Clinical Trials Register

Summary
EudraCT Number:	2012-004362-17
Sponsor's Protocol Code Number:	MITO-16b/MANGO-OV2b/ENGOT-OV17
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-25
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

Greece - EOF

A.2

EudraCT number

2012-004362-17

A.3

Full title of the trial

A multicenter phase III randomized study with second line chemotherapy plus or minus bevacizumab in patients with platinum sensitive epithelial ovarian cancer recurrence after a bevacizumab/chemotherapy first line

Πολυκεντρική φάσης ΙΙΙ τυχαιοποιημένη μελέτη με χημειοθεραπεία δεύτερης γραμμής με ή χωρίς bevacizumab σε ασθενείς με επιθηλιακό καρκίνο ωοθηκών ευαίσθητο στην πλατίνα με υποτροπή μετά από πρώτης γραμμής bevacizumab/χημειοθεραπεία

A.3.1

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

A.4.1

Sponsor's protocol code number

MITO-16b/MANGO-OV2b/ENGOT-OV17

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 NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI - FONDAZIONE 'G. PASCALE'
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	Roche
B.4.2	Country	Greece
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Istituto Nazionale dei Tumori di Napoli ''Fondazione G.Pascale''
B.5.2	Functional name of contact point	Unità sperimentazioni cliniche
B.5.3	Address:
B.5.3.1	Street Address	Via M. Semmola
B.5.3.2	Town/ city	Napoli
B.5.3.3	Post code	80131
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390815903571
B.5.5	Fax number	00390817702938
B.5.6	E-mail	gennaro.daniele@usc-intnapoli.net

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	Avastin 25mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Bevacizumab
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
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	25
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.2.1.1.1	Trade name	Avastin 25mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Bevacizumab
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
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	25
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

Platinum sensitive ovarian cancer patients progressing or recurring after a first-line treatment including bevacizumab.

Ασθενείς με καρκίνο ωοθηκών ευαίσθητο στην πλατίνα που έχουν επιδεινωθεί ή υποτροπιάσει μετά από θεραπεία πρώτης γραμμής που περιελάμβανε bevacizumab

E.1.1.1

Medical condition in easily understood language

Platinum sensitive ovarian cancer patients progressing or recurring after a first-line treatment including bevacizumab.

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	10066697
E.1.2	Term	Ovarian cancer recurrent
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

The primary objective of this trial is to test whether the addition of bevacizumab to second-line chemotherapy can prolong progression-free survival (PFS) of platinum sensitive ovarian cancer patients progressing or recurring after a first-line treatment including bevacizumab.

Ο πρωταρχικός σκοπός αυτής της μελέτης είναι να δοκιμάσει αν η προσθήκη του bevacizumab στη χημειοθεραπεία δεύτερης γραμμής μπορεί να παρατείνει την ελεύθερη προόδου νόσου επιβίωση (PFS) των ασθενών με καρκίνο ωοθηκών ευαίσθητο στην πλατίνα οι οποίες έχουν επιδεινωθεί ή υποτροπιάσει μετά από θεραπεία πρώτης γραμμής που περιείχε bevacizumab.

E.2.2

Secondary objectives of the trial

Overall Survival (OS), response rate (RR), safety, as secondary end-points, will be also assessed.
Exploratory objectives for this study are to assess the correlation of baseline plasma biomarker expression with clinical outcome, as measured by PFS and OS and to evaluate the association of other potential biomarkers, including, but not limited to, the single-nucleotide polymorphisms (SNPs), and tumor-specific markers as well as clinical factors with clinical outcome. Describing the prevalence of use of oral antidiabetic as well as antithrombotic drugs will also be considered as a secondary objective.

