Clinical Trials Register

Summary
EudraCT Number:	2011-000195-34
Sponsor's Protocol Code Number:	MO25616
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-12-28
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

2011-000195-34

A.3

Full title of the trial

A single arm, open-label, phase II, multicentre study to assess the safety of vismodegib (GDC-0449) in patients with locally advanced or metastatic basal cell carcinoma (BCC).

Studio multicentrico, a braccio singolo, in aperto, di fase II volto a valutare la sicurezza di vismodegib (GDC-0449) in pazienti affetti da carcinoma basocellulare (BCC) localmente avanzato o metastatico.

A.3.1

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

A single arm, open-label, phase II, multicentre study to assess the safety of vismodegib (GDC-0449) in patients with locally advanced or metastatic basal cell carcinoma (BCC).

A.4.1

Sponsor's protocol code number

MO25616

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	ROCHE
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	F.Hoffmann-La Roche Ltd.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Roche S.p.A
B.5.2	Functional name of contact point	Ethics & Administrative Trial Unit
B.5.3	Address:
B.5.3.1	Street Address	Viale G.B. Stucchi, 110
B.5.3.2	Town/ city	Monza
B.5.3.3	Post code	20900
B.5.3.4	Country	Italy
B.5.4	Telephone number	039 247 5055
B.5.5	Fax number	039 247 5085
B.5.6	E-mail	ITALY.INFO_CTA@ROCHE.COM

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	No
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.3.2	Product code	GDC-0449
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Vismodegib
D.3.9.1	CAS number	879085-55-9
D.3.9.2	Current sponsor code	GDC-0449
D.3.9.3	Other descriptive name	Hedgehog Pathway Inhibitor
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	150
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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

Locally advanced or metastatic basal cell carcinoma (BCC).

Carcinoma basocellulare (BCC) localmente avanzato o metastatico

E.1.1.1

Medical condition in easily understood language

Locally advanced or metastatic basal cell carcinoma (BCC).

Carcinoma basocellulare (BCC) localmente avanzato o metastatico

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	14.1
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 assess the safety of vismodegib (GDC-0449) in patients with locally advanced or metastatic BCC.

Valutare la sicurezza di vismodegib (GDC-0449) in pazienti affetti da BCC localmente avanzato o metastatico.

E.2.2

Secondary objectives of the trial

- To assess the overall response (according to RECIST Version 1.1) in those patients with measurable disease as permitted by local regulatory requirement. - To assess other efficacy parameters such as time to response, duration of response, progression-free survival and overall survival.

- Valutare la risposta complessiva (in base ai criteri RECIST, versione 1.1) nei pazienti con malattia misurabile, ai sensi dei requisiti normativi locali. - Valutare altri parametri di efficacia, quali tempo alla risposta, durata della risposta, sopravvivenza libera da progressione e sopravvivenza complessiva.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written, signed informed consent. 2. Age ≥ 18 years. 3. Eastern Cooperative Oncology Group (ECOG)Performance Status of 0, 1 or 2. 4. For patients with metastatic BCC, histologic confirmation of distant BCC metastasis. 5. For patients with locally advanced BCC, at least one histologically confirmed lesion 10 mm or more in diameter and written confirmation from a surgical specialist that the tumor is considered inoperable or that surgery is contraindicated. Examples of medical contraindications to surgery include but are not limited to: • BCC that has recurred in the same location after two or more surgical procedures and curative resection is deemed unlikely. • 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). 6. For patients with locally advanced BCC, radiotherapy must have been previously administered for locally advanced BCC, unless radiotherapy is contraindicated or inappropriate (e.g., hypersensitivity to radiation due to genetic syndrome such as Gorlin syndrome, limitations because of location of tumor, or cumulative prior radiotherapy dose). For patients whose locally advanced BCC has been irradiated, disease must have progressed after radiation. 7. Patients with Gorlin syndrome may enroll in this study but must meet the criteria for locally advanced or metastatic disease listed above. 8. Patients with measurable and/or non-measurable disease (as defined by RECIST Version 1.1) are allowed. 9. Adequate organ function, as evidenced by the following laboratory results: • Hemoglobin > 8.5 g/dL. • Granulocyte count ≥ 1000/μL. • Platelet count ≥ 75,000/μL. • AST and ALT ≤ 3 × the upper limit of normal (ULN). • Total bilirubin ≤ 1.5 × the ULN or within 3 × the ULN for patients with documented Gilbert syndrome. 10. Fertile men and women must use two highlyeffective methods of contraception during treatment and for at least 7 months after completion of treatment as directed by their physician. Highlyeffective 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 (for example implants, injectables, combined oral contraception or intra-uterine devices), please refer to Appendix 2 for more detail. At the discretion of the investigator, acceptable methods of contraception may include total abstinence. [Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.] 11. For male patients with female partners of childbearing potential, agreement to use a condom, and to advise their female partner to use an additional method of contraception during the study and for 7 months after discontinuation of vismodegib (GDC-0449). 12. Agreement not to donate blood or blood products during the study and for at least 7 months after discontinuation of vismodegib (GDC-0449); for male patients, agreement not to donate sperm during the study and for at least 7 months after discontinuation of vismodegib (GDC-0449). 13. Life expectancy > 12 weeks. 14. Negative serum pregnancy test within 96 hours prior to commencement of dosing in premenopausal women. Women of nonchildbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year.

