Clinical Trials Register

Summary
EudraCT Number:	2016-002364-13
Sponsor's Protocol Code Number:	M16VIB
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-12-15
Trial results	View 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

2016-002364-13

A.3

Full title of the trial

MoTriColor: A phase II study of vinorelbine in advanced BRAF-like colon cancer

Motricolor: uno studio di fase II di vinorelbina nel tumore del colon avanzato con signature “BRAF-like”

A.3.1

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

Trial with vinorelbine, a form of chemotherapy, in intestinal cancer with a BRAF-like signature

Prova con vinorelbina, una forma di chemioterapia, nel cancro intestinale con una firma simile a BRAF

A.3.2

Name or abbreviated title of the trial where available

Trial with vinorelbine, a form of chemotherapy, in intestinal cancer with a BRAF-like signature

trial con vinorelbina, una forma di chemioterapia, nel cancro intestinale con una firma simile a BRA

A.4.1

Sponsor's protocol code number

M16VIB

A.5.4

Other Identifiers

Name:

EORTC

Number:

1616

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	THE NETHERLANDS CANCER INSTITUTE
B.1.3.4	Country	Netherlands
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	Horizon 2020
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	EORTC
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	Antoni van Leeuwenhoek
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Netherlands Cancer Institute
B.5.2	Functional name of contact point	Dept of Med. Oncology
B.5.3	Address:
B.5.3.1	Street Address	Plesmanlaan 121
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1066 CX
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31205122446
B.5.5	Fax number	31205122572
B.5.6	E-mail	j.schellens@nki.nl

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	VINORELBINA ACTAVIS - 10 MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONCINO DI VETRO DA 5 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ACTAVIS ITALY S.P.A.
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	vinorelbine
D.3.2	Product code	[vinorelbine]
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	VINORELBINE
D.3.9.1	CAS number	71486-22-1
D.3.9.2	Current sponsor code	Vinorelbin
D.3.9.4	EV Substance Code	SUB00069MIG
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	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

colon carcinoma

carcinoma del colon

E.1.1.1

Medical condition in easily understood language

intestinal cancer

cancro intestinale

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

To determine the anti-tumor activity, as defined as doubling of progression free survival (PFS) of vinorelbine treatment in patients with BRAF-like colon cancer. This means that by vinorelbine treatment the rate of progression at 6 weeks drops to 25%.

Determinare l’attività antitumorale, definita come raddoppiamento della sopravvivenza libera da progressione (PFS), del trattamento con vinorelbina in pazienti affetti da tumore del colon BRAF-like. Ciò significa che il tasso di progressione a 6 settimane scende al 25% mediante trattamento con vinorelbina.

E.2.2

Secondary objectives of the trial

• To characterize the safety and tolerability of vinorelbine, as assessed by the incidence and severity of adverse events.
• To assess efficacy of vinorelbine, as measured by overall response rate, duration of response, time to response and overall survival (OS).
• To explore determinants (gene alteration/expression) of response to vinorelbine, as measured by baseline molecular status (mutation/ expression) in tumor tissue of potential predictive markers of tumor response.
• To explore the potential mechanism of resistance to vinorelbine, as measured by gene alterations/expression profiles (i.e. baseline, relapse) in tumor tissue upon progression.

• Caratterizzare la sicurezza e la tollerabilità di vinorelbina, valutate in base a incidenza e gravità degli eventi avversi.
• Valutare l’attività antitumorale di vinorelbina, misurata in base a tasso di risposta complessiva, durata della risposta, tempo alla risposta e sopravvivenza complessiva (OS).
• Analizzare i determinanti (alterazione/espressione genica) della risposta a vinorelbina, valutati in base allo stato molecolare basale (mutazione/espressione) nel tessuto tumorale di potenziali marcatori predittivi di risposta del tumore.
• Esplorare il potenziale meccanismo di resistenza a vinorelbina, valutato in base ai profili di alterazione/espressione genica (ovvero, al basale, alla recidiva) nel tessuto tumorale al momento della progressione.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent (+ TR (translational research)) must be given according to ICH/GCP and national/local regulations
2. Written documentation of BRAF-like signature CC, including BRAFm and BRAFwt, as determined by the validated assay of Agendia
3. Age = 18 years
4. Histologically proven and measurable (RECIST criteria v.1.1) metastatic adenocarcinoma of the colon not in a previously irradiated area, treated with one or two lines of standard of care therapy, including BRAF inhibitors, for locally advanced disease and metastatic disease
5. WHO performance status of 0-1
6. Life expectancy > 3 months allowing adequate follow up of toxicity evaluation and antitumor activity
7. Negative urine pregnancy test for female patients with childbearing potential