Θα εκτιμηθούν επίσης, η ολική επιβίωση (OS), το ποσοστό ανταπόκρισης (RR), η ασφάλεια, σαν
δευτερεύοντες σκοποί.
Οι διερευνητικοί σκοποί για την παρούσα μελέτη είναι να αξιολογηθεί η συσχέτιση της έκφρασης βιοδεικτών στο πλάσμα κατά την έναρξη (baseline), με την κλινική έκβαση, όπως θα
μετρηθούν με την PFS και την OS και να εκτιμηθεί η σύνδεση άλλων πιθανών βιοδεικτών, συμπεριλαμβανομένων και μη περιοριστικά των μονονουκλεοτιδικών πολυμορφισμών (SNPs) ,συγκεκριμένων δεικτών του όγκου και κλινικών παραγόντων με την κλινική έκβαση. Η περιγραφή της επικράτησης της χρήσης των απο του στόματος αντι-διαβητικών, καθώς και αντι-θρομβωτικών φαρμάκων, θα θεωρηθεί επίσης ένας δευτερεύων σκοπός.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Female patients >=18 years of age.
• Patients with histologically confirmed EOC, fallopian tube carcinoma or PC, including mixed Mullerian Tumours
• Recurrence or progression at least 6 months after the last chemotherapy cycle of a first line carboplatin + paclitaxel chemotherapy including bevacizumab (recurrence or progression might occur either during or after bevacizumab as maintenance)
• Patients can be included if they have a RECIST progression, with either measurable or non-measurable disease
• ECOG Performance Status of 0–2.
• Life expectancy of >=12 weeks.
• Signed informed consent obtained prior to initiation of any study-specific procedures and treatment as confirmation of the patient’s awareness and willingness to comply with the study requirements including blood samples for molecular analyses.
• Availability of tumour samples for molecular analyses from primary surgery (mandatory) and secondary surgery (when available)

• Γυναίκες ασθενείς ηλικίας >= 18 ετών
• Ασθενείς με ιστολογικά επιβεβαιωμένο επιθηλιακό καρκίνο ωοθηκών (ΕOC), σαλπίγγων ή πρωτοπαθή περιτοναϊκό καρκίνο, συμπεριλαμβανομένων και των Μυλλέριων Όγκων
• Επιδείνωση ή υποτροπή σε τουλάχιστον 6 μήνες μετά τον τελευταίο κύκλο χημειοθεραπείας πρώτης γραμμής με carboplatin + paclitaxel που περιείχε και bevacizumab (υποτροπή ή επιδείνωση που εμφανίστηκε είτε κατά τη διάρκεια, είτε μετά τη θεραπεία συντήρησης με bevacizumab).
• Οι ασθενείς μπορούν να εντάσσονται αν έχουν εμφανίσει υποτροπή της νόσου σύμφωνα με τα κριτήρια RECIST, με μετρήσιμη ή μη μετρήσιμη νόσο.
• Κατάσταση ικανότητας 0-2 κατά ECOG.
• Προσδόκιμο επιβίωσης >=12 εβδομάδες.
• Υπογεγραμμένο έντυπο συγκατάθεσης πριν από την έναρξη οποιασδήποτε διαδικασίας ειδικής για τη μελέτη και της θεραπείας, σαν επιβεβαίωση της επίγνωσης και της προθυμίας της ασθενούς να συμμορφωθεί με τις απαιτήσεις της μελέτης,
συμπεριλαμβανομένων και των δειγμάτων αίματος για μοριακές αναλύσεις.
• Διαθεσιμότητα των δειγμάτων ιστού για μοριακές αναλύσεις από το αρχικό
χειρουργείο (υποχρεωτικό) και από το δευτερεύον χειρουργείο (όταν είναι διαθέσιμο).

E.4

Principal exclusion criteria

• Ovarian tumours with low malignant potential (i.e. borderline tumours)
• History or evidence of synchronous primary endometrial carcinoma, unless all of the following criteria related to the endometrial carcinoma are met:
o stage ≤Ia
o no more than superficial myometrial invasion
o no lymphovascular invasion
o not poorly differentiated (grade 3 or papillary serous or clear cell carcinoma).
• Other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer.

