Clinical Trials Register

Summary
EudraCT Number:	2018-002893-38
Sponsor's Protocol Code Number:	CA209-8PA
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

2018-002893-38

A.3

Full title of the trial

Phase II Study on NIVolumab in combination with FOLFOXIRI/Bevacizumab in first line chemotherapy of Advanced COloRectal cancer RASm/BRAFm patients

Studio di fase II con Nivolumab in combinazione con FOLFOXIRI/Bevacizumab come trattamento di I linea in pazienti con tumore colorettale avanzato RAS/BRAF mutato

A.3.1

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

Phase II Study on NIVolumab in combination with FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan)/Bevacizumab in first line chemotherapy of Advanced COloRectal cancer patients with mutated RAS or BRAF genes.

Studio di fase II con Nivolumab in combinazione con FOLFOXIRI (fluorouracile, acido folinico, oxaliplatino e irinotecano)/Bevacizumab come trattamento di I linea in pazienti con tumore colorettale avanzato con mutazione dei geni RAS o BRAF.

A.3.2

Name or abbreviated title of the trial where available

NIVACOR GOIRC-03-2018

A.4.1

Sponsor's protocol code number

CA209-8PA

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	GRUPPO ONCOLOGICO ITALIANO DI RICERCA CLINICA (GOIRC)
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
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Bristol-Myers Squibb
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharmaceutical Development and Services srl
B.5.2	Functional name of contact point	Servizio Informazione sulla Sperime
B.5.3	Address:
B.5.3.1	Street Address	via dei Pratoni, 16
B.5.3.2	Town/ city	Scandicci (FI)
B.5.3.3	Post code	50018
B.5.3.4	Country	Italy
B.5.4	Telephone number	0557224179
B.5.5	Fax number	0557227014
B.5.6	E-mail	edimartino@pharmades.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	OPDIVO - 10 MG/ML- CONCENTRATO PER SOLUZIONE PER INFUSIONE- USO ENDOVENOSO- FLACONCINO (VETRO)- 10 ML- 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	BRISTOL-MYERS SQUIBB PHARMA EEIG
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	Nivolumab
D.3.2	Product code	[Nivolumab]
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	Nivolumab
D.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	Nivolumab
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)	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

Advanced colorectal cancer

Carcinoma colorettale avanzato

E.1.1.1

Medical condition in easily understood language

Tumor pathology of the large intestine in advanced stages.

Patologia tumorale del grosso intestino in stadio avanzato.

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10052358
E.1.2	Term	Colorectal cancer metastatic
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

Evaluate the activity of Nivolumab in combination with FOLFOXIRI and bevacizumab.

Valutare l'attività di Nivolumab in combinazione con FOLFOXIRI e bevacizumab.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy and safety of the combined treatment, the time of progression and the duration of the treatment response and the quality of life of the patients.
To evaluate the Tumor Mutation Burden , MSI status and the role of genetic and molecular pattern with patient’s outcome.

Valutare l'efficacia e la sicurezza del trattamento combinato, il tempo di progressione e la durata della risposta al trattamento e la qualità di vita dei pazienti.
Valutare il Tumor Mutation Burden, lo stato MSI e l’impatto dei modelli genetici e molecolari con l’outcome dei pazienti.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age = 18 years on day of signing informed consent.
• Histologically confirmed metastatic CRC RAS/BRAF mutated.
• Suitable for first line chemotherapy.
• Life expectancy > 3 months.
• At least one site of measurable disease per RECIST criteria.
• Performance status of 0-1 on the ECOG Performance Scale.
• Adequate organ function, all screening labs should be performed within 28 days of treatment initiation.
• Availability of 1 tumor block at baseline.

• Età = a 18 anni al momento della firma del consenso.
• Conferma istologica di carcinoma colorettale metastatico RAS/BRAF mutato.
• Paziente candidato a terapia di prima linea.
• Aspettativa di vita > di 3 mesi.
• Almeno una lesione misurabile secondo criteri RECIST.
• ECOG Performance status 0-1.
• Adeguata funzione d’organo, tutti gli esami di screening devono essere effettuati entro 28 giorni dall’inizio del trattamento.
• Disponibilità di due blocchetti tumorali allo screening.

E.4

Principal exclusion criteria

• Prior chemotherapy.
• Systemic corticosteroids within 2 weeks of the first dose of nivolumab.
• Diagnosis of immunodeficiency or patient who is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment.
• Additional malignancy in the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• Active and untreated brain (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are not using steroids for at least 7 days prior to trial treatment.
• Evidence of interstitial lung disease, active non-infectious pneumonitis, or a history of grade 3 or greater pneumonitis.
• Active infection requiring systemic therapy.
• History of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Live vaccine within 30 days prior to the first dose of trial treatment.
• Women with a positive pregnancy test at enrollment or prior to administration of study medication.

