Clinical Trials Register

Summary
EudraCT Number:	2013-000266-11
Sponsor's Protocol Code Number:	2012-772
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:	2013-06-07
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

2013-000266-11

A.3

Full title of the trial

Multicenter, randomized trial of carboplatin +/- paclitaxel in vulnerable elderly patients with stage III-IV advanced ovarian cancer.

Studio multicentrico randomizzato di fase III di confronto tra 3 diversi regimi chemioterapici nelle pazienti anziane e fragili affette da carcinoma dell’ovaio stadio FIGO III-IV

A.3.1

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

elderly patients with stage III-IV advanced ovarian cancer.

Pazienti anziane con diagnosi di carcinoma ovarico III-IV stadio che hanno ricevuto chirurgia citoriduttiva ottimale o sono candidabili a chirurgia d’intervallo

A.3.2

Name or abbreviated title of the trial where available

EWOC-1

A.4.1

Sponsor's protocol code number

2012-772

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	HOSPICES CIVILS DE LYON
B.1.3.4	Country	France
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	none
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione IRCCS Istituto Nazionale dei Tumori
B.5.2	Functional name of contact point	Lorusso Domenica
B.5.3	Address:
B.5.3.1	Street Address	Via Giacomo Venezian,1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390223903697
B.5.5	Fax number	00390223903814
B.5.6	E-mail	domenica.lorusso@istitutotumori.mi.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	Yes
D.2.1.1.1	Trade name	Carboplatino
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Italia
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	Carboplatino
D.3.2	Product code	Carboplatino
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	Carboplatinum
D.3.9.1	CAS number	41575-94-4
D.3.9.3	Other descriptive name	CARBOPLATIN
D.3.9.4	EV Substance Code	SUB06614MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/h milligram(s)/hour
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2 to 6
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)	Yes
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	Paclitaxel
D.2.1.1.2	Name of the Marketing Authorisation holder	Mylan Italia
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	Paclitaxel
D.3.4	Pharmaceutical form	Solution for injection
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	paxene
D.3.9.1	CAS number	33069-62-4
D.3.9.4	EV Substance Code	SUB09583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	60 to 175
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)	Yes
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

Vulnerable elderly women with newly diagnosed stage III-IV ovarian cancer after an initial debulking surgery or with a planned interval debulking surgery.

Pazienti anziane con diagnosi di carcinoma ovarico III-IV stadio che hanno ricevuto chirurgia citoriduttiva ottimale o sono candidabili a chirurgia d’intervallo

E.1.1.1

Medical condition in easily understood language

stage III-IV advanced ovarian cancer in vulnerable elderly patients

Carcinoma ovarico avanzato in pazienti anziane e fragili

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 evaluate the success rate of 3 different chemotherapy regimens in women > 70 with ovarian cancer stage III-IV, considered as vulnerable upon defined Geriatric Vulnerability Score (GVS). Success is defined as the ability to deliver to patients 6 courses of chemotherapy without premature termination for progression, death or unacceptable toxicity. Patients will be randomised to receive 6 courses of one of the 3 following regimens:
- Arm A: Paclitaxel 175 mg/m²/3 hours, I.V. and carboplatin AUC 5, I.V. every 3 weeks,
- Arm B: Carboplatin monotherapy AUC 5 or 6 every 3 weeks,
- Arm C: Weekly paclitaxel 60 mg/m²/1 hour and weekly carboplatin AUC 2 (d1, d8, d15 every 4 weeks).

Valutare il regime chemioterapico di maggior successo t fra tre diversi schemi in donne con età superiore ai 70 anni che presentano diagnosi di carcinoma ovarico stadio III-IV, considerate vulnerabili mediante la scala di vulnerabilità Geriatrica (GVS). Il successo terapeutico viene definito come la capacità di somministrare alle pazienti 6 cicli di chemioterapia senza interruzione prematura dovuta a progressione, morte o tossicità inaccettabile. Le pazienti saranno randomizzate a ricevere 6 cicli di uno dei tre seguenti regimi:
- Braccio A: Paclitaxel 175 mg / m² / 3 ore, I.V. e
carboplatino AUC 5, I.V. q21,
- Braccio B: Carboplatino in monoterapia AUC 5 o 6
q21,
- Braccio C: paclitaxel settimanale 60 mg / m² / 1 ora
e carboplatino settimanale AUC 2 (d1, d8, d15/ q28).

E.2.2

Secondary objectives of the trial

• Valutare la fattibilità della strategia terapeutica (chemioterapia neoadiuvante seguita da chirurgia vs chirurgia citoriduttiva ottimale in prima istanza seguita da chemioterapia);
• Valutare la fattibilità della chirurgia di intervallo;
• Valutare la fattibilita’ della chemioterapia post operatoria;
• Valutare sopravvivenza libera da progressione (PFS);
• Valutare la sopravvivenza globale (OS);
• Valutare la qualità della vita (QOL);
• Valutare sicurezza e tollerabilità del trattamento

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Woman >70 year old: a patient can be included the day after her 70th birthday.
- Histologically or cytologically proven FIGO stage III to IV epithelial ovarian cancer or peritoneal primary or fallopian tube. A cytological proof is accepted if associated with a ratio of CA125/CEA >25 and a radiological pelvic mass.
- GVS (Geriatric Vulnerability Score) >3.
- Adequate bone marrow function including the following: Neutrophils ≥ 1.5 x 109/L , platelets ≥100 x 109/L and hemoglobin ≥9 g/dL.
- Adequate glomerular filtration rate >40 ml/min (estimates based on MDRD or Chatelut formula are sufficient)
- No icterus.
- Life expectancy > 3 months.
- Written informed consent obtained.
- Covered by a Health System where applicable.