• Όγκοι ωοθηκών χαμηλής δυνητικής κακοήθειας (π.χ. όγκοι οριακής κακοήθειας)
• Ιστορικό ή απόδειξη σύγχρονου πρωτοπαθούς καρκινώματος ενδομητρίου, εκτός αν πληρούνται τα παρακάτω κριτήρια για τη νόσο του καρκινώματος του ενδομητρίου:
o Στάδιο ≤Ia
o Επιφανειακή μόνο διήθηση του μυομητρίου
o Απουσία λεμφαγγειακής διήθησης
o Νόσος που δεν είναι χαμηλής διαφοροποίησης (βαθμού 3 ή ορώδης θηλώδης ή
καρκίνωμα εκ διαυγών κυττάρων)
• Άλλη κακοήθεια εντός των 5 τελευταίων ετών, εκτός του επαρκώς θεραπευμένου in situ καρκινώματος του τραχήλου ή του πλακώδους καρκινώματος του δέρματος, ή του επαρκώς
ελεγχόμενου βασικοκυτταρικού καρκίνου του δέρματος.

E.5 End points

E.5.1

Primary end point(s)

Progression-Free Survival (PFS) will be the primary end-point.

Η ελεύθερη προόδου νόσου επιβίωση (PFS) θα είναι το πρωτεύον τελικό σημείο.

E.5.1.1

Timepoint(s) of evaluation of this end point

PFS will be measured from the date of randomization to the date of progression (defined by the investigator) or the date of death, whichever comes first.

Η PFS θα μετρηθεί από την ημερομηνία τυχαιοποίησης μέχρι την ημερομηνία υποτροπής (όπως εκτιμήθηκε από τον ερευνητή) ή την ημερομηνία θανάτου, όποιο από τα δύο συμβεί πρώτο

E.5.2

Secondary end point(s)

1. Overall Survival (OS)
2. PFS as assessed by the central independent review
3. Objective response rate (ORR) assessed according to RECIST version 1.1
4. Identification of prognostic and predictive molecular factors

1. Η ολική επιβίωση (OS)
2. H PFS όπως ορίζεται απότην κεντρική ανεξάρτητη ανασκόπηση των περιστατικών.
3. Το ποσοστό της αντικειμενικής ανταπόκρισης (ORR) σύμφωνα με τα κριτήρια RECIST έκδοση 1.1
4. Αναγνώριση των προγνωστικών και προβλεπτικών μοριακών παραγόντων

E.5.2.1

Timepoint(s) of evaluation of this end point

1. OS will be measured as the time between the randomisation and patient's death from any cause.
2. From the date of randomisation until the date of progression (assessed by central independent review) or the date of death, whichever occurs first
3. Imaging assessment will be performed prior to Day 1, Cycle 1, at the end of Cycles 3 and 6 and then every 3 cycles while the patient receives bevacizumab as maintenance and then at discontinuation of bevacizumab
4. Collection of tumor tissue samples at baseline and at progression if available. Plasma samples will be collected at baseline at time of recurrence, after the end of chemotherapy (second line) and at progression

1. Η OS θα μετρηθεί ως το διάστημα μεταξύ της τυχαιοποίησης και του θανάτου του ασθενούς από οποιαδήποτε αιτία
2. Aπό την ημερομηνία τυχαιοποίησης μέχρι την ημερομηνία υποτροπής (όπως αυτή εκτιμήθηκε από την κεντρική ανεξάρτητη ανασκόπηση), ή την ημερομηνία θανάτου, όποιο από τα δύο συμβεί πρώτο
3. Ο απεικονιστικός έλεγχος θα πραγματοποιείται πριν την Ημέρα 1του κύκλου 1, στο τέλος των κύκλων 3 και 6 και μετά, κάθε τρείς κύκλους ενώ η ασθενής λαμβάνει bevacizumab για συντήρηση και μετά κατά τη διακοπή του bevacizumab
4. Συλλογή δειγμάτων ιστού του όγκου στην έναρξη και στην υποτροπή εάν είναι διαθέσιμα. Λήψη δειγμάτων πλάσματος στην έναρξη στην υποτροπή της νόσου, μετά το τέλος της χημειοθεραπείας (δεύτερης γραμμής) και στην επιδείνωση.

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

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

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

Yes

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

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

Τελευταία επίσκεψη του τελευταίου ασθενούς

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

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

400

F.4.2.2

In the whole clinical trial

400

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

Κανένα

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

2014-09-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-01-08

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