Clinical Trials Register

Summary
EudraCT Number:	2018-002172-40
Sponsor's Protocol Code Number:	IEO838
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

2018-002172-40

A.3

Full title of the trial

Primary Ipilimumab and Nivolumab combo-immunotherapy followed by adjuvant Nivolumab in locally advanced or limited metastatic melanoma.

Combo-Immunoterapia primaria con Ipilimumab e Nivolumab seguita da terapia adiuvante con Nivolumab in pazienti con melanoma localmente avanzato o oligometastatico.

A.3.1

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

Ipilimumab in combination with Nivolumab followed by Nivolumab monotherapy in patients with unresectable or oligometastatic melanoma.

Ipilimumab in combinazione con Nivolumab seguito da Nivolumab in monoterapia nei pazienti affetti da Melanoma localmente avanzato o oligometastatico.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

IEO838

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 EUROPEO DI ONCOLOGIA
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	Bristol Myers Squibb Pharma
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	Istituto Europeo di Oncologia
B.5.2	Functional name of contact point	Ufficio Studi Clinici ed Attività R
B.5.3	Address:
B.5.3.1	Street Address	Via Adamello 16
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20139
B.5.3.4	Country	Italy
B.5.4	Telephone number	0257489848
B.5.5	Fax number	0257489781
B.5.6	E-mail	ufficio.studiclinici@ieo.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.2.1.2	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	OPDIVO
D.3.2	Product code	[BMS-936558]
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	NIVOLUMAB
D.3.9.2	Current sponsor code	BMS-936558
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	10
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	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)	Yes
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.3.1	Product name	YERVOY
D.3.2	Product code	[BMS-734016]
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	ipilimumab
D.3.9.2	Current sponsor code	BMS-734016
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	5
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	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)	Yes
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

Patients with histologically or cytologically confirmed AJCC (8th ed.) Stage IIIB -IV resectable melanoma.

Pazienti con melanoma stadio IIIB-IV, stadiazione AJCC (8 ° ed.), oligometastatico e resecabile.

E.1.1.1

Medical condition in easily understood language

Patients with oligometastatic resectable melanoma

Pazienti affetti da melanoma oligometastatico e resecabile.

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10053571
E.1.2	Term	Melanoma
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

evaluation of efficacy in terms of pathological complete response rates

valutazione dell'efficacia attraverso il tasso di risposte patologiche complete.

E.2.2

Secondary objectives of the trial

Feasibility and safety. Identification of outcome-related biomarkers

Sicurezza e fattibilità. Identificazione di biomarcatori predittivi dell'outcome.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must have histologically or cytologically confirmed 8th ed. AJCC Stage IIIB/C/D
or Stage IV oligometastatic resectable melanoma. Patients with cutaneous, mucosal, acral,
ocular or unknown primary melanomas are eligible for enrollment. Oligometastatic
melanoma is defined as three or fewer areas of resectable disease excluding central
nervous system and bone involvement. In case of involvement of three areas, one must be
superficial (cutaneous-subcutaneous). Resectable tumors are defined as having no
significant vascular, neural or bony involvement. A multidisciplinary discussion within
surgical oncologists, medical oncologists, and radiologist will assess if disease is
resectable.
· Signed Written Informed Consent.
· Patients must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests and all protocol procedures.
· Males and Females, ages =18 years of age.
· Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
· Have measurable disease based on RECIST 1.1.
· Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor
lesion at baseline and at the time points specified in the Study Procedure Tables.
· Known BRAF V600 mutation status as determined by local institutional standard. All
BRAF statuses (BRAF wild type or BRAF 600 mutation positive) are eligible.
· Patients who have been previously treated in the adjuvant setting for melanoma will be
eligible for treatment after a 28 day washout period.
· Patients must be medically fit enough to undergo surgery as determined by the treating
medical and surgical oncology team.
· Demonstrate adequate organ function as defined below: Hematologic Absolute neutrophil
count (ANC) >/= 1.5 X 10^9/L; Hemoglobin >/= 9.5 g/dL Platelets >/= 100 X 10^9/L
PT/INR and PTT </= 1.5 X ULN. Hepatic Total bilirubin </= 1.5 X ULN (isolated bilirubin
>1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) AST and
ALT Albumin </= 2.5 X ULN 1 >/=2.5 g/dL Renal Creatinine OR Calculated creatinine
clearance OR 24-hour urine creatinine clearance </=1.5 X ULN 2 >/= 50 mL/min >/= 50
mL/min.
· Women are eligible to participate if: non-childbearing potential defined as pre-menopausal
females with a documented tubal ligation or hysterectomy; or postmenopausal defined as
12 months of spontaneous amenorrhea

