Clinical Trials Register

Summary
EudraCT Number:	2015-004543-40
Sponsor's Protocol Code Number:	ONC-2015-001/ML29968
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:	2018-08-23
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

2015-004543-40

A.3

Full title of the trial

A SINGLE ARM, PHASE II, MULTICENTER STUDY TO ASSESS THE EFFICACY AND SAFETY OF VISMODEGIB AND RADIOTHERAPY IN PATIENTS WITH HIGH RISK OR LOCALLY ADVANCED BASAL CELL CARCINOMA NOT AMENABLE TO RADICAL SURGERY (VIRGILIO)

A.3.1

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

MULTICENTER STUDY TO ASSESS THE EFFICACY AND SAFETY OF VISMODEGIB AND RADIOTHERAPY IN PATIENTS WITH HIGH RISK OR LOCALLY ADVANCED BASAL CELL CARCINOMA NOT AMENABLE TO RADICAL SURGERY

STUDIO MULTICENTRICO PER VALUTARE L'EFFICACIA E LA SICUREZZA DI VISMODEGIB E RADIOTERAPIA IN PAZIENTI AFFETTI DA CARCINOMA BASOCELLULARE AD ALTO RISCHIO DI RECIDIVA O LOCALMENTE AVANZATO NON SUSCETTIBILE DI CHIRURGIA RADICALE

A.3.2

Name or abbreviated title of the trial where available

VIRGILIO STUDY

STUDIO VIRGILIO

A.4.1

Sponsor's protocol code number

ONC-2015-001/ML29968

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	IRCCS ISTITUTO CLINICO HUMANITAS
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	Roche S.p.A.
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	CD Pharma Group S.r.l.
B.5.2	Functional name of contact point	CRO
B.5.3	Address:
B.5.3.1	Street Address	Piazza De Angeli 7
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20146
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 0289051076
B.5.5	Fax number	+39 0289051088
B.5.6	E-mail	simona.manzi@cdpharma.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	ERIVEDGE - 150 MG - CAPSULA RIGIDA - USO ORALE - FLACONE (HDPE) CON CHIUSURA DI SICUREZZA - 1 FLACONE DA 28 CAPSULE
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
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	Vismodegib
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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

HIGH RISK OR LOCALLY ADVANCED BASAL CELL CARCINOMA NOT AMENABLE TO RADICAL SURGERY

CARCINOMA BASOCELLULARE AD ALTO RISCHIO DI RECIDIVA O LOCALMENTE AVANZATO NON SUSCETTIBILE DI CHIRURGIA RADICALE

E.1.1.1

Medical condition in easily understood language

HIGH RISK OR LOCALLY ADVANCED BASAL CELL CARCINOMA NOT AMENABLE TO RADICAL SURGERY

CARCINOMA BASOCELLULARE AD ALTO RISCHIO DI RICADUTA O LOCALMENTE ESTESO NON OPERABILE IN MODO RADICALE

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	10004146
E.1.2	Term	Basal cell 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 evaluate the activity of the study therapy (radiotherapy followed by six cycles of Vismodegib 150 mg/d continuously) in terms of proportion of patients progression free at 12 months.

valutare l’attività della terapia in studio (radioterapia seguita da sei cicli di Vismogedib 150 mg/die continuativamente) in termini di percentuale di pazienti liberi da progressione a 12 mesi.

E.2.2

Secondary objectives of the trial

to evaluate the efficacy of the study therapy in terms of progression free survival (PFS) and overall survival (OS); to assess the response in terms of ORR (CR, PR, SD, PD); to assess duration of response (DoR); to assess the safety in terms of incidence, type, and severity of AEs and SAEs; to measure the effects of skin disease on quality of life (QoL) of patients under therapy (Skindex-16)