1. Consenso informato scritto (+ TR [ricerca traslazionale]) in conformità alle norme di Buona pratica clinica della Conferenza internazionale sull’armonizzazione (ICH/GCP) e alla normativa nazionale/locale
2. Documentazione scritta di CC con profilo BRAF-like, tra cui BRAFm e BRAFwt, determinato mediante test validato di Agendia
3. Età >18 anni
4. Adenocarcinoma metastatico del colon istologicamente dimostrato e misurabile (Criteri di valutazione della risposta nei tumori solidi [RECIST] v.1.1), con sede in un’area non precedentemente irradiata, trattato con una o due linee di terapia standard, inclusi gli inibitori di BRAF, per malattia localmente avanzata e malattia metastatica
5. Stato di validità OMS di 0-1
6. Soggetto in grado di, e disponibile a sottoporsi a prelievi di sangue per l’analisi farmacodinamica (PD)
7. Soggetto in grado di, e disponibile a sottoporsi a biopsia tumorale prima dell’avvio, durante e alla fine del trattamento
8.Aspettativa di vita >3 mesi, che consenta un follow-up adeguato della valutazione della tossicità e dell’attività antitumorale
9. Valori minimi accettabili degli esami di laboratorio per la sicurezza:
a. Conta assoluta dei neutrofili (ANC) >1,5 x 109/l
b. Conta piastrinica >100 x 109/l
c. Emoglobina >6,0 mM/l
d. Funzione epatica definita da livelli sierici di bilirubina <1,5 x il limite superiore della norma (ULN), ALAT e ASAT <2,5 x ULN o ALAT e ASAT <5 x ULN nei pazienti con metastasi epatiche
e. Funzione renale definita da livelli sierici di creatinina <1,5 x ULN
f. Clearance della creatinina >50 ml/min (secondo la formula di Cockroft-Gault)
10. Test di gravidanza urinario negativo per le pazienti in età fertile

E.4

Principal exclusion criteria

1. Any treatment with investigational drugs, including BRAF inhibitors, within 28 days prior to receiving the first dose of investigational treatment
2. Symptomatic or untreated leptomeningeal disease
3. Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anticonvulsant therapy (for at least 4 weeks) are allowed to enroll. Radiotherapy for brain metastasis must have been completed at least 6 weeks prior to start of study treatment. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs or corticosteroids
4. Impairment of gastrointestinal (GI) function or GI disease (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, any condition inducing malabsorption, small bowel resection)
5. Other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection
6. Known allergy or any other adverse reaction to any of the drugs or to any related compound
7. Women who are pregnant or breast feeding
8. Unreliable contraceptive methods. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms)
9. Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery
10. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients
11. Patients with a known history of hepatitis B or C
12. Known hypersensitivity to study drug or excipients