1.Firma per iscritto del consenso informato. 2.Età ≥ 18 anni. 3.Punteggio del performance status (PS) secondo l'Eastern Cooperative Oncology Group (ECOG) di 0, 1 o 2. 4.Per i pazienti con BCC metastatico, la conferma istologica di metastasi a distanza del BCC. 5.Per i pazienti con BCC localmente avanzato, almeno una lesione istologicamente confermata del diametro di almeno 10 mm, e conferma scritta di uno specialista in chirurgia che il tumore sia da ritenersi inoperabile o che la chirurgia sia controindicata. Tra gli esempi di controindicazioni mediche vi sono, a titolo esemplificativo e non esaustivo, i seguenti: •BCC recidivato nella stessa sede dopo due o più procedure chirurgiche e la resezione curativa è ritenuta improbabile. •Morbilità e/o deformità rilevanti derivanti dalla chirurgia (quali asportazione in parte o in toto di una struttura facciale, come naso, orecchio, palpebra; oppure necessità di amputare un arto). 6.Per i pazienti con BCC localmente avanzato, deve essere stata precedentemente effettuata radioterapia per il BCC localmente avanzato, a meno che l’utilizzo di terapie radianti sia controindicato o inappropriato (p.es. in presenza di ipersensibilità a radiazioni dovuta a una sindrome genetica come la sindrome di Gorlin, limitazioni imposte dalla localizzazione del tumore, oppure dose cumulativa della radioterapia precedente). Per i pazienti con BCC localmente avanzato sottoposto a radioterapia, la malattia deve aver mostrato una progressione dopo tale terapia. 7.I pazienti affetti da sindrome di Gorlin possono essere arruolati nello studio, ma devono soddisfare i criteri di malattia localmente avanzata o metastatica sopra specificati. 8.Sono ritenuti idonei i pazienti con malattia misurabile e/o non misurabile (definita in base ai criteri RECIST, versione 1.1). 9.Adeguata funzionalità d'organo, testimoniata dai seguenti valori di laboratorio: •Emoglobina > 8,5 g/dl •Conta dei granulociti ≥ 1000/μl. •Conta delle piastrine ≥ 75.000/μl. •AST e ALT ≤ 3 × limite superiore di normalità (ULN). •Bilirubina totale ≤ 1,5 × ULN o entro 3 × ULN per i pazienti con sindrome di Gilbert documentata. 10.Uomini e donne fertili devono utilizzare due metodi di contraccezione altamente efficaci durante il trattamento e per almeno 7 mesi dopo il suo completamento, attenendosi alle indicazioni del proprio medico. Si definiscono altamente efficaci i metodi di contraccezione che determinano un basso tasso di insuccesso (inferiore all'1% all'anno) se usati costantemente e correttamente (ad esempio impianti, contraccettivi iniettabili, contraccettivi orali combinati o dispositivi intrauterini); per maggiori informazioni consultare l'Appendice 2. L'astinenza può essere considerata, a discrezione dello sperimentatore, un metodo di contraccezione accettabile. [Astinenza periodica (calcolo dei giorni fertili e dell'ovulazione, metodo sintotermico, metodo postovulazione) e coito interrotto non sono ritenuti metodi di contraccezione accettabili]. 11.Per i pazienti di sesso maschile con partner potenzialmente fertili, impegno a utilizzare un preservativo e ad avvisare la partner di utilizzare un metodo contraccettivo aggiuntivo durante lo studio e per i 7 mesi successivi all'interruzione di vismodegib (GDC-0449). 12.Impegno a non donare sangue, né emoderivati durante lo studio e per almeno 7 mesi dopo l'interruzione di vismodegib (GDC-0449); per i pazienti di sesso maschile, impegno a non donare sperma durante lo studio e per almeno 7 mesi dopo l'interruzione di vismodegib (GDC-0449). 13. Aspettativa di vita > 12 settimane. 14. Test di gravidanza sul siero negativo nelle 96 ore precedenti l'avvio della somministrazione in donne in premenopausa. Le donne non potenzialmente fertili possono essere incluse soltanto se chirurgicamente sterili o in postmenopausa da ≥ 1 anno.