valutare l’efficacia della terapia in studio in termini di sopravvivenza libera da progressione (PFS) e sopravvivenza globale (OS); valutare la risposta in termini di tasso di risposta totale ORR (Remissione Completa, Remissione Parziale, Stabilizzazione, Progressione); valutare la durata della risposta (DoR); valutare la safety in termini di incidenza, tipo e severità degli Eventi Avversi e Eventi Avversi Seri; misurare gli effetti della malattia della pelle sulla qualità della vita (QoL) dei pazienti in terapia (Skindex-16).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written, signed informed consent
2. Age ≥ 18 years
3. Histopathologic confirmation that the lesion is BCC before enrollment
4. Patients with high risk of relapse BCC not undergone radical surgery, for which treating physician must consider the disease to be no more operable.
5. Clinical features defining high risk of relapse include infiltrative growth margins, size, tumor location, histological subtype (the morpheaform, the sclerosing, the infiltrating, the micronodular and the metatypical subtypes are associated with higher risk of relapse as compared to the risk associated with the superficial and the nodular types), recurrent-refractory tumors (see Table 1), basal cell carcinoma size (largest tumor diameter) ≤ 5 cm for head and neck tumors
6. Clinical features for definition of “BCC not amenable for radical surgery” include:
- BCC that has recurred in the same location after minimum 2 surgical procedures (excluding biopsies) and/or curative resection is deemed unlikely
- multifocal BCC or extensive tumors (see table 1) with bleeding or infected areas
- anticipated substantial morbidity and/or deformity from surgery (e.g., removal of all or part of a facial structure, such as nose, ear, eyelid, eye; or requirement for limb amputation)
7. Patients with BCCs localized where surgery is technically difficult, or would result in unacceptable tissue destruction
8. Patients with a clinical contraindication to surgery
9. Previous radiotherapy on other BCC
10. Patients with measurable and/or non-measurable disease (as defined by RECIST, v1.1) are allowed
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
12. Adequate hematopoietic capacity, defined as the following:
- Hemoglobin > 8.5 g/dl
- Absolute neutrophil count (ANC) ≥ 1500/L
- Platelet count ≥ 75,000/L
13. Adequate hepatic function, defined as the following:
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal (ULN). Total bilirubin ≤ 1.5 × ULN or within 3 × ULN for patients with documented Gilbert syndrome.
14. Adequate renal function, defined by calculated serum creatinine clearance (CrCl) ≥ 30 mL/min
15. For women of childbearing potential, a negative serum pregnancy test within 7days prior to commencement of dosing is required.
16. Women of child-bearing potential must use two methods of acceptable contraception including one highly effective method and a barrier method, as directed by their physician, during treatment and for at least 24 months after completion of study treatment. Highly effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (e.g., implants, injectables, combined oral contraception, or intra-uterine devices). At the discretion of the Investigator, acceptable methods of contraception may include total abstinence. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and post ovulation methods) and withdrawal are not acceptable methods of contraception (See Appendix B).
17. Male patients mustn’t donate sperm while being treated with Vismodegib, and for 2 months after completion of study treatment.
18. For male patients with female partners of childbearing potential, agreement to use a condom, even after a vasectomy, during sexual intercourse with female partners while being treated with Vismodegib, and for 2 months after completion of study treatment
19. Agreement not to donate blood or blood products during the study and for at least 24 months after completion of study treatment (Vismodegib).

1. Firma del consenso informato scritto
2. Età ≥ 18 anni
3. Conferma istopatologica, prima dell’arruolamento, che la lesione è dovuta a carcinoma basocellulare.
4. Pazienti con elevato rischio di recidiva di carcinoma basocellulare non sottopposto a intervento chirurgico radicale, per cui la malattia non può essere operabile.
5. Caratteristiche cliniche definite ad alto rischio di recidiva includono: crescita dei margini infiltrativi, dimensione, posizione del tumore, sottotipi istologici (sclerodermiforme, infiltrativo, micronodulare, meta tipico sono associate ad un maggiore rischio di recidiva rispetto al rischio associato alla tipologia superficiale e nodulare), tumori refrattari ricorrenti, dimensione del carcinoma basocellulare (maggiore diametro del tumore) ≤ 5 cm per i tumori della testa e del collo
6. Caratteristiche cliniche per la definizione di “carcinoma basocellulare non suscettibile a operazione chirurgica radicale” includono:
- Carcinoma basocellulare che si è ripresentato nella stessa posizione dopo minimo due procedure chirurgiche (escluse biopsie) e/o per cui l’asportazione chirurgica è ritenuta improbabile
- Carcinoma basocellulare multifocale o tumori estesi (v. tabella 1 nel Protocollo di Studio) con sanguinamento o aree infette
- Morbilità sostanziali attese e/o deformità dovute all’operazione chirurgica (e.g. rimozione di tutta o parte della struttura facciale, come per esempio naso, orecchie, palpebra, occhio; o necessità di amputazione di un arto)
7. Pazienti con carcinoma basocellulare localizzato dove l’operazione chirurgica è tecnicamente difficile o comporterebbe distruzione tissutale inaccettabile
8. Pazienti con controindicazione clinica all’operazione chirurgica
9. Precedente radioterapia su un altro carcinoma basocellulare
10. Pazienti con malattia misurabile e/o non misurabile (come definito da RECIST, v1.1) sono arruolabili
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
12. Adeguata capacità ematopoietica, definita come segue:
- Emoglobina > 8.5 g/dl
- Conta assoluta dei neutrofili (ANC) ≥ 1000/L
- Conta delle piastrine ≥ 75,000/L
13. Adeguata funzionalità epatica, definita come segue:
Aspartato aminotrasferasi (AST) e alanina aminotransferasi (ALT) ≤ 3 volte il limite superiore di normalità (ULN). Bilirubina totale ≤ 1.5 volte il limite superiore di normalità o entro 3 volte il limite superiore di normalità per pazienti con documentata sindrome di Gilbert.
14. Adeguata funzionalità renale, definita da Creatinina Clearance (CrCl) ≥ 30 mL/min
15. Per donne in età fertile, è necessario un test di gravidanza negativo entro 7 giorni prima dell’inizio del trattamento
16. Donne in età fertile devono usare due metodi contraccettivi che comprendono un metodo altamente efficace di contraccezione ed un metodo di barriera, come indicato dallo sperimentatore, durante tutto il periodo di trattamento e per almeno 24 mesi dopo il completamento del trattamento. I metodi altamente efficaci di contraccezione sono definiti come quelli che presentano un basso tasso di fallimento (meno dell’’1% all’anno) se usati in modo coerente e corretto (ad esempio impianti, iniettabili, contraccezione orale combinata, o dispositivi intra-uterini). A discrezione dello Sperimentatore, un metodo contraccettivo accettabile potrebbe includere la totale astinenza.
L’astinenza periodica (per esempio calendario, ovulazione, metodo sintotermico e metodi postovulazione) ed il coito interrotto non sono metodi contraccettivi accettabili.
17. Per pazienti di sesso maschile accordo a non donare il seme durante il trattamento con Vismodegib e per 2 mesi dopo il completamento del trattamento.
18. Per pazienti di sesso maschile con una partner di sesso femminile in età fertile, accordo all’uso del preservativo, anche dopo una vasectomia, durante i rapporti sessuali con la partner durante il trattamento con Vismodegib e per 2 mesi dopo il completamento del trattamento.
19. Accordo a non donare sangue o prodotti del sangue durante lo studio e per almeno 24 mesi dopo il completamento del trattamento (Vismogedib).

