Clinical Trials Register

Summary
EudraCT Number:	2018-000580-90
Sponsor's Protocol Code Number:	ASSTBS-ONCO-ACACIA-18
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:	2020-11-04
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

2018-000580-90

A.3

Full title of the trial

Multicenter randomized open-label phase III trial of Adjuvant Chemotherapy vs. observation or mitotane after primary surgical resection of localized

Multicenter randomized open-label phase III trial of Adjuvant Chemotherapy vs. observation or mitotane after primary surgical resection of localized Adrenocortical CarcInomA with high risk of recurrence

A.3.1

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

Multicenter randomized open-label phase III trial of Adjuvant Chemotherapy vs. observation or mitotane after primary surgical resection of localized

Studio multicentrico, randomizzato, in aperto di fase III volto a valutare l’attività di chemioterapia adiuvante versus osservazione/mitotane dopo chirurgia di prima linea in pazienti affetti da carcinoma corticosurrenale localizzato ad alto rischio di recidiva (ACACIA)

A.3.2

Name or abbreviated title of the trial where available

ACACIA

A.4.1

Sponsor's protocol code number

ASSTBS-ONCO-ACACIA-18

A.5.4

Other Identifiers

Name:

ACACIA

Number:

ASSTBS-ONCO-ACACIA-18

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	AZIENDA SOCIO SANITARIA TERRITORIALE DEGLI SPEDALI CIVILI DI BRESCIA
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	AIFA - Italian Medicines Agency
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	ASST SPEDALI CIVILI DI BRESCIA
B.5.2	Functional name of contact point	PROGETTAZIONE RICERCA CLINICA E STU
B.5.3	Address:
B.5.3.1	Street Address	P.LE SPEDALI CIVILI 1
B.5.3.2	Town/ city	BRESCIA
B.5.3.3	Post code	25124
B.5.3.4	Country	Italy
B.5.4	Telephone number	0303996851
B.5.5	Fax number	0303996125
B.5.6	E-mail	coordinamento.ricerca@asst-spedalicivili.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	CISPLATINO ACCORD HEALTHCARE ITALIA - 1MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONCINO IN VETRO DA 10 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ACCORD HEALTHCARE ITALIA S.R.L.
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	CISPLATINO
D.3.2	Product code	[CISPLATINO]
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	CISPLATINO
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	CISPLATINO
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	80
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	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)	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	ETOPOSIDE TEVA - 1 FLACONE 10 ML 20MG/ML
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA PHARMA B.V.
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	etoposide
D.3.2	Product code	[etoposide]
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	ETOPOSIDE
D.3.9.2	Current sponsor code	etoposide
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
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	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)	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: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	LYSODREN - 500 MG-COMPRESSE-USO ORALE-FLACONE(HDPE) 100 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATOIRE HRA PHARMA
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	mitotano
D.3.2	Product code	[mitotano]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MITOTANO
D.3.9.2	Current sponsor code	mitotano
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	1
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	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)	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

localized Adrenocortical CarcInomA with high risk of recurrence

pazienti affetti da carcinoma corticosurrenale localizzato ad alto rischio di recidiva

E.1.1.1

Medical condition in easily understood language

Adrenocortical CarcInomA

carcinoma corticosurrenale

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	10001388
E.1.2	Term	Adrenocortical carcinoma
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 compare the efficacy of adjuvant chemotherapy with cisplatin plus etoposide at the above mentioned doses with or without mitotane (according to center preferences) (arm A) versus no treatment or adjuvant mitotane (according to center preference) (arm B) in terms of recurrence-free survival (RFS). Recurrence will be objectively assessed every 16 weeks by imaging the chest/abdomen/pelvis by either computed tomography (CT; with slice thickness of 5 mm or less) or magnetic resonance imaging (MRI). Suspected lesions will be accurately measured in at least one dimension (the longest diameter in the plane of measurement will be recorded). Soft tissue lesions must have a minimum size of 10 mm, and suspected malignant lymph nodes must be more than 15 mm (short axis) to be considered pathological.
Radiologists will be blinded to treatment group. Raised levels of adrenocortical hormones as the only sign of disease progression will not be considered as true progression

Confrontare l’efficacia della chemioterapia con cisplatino + etoposide con o senza mitotane (in base alle preferenze del centro) (braccio A) verso l’assenza di trattamento o il mitotane adiuvante (in base alle preferenze del centro) (braccio B) in termini di sopravvivenza senza recidiva.

E.2.2

Secondary objectives of the trial

- To assess overall survival (OS), defined as the time interval between the date of randomization and the date of death from any cause.
- To assess toxicity and adverse events, graded according to the NCI-CTCAE (version 4.03).
- To assess the effect of disease stage, microscopically positive margins (R1) and Ki67 expression on clinical outcomes.
- To assess the predictive role of Ki67 expression for chemotherapy efficacy
- To assess the predictive role of histopathologic characteristics (Weiss-score) for chemotherapy efficacy