E.4

Principal exclusion criteria

1. Inability or unwillingness to swallow capsules. 2. Pregnancy or lactation. 3. Concurrent non–protocol-specified anti-tumor therapy (e.g., chemotherapy, other targeted therapy, radiation therapy, or photodynamic therapy, including participation in an experimental drug study; note that treatment breaks up to 8 weeks for radiation therapy are allowed (see Section 6.1.1)). 4. Completion of most recent anti-tumor therapy less than 21 days prior to initiation of treatment. 5. Uncontrolled medical illnesses such as infection requiring treatment with intravenous antibiotics. 6. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or renders the patient at high risk from treatment complications. 7. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol. 8. Corrected QT (QTc) interval ≥ 450 msec at baseline.

1.Incapacità o riluttanza a ingerire capsule. 2.Gravidanza o allattamento. 3.Concomitanti terapie antitumorali non specificate dal protocollo (chemioterapia, altra terapia mirata, terapia radiante o terapia fotodinamica, inclusa la partecipazione a studi con farmaci sperimentali; da notare che per la terapia radiante sono consentite pause nel trattamento fino a 8 settimane (vedere paragrafo 6.1.1)). 4.Completamento della più recente terapia antitumorale meno di 21 giorni prima dell'avvio del trattamento. 5.Patologia non controllata, come infezione che richieda un trattamento con antibiotici per via endovenosa. 6.Anamnesi di qualsiasi altra malattia, disfunzione metabolica, riscontro all’esame obiettivo o riscontro negli esami di laboratori che faccia sospettare una malattia o una condizione patologica che controindichi l’impiego di un farmaco in fase di sperimentazione, o che potrebbe interferire nell'interpretazione dei risultati dello studio, oppure ancora che porrebbe il paziente a maggior rischio di complicanze correlate al trattamento. 7.Paziente ritenuto dallo sperimentatore riluttante o incapace di soddisfare i requisiti del protocollo. 8.Intervallo QT corretto (QTc) ≥ 450 msec al basale.

E.5 End points

E.5.1

Primary end point(s)

SAFETY: Incidence, type, and severity of AEs; Incidence and nature of serious adverse events (SAEs); Incidence of AEs leading to vismodegib (GDC-0449) discontinuation or interruption; Cause of death on study (if not linked to disease progression). EFFICACY :For patients with measurable disease at baseline, tumor responses categorized according to investigator assessment following RECIST Version 1.1 as allowed by local regulatory guidelines. Information about other efficacy parameters such as time to response, duration of response, progression-free survival and overall survival will be also collected.

SICUREZZA:Incidenza, tipo e gravità degli eventi avversi (AE); Incidenza e natura degli eventi avversi gravi (SAE); Incidenza degli AE che determinano l'interruzione o la sospensione di vismodegib (GDC-0449). Causa del decesso in corso di studio (se non legato alla progressione della malattia). EFFICACIA: Per i pazienti con una malattia misurabile al basale, risposta tumorale classificata secondo il giudizio dello sperimentatore in base ai criteri RECIST, versione 1.1, ai sensi delle linee guida normative locali. Saranno inoltre raccolte informazioni su altri parametri di efficacia, quali tempo alla risposta, durata della risposta, sopravvivenza libera da progressione e sopravvivenza complessiva.

E.5.1.1

Timepoint(s) of evaluation of this end point

n.a.

E.5.2

Secondary end point(s)

n.a.

E.5.2.1

Timepoint(s) of evaluation of this end point

n.a.

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

Yes

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