a. diagnosi istologica o citologica di melanoma in stadio IIIB/C/D o stadio IV(sec. 8th ed. AJCC) con malattia oligomestastatica e potenzialmente resecabile. La malattia oligometastatica è definita dalla presenza di non più di tre aree di malattia
potenzialmente resecabile, escluse le localizzazioni ossee e del sistema nervoso centrale. In caso di coinvolgimento di tre aree, una deve essere una zona superficiale (cute/sottocute). La resecabilità
è definita dall’assenza di un significativo ciondolamento osseo, vascolare, neurale. La resecabilità della malattia verrà definita da una discussione multidisciplinare tra oncologo, chirurgo e radiologo.
b. Consenso informato scritto
c. I pazienti dovranno essere in grado di effettuare le visite programmate, il trattamento, I test di laboratorio e tutte le procedure del protocollo
d. Età = 18 anni.
e. Performance status di 0-1, sec. Eastern Cooperative Oncology Group (ECOG)
f. Malattia misurabile sec. I criteri RECIST 1.1.
g. Disponibilità di tessuto proveniente da una nuova biopsia incisonale o escissionale secondo le tempistiche definite dal protocollo
h. Stato mutazionale di BRAF V600 noto. I Pazienti sono eleggibili indipendentemente dallo stato mutazionale di BRAF
i. I pazienti sottoposti a precedenti terapie adiuvanti per melanoma sono includibili dopo un periodo di 28 giorni di washout.
j. I pazienti devono essere idonei per essere sottoposti all’intervento chirurgico programmato dall’equipe chirurgica
k. Funzione d’organo adeguata così definite:
conta assoluta dei neutrofili (ANC) >/= 1.5 X 10^9/L; emoglobina >/= 9.5 g/dL piastrine >/= 100
X 10^9/L PT/INR e PTT </= 1.5 X ULN. Bilirubina totale </= 1.5 X ULN AST, ALT Albumina </=
2.5 X ULN 1 >/=2.5 g/dL creatininemia o clearance della creatinina calcolata o clearance della
creatinina nelle 24-ore </=1.5 X ULN 2 >/= 50 mL/min >/= 50 mL/min.
l. Pazienti di sesso femminile sono includibili in età fertile se che accettano di utilizzare uno dei metodi contraccettivi efficaci e avere un test di gravidanza negativo entro le 24 ore precedenti la
somministrazione del trattamento

E.4

Principal exclusion criteria

oncological therapies or other concomitant experimental oncologic treatments.
B. Major surgery within the previous 3 weeks
C. Cerebral, leptomeningee or bone metastases
D. Pregnancy or lactation.
E. Concomitant pathologies that increase, in the opinion of investigators, the risk associated with
the Participation in the study, the administration of the treatment or interfering with the
interprettazioen of Results
F. Active oncological pathologies arising in the two years preceding enlistment except
Pre-existing diagnosis of melanoma and treatable neoplasia and apparently treated with local
therapies,
G. Patients with autoimmune diseases known or suspected, with the exception of vitiligo, diabetes
mellitus of type I, hypothyroidism resulting from autoimmune diseases and requiring substitution
therapy, Psoriasis that does not require systemic therapy, or conditions that you expect a flare to
Cause of external factors
H. Corticosteroid therapy (> 10 mg/day of prednisone or equivalent) or other treatment
Immunosuppressants within 14 days of administration of treatment
I. Topical or inhalatory steroids and replacement therapy for adrenal insufficiency with > 10
mg/day of prednisone or equivalents are allowed in the absence of an active autoimmune disease
J. Previous anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody therapy.

a. terapie oncologiche o altri trattamenti oncologici sperimentali concomitanti.
b. intervento chirurgico maggiore entro le 3 settimane precedenti
c. metastasi cerebrali, leptomeningee o ossee
d. gravidanza o allattamento.
e. patologie concomitanti che aumentino, nell’opinione degli investigatori, il rischio associato alla
partecipazione allo studio, alla somministrazione del trattamento o interferire con l’interpretazioen
dei
risultati
f. Patologie oncologiche attive insorte nei due anni precedente l’arruolamento ad eccezione di
diagnosi pregressa di melanoma e neoplasia curabili e apparentemente curati con terapie locali,
g. Pazienti con malattie autoimmune note o sospette, ad eccezione della vitiligine, diabete mellito
di tipo I, ipotiroidismi conseguenti a patologie autoimmuni e che richiedano terapia sostitutiva,
psoriasi che non richiede terapia sistemica, o condizioni di cui ci si attende una riacutizzazione a
causa di fattori esterni
h. Terapia con corticosteroidi (> 10 mg/die di prednisone o equivalenti) o altri trattamento
immunosoppressivi entro 14 giorni dalla somministrazione del trattamento
i. Steroidi ad uso topico o inalatorio e Terapia sostitutiva per insufficienza surrenalica con > 10
mg/die di prednisone o equivalenti sono ammessi in assenza di una malattia autoimmune attiva
j. pregressa Terapia con anticorpi anti anti-PD-1, anti-PD-L1 o anti-CTLA-4.

E.5 End points

E.5.1

Primary end point(s)

pathological complete response rates after surgery.

percentuale di risposte patologiche complete dopo la chirurgia.

E.5.1.1

Timepoint(s) of evaluation of this end point

after surgery.

dopo l'intervento chirurgico.

E.5.2

Secondary end point(s)

Rates of grade 3-4 AE rates (immune related or not) of neoadjuvant and adjuvant regimen and overall AE rates
· Overall Response Rate (ORR), according to RECIST 1.1 criteria and overall pathological response rate
· Overall Survival (OS)
· Health related quality of life (HRQoL)

• percentuali di eventi avversi di grado 3-4 e quelli complessivi.
• Tasso di risposta globale (ORR), secondo i criteri RECIST 1,1 e tasso di risposta patologico complessivo
• Sopravvivenza complessiva (OS)
• qualità di vita correlata alla salute (HRQOL)

E.5.2.1

Timepoint(s) of evaluation of this end point

every cycle/ end of treatment

a ogni ciclo/fine del trattamento

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

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

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.8.2.4

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:

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

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)

best available treatment option.

il miglior trattamento convenzionale disponibile.

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

2019-01-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-23

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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