- Determinare la sopravvivenza globale, considerata come l’intervallo di tempo compreso fra la data della randomizzazione e la data del decesso, indipendentemente dalla causa di morte.
- Valutare la tossicità e gli eventi avversi, classificati secondo sistema NCI-CTAE (versione 4.03).
- Valutare l’effetto del grado di malattia, dei margini miscroscopicamente positivi (R1) e dell’espressione del Ki67 sugli indici di outcome del paziente.
- Misurare il valore predittivo dell’espressione di Ki67 per l’efficacia chemioterapica.
- Misurare il valore predittivo del profilo istopatologico (Weiss score) per l’efficacia chemioterapica.
- Valutare l’efficacia della chemioterapia adiuvante in confronto al braccio di controllo in pazienti stratificati a seconda del profilo ormonale del tumore: per esempio tumori secernenti cortisolo vs tumori secernenti androgeni vs tumori non secernenti.
- Valutare l’efficacia della chemioterapia adiuvante rispetto al braccio di controllo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Histologically confirmed diagnosis of ACC (Weiss score of = 3); all tumor specimens can be reviewed a posteriori by a reference pathologis
- High risk of relapse within 60 days of surgical resection of primary tumor with curative intent with either microscopically complete resection (R0, microscopically positive margins (R1), or undetermined margins (RX, based on surgical or pathological reports without unequivocal evidence of metastasis in the perioperative imaging).
- Ki67=10% (to be determined by an experienced pathologist in each participating center and preferably via quantitative imaging analysis).
- Have perioperative imaging (CT with contrast or MRI of the chest/abdomen/pelvis) demonstrating no unequivocal evidence of disease within 4 weeks before randomization. Patients with indeterminate non-specific nodules (<1 cm for soft tissue lesions and <1.5 cm in the short dimension for lymph nodes) will be permitted to participate in this study.

- Diagnosi istologica di ACC (Weiss score =3); ogni campione del tumore può essere revisionata a posteriori da un anatomopatologo di riferimento
- Alto rischio di recidiva a 60 giorni dalla resezione del tumore primitivo con intento curativo, con resezione completa microscopicamente (R0), margini microscopicamente positivi (R1), o margini indeterminati (RX), sulla base di referto chirurgico o anatomopatologico senza evidenza certa di metastasi nelle immagini perioperatorie
- Ki67=10% (determinato da un anatomopatologo esperto in ogni centro partecipante e preferibilmente tramite un’analisi di immagine quantitativa)
- Avere un’imaging perioperatoria (CT con mezzo di contrasto o RM del torace/addome/pelvi) che non dimostri un’evidenza certa di malattia nelle 4 settimane precedenti la randomizzazione
- Pazienti con noduli indeterminati non-specifici (<1 cm lesione di consistenza molle e <1,5 cm nel lato corto per linfonodo) potranno partecipare allo studio

E.4

Principal exclusion criteria

- The time between primary surgery and randomization is >60 days
- They have undergone repeated surgery for recurrence of disease
- They have a history of recent or active prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, breast ductal carcinoma in situ, or other treated malignancies where there has been no evidence of disease for at least 2 years
- They have renal insufficiency (estimated glomerular filtration rate [GFR] <50 mL/min/1.73 m2) or significant liver insufficiency (serum bilirubin>2 times the upper normal range and/or serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST]>3 times the upper normal range). GFRs will be calculated according to the validated formula (MDRD)
- They are pregnant or breast feeding

- Il tempo trascorso tra la prima chirurgia e la randomizzazione è > 60 giorni
- Sono stati sottoposti a ripetuti interventi chirurgici per ripresa di malattia
- Hanno una storia di recente o attiva neoplasia maligna primitiva, eccetto che si tratti di un tumore cutaneo non-melanoma trattato ad intento curativo, carcinoma cervicale in situ trattato ad intento curativo, carcinoma duttale in situ della mammella, od altri tumori maligni trattati senza evidenza di malattia nei due anni successivi
- Affetti da insufficienza renale (valore di filtrazione glomerulare [GFR] <50 mL/min/1.73m2) o significativa insufficienza epatica (bilirubinemia > 2 volte il limite superiore del range di normalità e/o livelli ematici di alanina aminotransferasi [ALT] o aspartato aminotransferasi [AST] > 3 volte il limite superiore del range di normalità). GFRs verrà calcolato con la formula concordata (MDRD)
- Pazienti gravide o in allattamento

E.5 End points

E.5.1

Primary end point(s)

The primary end point of will be the assessment of therapy efficacy through the evaluation of progression free survival (PFS). Analysis will be performed every 16 weeks (overall 2 years treatment) by imaging the chest/abdomen/pelvis by either computed tomography (CT; with slice thickness of 5 mm or less) or magnetic resonance imaging (MRI).

valutazione dell'efficacia della terapia attraverso la valutazione della sopravvivenza libera da progressione (PFS). L'analisi verrà eseguita ogni 16 settimane (in generale 2 anni di trattamento) mediante imaging del torace / addome / pelvi mediante tomografia computerizzata (TC, con spessore della sezione di 5 mm o inferiore) o risonanza magnetica

E.5.1.1

Timepoint(s) of evaluation of this end point

every 16 weeks (overall 2 years treatment)

OGNI 16 SETTIMANE PER I 2 ANNI DI STUDIO

E.5.2

Secondary end point(s)

serius event adverse

misurazione del numero di eventi avversi in corso di studio

E.5.2.1

Timepoint(s) of evaluation of this end point

every time in the study

per tutta la durata dello 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

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)

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

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

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.1.1.1

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:

180

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

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

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

200

F.4.2.2

In the whole clinical trial

200

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)

the patients will be treated by national health system

i pazienti saranno trattati secondo sistema sanitario nazionale

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	l’AOU Città della Salute e della Scienza di Torino – CRPT
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

2018-06-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-03

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

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