1.Qualsiasi trattamento con farmaci sperimentali, inclusi gli inibitori di BRAF, nei 28 giorni precedenti la somministrazione della prima dose di trattamento sperimentale
2. Malattia leptomeningea sintomatica o non trattata
3.Metastasi cerebrali sintomatiche. È consentito l’arruolamento di pazienti, trattati o meno in precedenza per queste condizioni, che appaiano asintomatici in assenza di terapia corticosteroidea e anticonvulsivante (per almeno 4 settimane). La radioterapia per metastasi cerebrali deve essere stata completata almeno 6 settimane prima dell’avvio del trattamento dello studio. Le metastasi cerebrali devono essere stabili, con verifica mediante esami di imaging (ad es., RM o TC cerebrale eseguita allo screening che non dimostri alcuna attuale evidenza di metastasi cerebrali in progressione). I pazienti non possono ricevere farmaci antiepilettici induttori enzimatici o corticosteroidi
4. Compromissione della funzione gastrointestinale (GI) o patologia GI (ad es., patologie ulcerative, nausea non controllata, vomito, diarrea, qualsiasi condizione che induca malassorbimento, resezione dell’intestino tenue)
5. Altra malattia concomitante non controllata, tra cui grave infezione intercorrente non controllata
6. Allergia nota o qualsiasi altra reazione avversa a uno qualsiasi dei farmaci o a qualsiasi composto correlato
7. Donne in gravidanza o che allattano al seno
8.Metodi contraccettivi non affidabili. Sia gli uomini che le donne arruolati in questa sperimentazione devono acconsentire a utilizzare un metodo contraccettivo affidabile per tutta la durata dello studio (sono metodi contraccettivi adeguati il preservativo, la sterilizzazione, altre misure contraccettive di barriera preferibilmente in combinazione con preservativi)
9. Radioterapia, immunoterapia o chemioterapia nelle ultime 4 settimane prima della somministrazione della prima dose di trattamento sperimentale. È consentita la radioterapia palliativa (1 x 8 Gy)
10.Pazienti sottoposti a qualsiasi intervento chirurgico maggiore nelle ultime 2 settimane prima dell’avvio del farmaco dello studio o che non si siano ripresi completamente da un precedente intervento chirurgico
11. Pazienti con patologia infettiva non controllata o infezione nota da virus dell’immunodeficienza umana di tipo 1 (HIV-1) o 2 (HIV-2)
12. Pazienti con anamnesi nota di epatite B o C
13. Pazienti con comorbilità cardiache (infarto miocardico nei 6 mesi precedenti l’inizio dello studio, insufficienza cardiaca congestizia di classe =III in base alla classificazione della New York Heart Association [NYHA] [Associazione dei cardiologi di New York] o angina pectoris instabile), ipertensione non controllata (pressione arteriosa sistolica >150 mm Hg e/o pressione diastolica >90 mm Hg) o intervallo QT prolungato (>440 ms per gli uomini, >460 ms per le donne)
14. Altra condizione medica o psichiatrica o anomalia di laboratorio grave, acuta o cronica, che possa aumentare il rischio associato alla partecipazione allo studio o alla somministrazione del farmaco dello studio o che possa interferire con l’interpretazione dei risultati dello studio e che, a giudizio dello sperimentatore, renderebbe il paziente un candidato non idoneo per lo studio
15. Ipersensibilità nota al farmaco dello studio o agli eccipienti

E.5 End points

E.5.1

Primary end point(s)

To demonstrate the safety and anti-tumor activity of vinorelbine in paitents with BRAF-like colon cancer, who are previously treated with maximally two lines of standard of care therapy for advanced disease. The study will be powered to demonstrate a doubling of progression free survival (PFS) of vinorelbine treatment compared with historic controls. This means that by vinorelbine treatment the rate of progression at 6 weeks drops to 25%

L’endpoint primario è il raddoppiamento della PFS rispetto ai controlli storici.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the trial

alla fine del processo

E.5.2

Secondary end point(s)

Caratterizzare la sicurezza e la tollerabilità di vinorelbina, valutate in base a incidenza e gravità degli eventi avversi.
• Valutare l’attività antitumorale di vinorelbina, misurata in base a tasso di risposta complessiva, durata della risposta, tempo alla risposta e sopravvivenza complessiva (OS).
• Analizzare i determinanti (alterazione/espressione genica) della risposta a vinorelbina, valutati in base allo stato molecolare basale (mutazione/espressione) nel tessuto tumorale di potenziali marcatori predittivi di risposta del tumore.
• Esplorare il potenziale meccanismo di resistenza a vinorelbina, valutato in base ai profili di alterazione/espressione genica (ovvero, al basale, alla recidiva) nel tessuto tumorale al momento della progressione.

E.5.2.1

Timepoint(s) of evaluation of this end point

at the end of the trial

alla fine del processo

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

Yes

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

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

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-12-15.

Yes

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)

none

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	Motricolor
G.4.3.4	Network Country	Spain

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-11-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-14

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-03-17

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