1. Età ≥ 70 anni
2. Tumore ovarico, tumore alle tube di Fallopio o tumore peritoneale primario in stadio avanzato o metastatico stadio III-IV confermati istologicamente; oppure confermato mediante esame citologico se associato ad un rapporto di CA125/CEA> 25 e a massa pelvica evidenziata radiologicamente.
3. GVS (Geriatric Vulnerability Score)> 3
4. Adeguata funzionalità midollare: neutrofili ≥ 1,5 x 109 / l, piastrine ≥ 100 x 109 / L e di emoglobina ≥ 9 g / dl.
5. Adeguata velocità di filtrazione glomerulare> 40 ml / min (stime basate sui MDRD o Chatelut formula sono sufficienti)
6. Nessuna presenza di ittero
7. Aspettativa di vita non inferiore ai 3 mesi
8. Firma ed accettazione del Consenso Informato

E.4

Principal exclusion criteria

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.
- Prior history of chemotherapy.
- Prior history of radiotherapy which may affect patient tolerability to chemotherapy.
- Major perturbations of liver biology: Bilirubin > 2 fold the upper normal limit (UNL), SGOT-SGPT > 3 fold UNL.
- Patient unable to be regularly followed for any reason (geographic, familial, social, psychologic).
- Any mental or physical handicap at risk of interfering with the appropriate treatment.
- Known allergy to Cremophor ® EL -containing drugs.
- Any administrative or legal supervision where applicable.

9. Storia di malattia maligna negli ultimi 5 anni, ad eccezione di carcinoma adeguatamente trattato in situ della cervice o carcinoma squamoso della pelle o carcinoma basocellulare adeguatamente controllati;
10. Nessuna precedente linea chemioterapica o radioterapia;
11. Inadeguata funzionalità epatica: bilirubina> 2 UNL e SGOT-SGPT> 3 UNL;
12. Pazienti non in grado di essere regolarmente seguite per qualsiasi motivo (geografica, familiare, sociale, psicologico);
13. Qualsiasi condizione fisico o mentale che rischi di interferire con il trattamento;
14. Allergia nota ai componenti di Cremophor ® EL.

E.5 End points

E.5.1

Primary end point(s)

Main endpoint:
Treatment success is defined as the ability to deliver 6 courses of chemotherapy without premature termination for progression, death or unacceptable toxicity.
Unacceptable toxicity is defined as a major adverse event related to chemotherapy or treatment procedure leading either to early treatment stopping, to an unplanned hospital admission or to death or to a dose delay lasting more than 14 days or more than 2 dose reductions.
The proportion of patients with treatment success will be presented for each treatment arm with its confidence interval. The possible impact of geriatric prognostic factors on treatment success will be estimated using a logistic regression (multivariate analysis).

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months

24 mesi

E.5.2

Secondary end point(s)

Therapeutical strategy (feasibility of performing an optimal surgery and feasibility of performing neoadjuvant chemotherapy and surgery and post operative chemotherapy until 6 courses).
Interval debulking feasibility
Post-operative chemotherapy feasability
Overall Survival
OS is defined as the time period from the CTCAE version 4.3. Distributions of toxic events will be described by type of toxicity, by grade, by course and by patient, and for all courses.date of randomization to the date of death. OS will be analyzed by Kaplan-Meier method and will be estimated at 1 and 2 years (data points) for each treatment arm. An univariate analysis will be performed using the log-rank technique to determine the prognostic role of geriatric covariates and aging biomarkers. The adjusted prognostic value will be estimated in a multivariate analysis using a proportional hazards model.
Progression-free survival
PFS is defined as the time period from the date of randomization to the date of disease progression or death whichever occurs first. Tumor assessments will be performed at baseline and after 3 courses of chemotherapy and until progression or a minimum of 24 month follow-up whatever occurs first. Disease progression will be defined by RECIST v1.1 criteria and/or GCIG CA-125 kinetics and/or symptomatic deterioration.
Quality of Life (QOL)
Quality of life will be assessed using the FACT-O questionnaire.
Safety and tolerability
Clinical and laboratory AEs (grade 1-5) will be reported and graded according to NCI-

E.5.2.1

Timepoint(s) of evaluation of this end point

24 months

24 mesi

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

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

France

Germany

Italy

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

all patients will present progression of disease

Lo studio si concluderà quando tutte le pazienti avranno mostrato una progressione di malattia

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)

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:

240

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

230

F.4.2.2

In the whole clinical trial

240

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)

Follow-up visit every 3 months untill disease progression

Visite di Follow-up ogni 3 mesi fino a progressione

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	MITO Group "Multicenter Italian Trials in Ovarian Cancer"
G.4.3.4	Network Country	Italy

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-07-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-27

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

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Orphan Designation Number:
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