• Precedente chemioterapia
• Terapia con corticosteroidi entro 2 settimane dalla prima dose di nivolumab.
• Diagnosi di immunodeficenza o pazienti che ricevono terapia sistemica con steroidi o qualunque altro immunosoppressore entro 14 giorni dall’inizio del trattamento.
• Diagnosi di altro tumore negli ultimi 5 anni, ad eccezione del carcinoma basocellulare della pelle, carcinoma squamoso della pelle o carcinoma in situ della cervice che abbia ricevuto una terapia potenzialmente curativa.
• Metastasi al Sistema Nervoso Centrale attive e non trattate e/o meningite carcinomatosa. I pazienti con metastasi cerebrali già trattate possono partecipare se non utilizzano steroidi da almeno 7 giorni prima dell’inizio del trattamento
sperimentale.
• Evidenza di polmonite interstiziale, polmonite non infettiva attiva o storia di polmonite di grado 3 o superiori.
• Infezioni attive che richiedono una terapia sistemica.
• Positività per anticorpi anti HIV 1/2.
• Epatite B (HBsAg positive) o epatite C (HCV RNA positivo).
• Somministrazione di vaccini vivi entro 30 giorni della prima dose di trattamento sperimentale.
• Donne fertili con un test di gravidanza positivo all’arruolamento o prima della somministrazione del farmaco sperimentale.

E.5 End points

E.5.1

Primary end point(s)

To demonstrate that adding nivolumab to standard colorectal first line chemotherapy improves the Overall Response Rate as determinated by investigators using RECIST 1.1 criteria.

Dimostrare che l’aggiunta di nivolumab alla terapia standard per il carcinoma colorettale di prima linea migliora la Overall Response Rate, in base ai criteri RECIST 1.1 valutati dagli sperimentatori.

E.5.1.1

Timepoint(s) of evaluation of this end point

From the start of the study treatment until the end of treatment.

Dall'inizio del trattamento dello studio fino alla fine del trattamento.

E.5.2

Secondary end point(s)

To evaluate the safety of the combination treatment with folfoxiri + bevacizumab + nivolumab. Safety assessments will include the incidence, nature, and severity of Adverse Events (AEs) and laboratory abnormalities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03.; To evaluate the efficacy in terms of overall survival (OS) defined as the time from start of study drug to the date of death from any cause.; To evaluate the Time To Progression (TTP) defined as the time between the date of start of study drug and the first date of documented progression, based on investigator assessment (as per RECIST 1.1 criteria), or death due to any cause, whichever occurs first.; To evaluate the duration of response defined as the time between the date of first evidence of response (SD/PR/CR) and the date of documented progression or death due to any cause, whichever occurs first.; To evaluate the quality of life of patients determinated with the EQ-5D questionnaire.; To evaluate the Tumor Mutation Burden , MSI status and the role of genetic and molecular pattern with patient’s outcome.

Valutare la sicurezza del trattamento di combinazione di folfoxiri + bevacizumab + nivolumab. Le valutazioni di sicurezza includeranno l’incidenza, natura e severità degli eventi avversi e delle anormalità di laboratorio, in base al National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03.; Valutare l’efficacia in termini di sopravvivenza globale definita come il tempo dall’inizio dello studio alla data di morte per qualunque causa.; Valutare il tempo alla progressione definito come il tempo intercorso tra la data di inizio del farmaco sperimentale e la prima data di progressione accertata, basata sulla revisione dell’investigatore secondo i criteri RECIST 1.1 o la morte per qualunque causa, in base all’evento che si verifica per primo.; Valutare la durata della risposta definita come il tempo intercorso tra la data di prima evidenza di risposta (SD/PR/CR) e la data di progressione accertata o la morte per qualsiasi causa, in base all’evento che si verifica per
primo.; Valutare la qualità di vita dei pazienti utilizzando il questionario EQ-5D.; Valutare il Tumor Mutation Burden, lo stato MSI e l’impatto dei modelli genetici e molecolari con l’outcome dei pazienti.

E.5.2.1

Timepoint(s) of evaluation of this end point

From the date the patient entered in the study until the end of the study.; From start of study drug to the date of death from any cause.; From the date of start of study drug to the first date of documented progression or to death due to any cause,; From the date of first evidence of response to the date of documented progression or to death due to any cause.; Quality of life will be assessed at baseline, every 4 weeks during treatment and at study discontinuation visit.; At the end of the study.

Dalla data di entrata in studio fino alla fine dello studio.; Dall’inizio dello studio alla data di morte per qualunque causa.; Dalla data di inizio del farmaco sperimentale alla prima data di progressione accertata o alla morte per qualunque causa.; Dalla data di prima evidenza di risposta alla data di progressione accertata o alla morte per qualsiasi causa.; La qualità della vita sarà valutata al basale, ogni 4 settimane durante il trattamento e alla visita di interruzione dello studio.; A fine 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

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)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients with cognitive impairment.

Pazienti con deficit cognitivo.

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)

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

2019-02-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-03-05

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

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