6 mesi dall.ultimo ciclo di chemioterapia (popolazione resistente)
4. Performance status in scala ECOG 0 . 2
5. Aspettativa di 12 o piu` settimane
6. Normale funzionalita`cardiaca (LVEF 50%) e assenza di ipertensione non controllata
7.Adeguata funzionalita`midollare, epatica e renale
8. Almeno una lesione target (non precedentemente irradiata) che
potrebbe essere misurata in una dimensione, o solo malattia non-misurabile, in accordo ai criteri RECIST
9. Le pazienti possono essere state sottoposte a precedenti trattamenti in accordo alle seguenti condizioni:
a. Chirurgia e radioterapia: periodo di wash-out di 14 giorni
b. Terapia antitumorale sistemica: periodo di wash-out di 21 giorni
10. I pazienti devono aver dato il loro consenso informato scritto per partecipare allo studio

E.4

Principal exclusion criteria

1. Patients must not receive any other investigational agents while on study
2. More than two previous chemotherapy lines and previous treatment with anthracycline
3. Patients with myocardial infarction within the last six
months, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication
4. Prolonged QTc interval (congenital or acquired) > 450 ms
5. History or evidence upon physical examination of CNS
disease unless adequately treated (e.g., primary brain tumor, any brain metastasis, seizure not controlled with
standard medical therapy or history of stroke)
6. Patients with active or uncontrolled systemic disease/infections or with serious illness or medical conditions, which is incompatible with the protocol
7. Known hypersensitivity/allergic reaction to human
albumin preparations or to any of the excipients
8. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol
9. Pregnancy or lactation.

1. Le pazienti non devono ricevere nessun altro trattamento sperimentale durante lo studio
2. Piu` di due precedenti linee chemioterapiche e precedente trattamento con antraciclina
3. Pazienti con un infarto del miocardo nei precedenti sei mesi, angina instabile, scompenso cardiaco congestizio di grado II o peggiore secondo la classificazione New York Heart Association (NYHA) o seria aritmia cardiaca che richiede trattamento farmacologico
4. Intervallo QTc (congenito o acquisito) > 450 ms
5. Storia o evidenza di malattia a livello del SNC senza un adeguato trattamento (per esempio tumore primario al cervello, metastasi cerebrali, convulsioni non controllate da terapia standard o ictus) 6. Pazienti affetti da malattie/infezioni in fase attiva o non controllata o in condizioni cliniche serie o in condizioni mediche che sono incompatibili con il protocollo
7. Reazioni allergiche/ipersensibilita` note ai preparati a base di albumina o a qualsiasi altro eccipiente
8. Qualsiasi condizione psicologica, familiare, sociale o geografica che ostacolino la compliance del paziente con il protocollo
9. Gravidanza ed allattamento.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

Weekly

Settimanalmente

E.5.2

Secondary end point(s)

Documentare l’efficacia preliminare in termini di sopravvivenza libera da progressione di malattia, sopravvivenza globale, tasso di risposta, percentuale e durata del controllo della malattia nelle pazienti randomizzate a ricevere NGR-hTNF in combinazione con una antraciclina , in contronto alle pazienti randomizzate a ricevere la sola antraciclina

E.5.2.1

Timepoint(s) of evaluation of this end point

From 3 to 12 months

Da 3 a 12 mesi circa

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

E.6.4

Safety

Yes

E.6.5

Efficacy

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

Yes

E.6.13.1

Other scope of the trial description

Antitumor activity

Attività antitumorale

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

Yes

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)

Yes

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.8.6 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

The end of study corresponds to the date of close-out visit in the last center because only at this time all data have been validated and documents been checked

Per conclusione dello studio si intende la data della visita di chiusura dell`ultimo centro, in
quanto solo con la visita di chiusura tutti i dati saranno stati validati e i documenti dello
studio riverificati

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.1.1.1

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

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)

Upon clear evidence of disease progression (PD), all patients of both arms will be followed every 12 weeks for survival.
Patients of both arms who have been withdrawn from the study therapy before documentation of PD, will be followed every 8 weeks until week 32 and then every 12 weeks for disease progression (or until start of a new anticancer treatment) and then every 12 weeks for survival (including further administered therapies).

In caso di PD tutti i pazienti verrano seguiti ogni 12 settimane per la sopravvivenza. Tutti i
pazienti che avranno terminato il trattamento prima della PD verranno seguiti ogni 8
settimane fino alla 32° settimana e quindi ogni 12 settimane per la valutazione della
progressione di malattia (o fino all`inizio di una nuova terapia antitumorale) e quindi ogni
12 settimane per la sopravvivenza

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

2013-03-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-02-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-01-26

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