E.4

Principal exclusion criteria

1. Inability or unwillingness to swallow capsules
2. Inability or unwillingness to comply with study procedures
3. Pregnancy or lactation (lactation not allowed for at least 24 months after completion of study treatment)
4. Concurrent non–protocol-specified anti-tumor therapy (e.g., chemotherapy, other targeted therapy, photodynamic therapy, including participation in an experimental drug study)
5. Metastatic BCC
6. Gorlin Syndrome or any other contraindication to radiotherapy
7. Recent (i.e., within the past 28 days prior to enrollment in this study) or current participation in another experimental drug study
8. Uncontrolled medical illness, including advanced malignancies, at the discretion of the Investigator
9. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of the study or renders the patient at high risk for treatment complications
10. Known hypersensitivity to Vismodegib or any of the excipients
11. Patients in treatment with St. John’s Wort (Hypericum perforatum)

1. Incapacità o riluttanza a inghiottire la capsule
2. Incapacità o riluttanza a rispettare le procedure dello studio
3. Gravidanza o allattamento (allattamento non consentito per almeno 24 mesi dopo il completamento del trattamento)
4. Concomitante terapia antitumorale non specificata da protocollo (per esempio chemioterapia, altra terapia mirata, terapia fotodinamica, inclusa la partecipazione ad uno studio interventistico con farmaco sperimentale)
5. Carcinoma basocellulare metastatico
6. Sindrome Gorlin o ogni altra controindicazione alla radioterapia
7. Recente (per esempio entro 28 giorni dall’arruolamento nello studio) o concomitante partecipazione ad un’altra sperimentazione clinica
8. Disturbo medico incontrollato, inclusi tumori avanzati, a discrezione dello Sperimentatore
9. Storia di altre malattie, disfunzioni metaboliche, referti di esami fisici o referti clinici di laboratorio che diano il ragionevole sospetto di una malattia o condizione per cui è controindicato l’uso del farmaco sperimentale o che potrebbero impattare sull’interpretazione dei risultati dello studio o esporre il paziente ad un elevato rischio di complicazioni.
10. Ipersensibilità nota a Vismodegib o ad uno qualsiasi degli eccipienti.
11. Pazienti in trattamento con Erba di San Giovanni (Hypericum perforatum).

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients progression-free at 12 months.

Percentuale di pazienti liberi da progressione a 12 mesi.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

12 mesi

E.5.2

Secondary end point(s)

progression free survival (PFS)

sopravvivenza libera da progressione (PFS)

E.5.2.1

Timepoint(s) of evaluation of this end point

14 months from enrollment of LPI

14 mesi dall'arruolamento del LPI

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

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.8.5.1

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

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

Yes

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

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)

The subjects, at the end of the participation in the trial, will be followed according to the normal clinical practice

I pazienti al termine della sperimentazione saranno seguiti in accordo alla normale pratica clinica.

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

2016-09-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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