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    Summary
    EudraCT Number:2010-022629-14
    Sponsor's Protocol Code Number:CLDE225A2201
    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:2012-03-06
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2010-022629-14
    A.3Full title of the trial
    A phase II, randomized double-blind study of efficacy and safety of two dose levels of LDE225 in patients with locally advanced or metastatic basal cell carcinoma
    Studio randomizzato, in doppio cieco, di Fase II, di valutazione dell'efficacia e della sicurezza d'impiego di due livelli di dosaggio di LDE225 somministrati in pazienti con carcinoma a cellule basali in stadio localmente avanzato o metastatico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of LDE225 in patients with locally advanced or metastatic basal cell carcinoma
    Efficacia e sicurezza di LDE225 in pazienti con carcinoma a cellule basali in stadio localmente avanzato o metastatico
    A.3.2Name or abbreviated title of the trial where available
    BOLT
    BOLT
    A.4.1Sponsor's protocol code numberCLDE225A2201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01327053
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNOVARTIS FARMA
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNOVARTIS FARMA
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressLargo Umberto Boccioni, 1
    B.5.3.2Town/ cityORIGGIO
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number02-96541
    B.5.5Fax number02-9659066
    B.5.6E-mailinfo.studiclinici@novartis.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNA
    D.3.2Product code LDE225
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNA
    D.3.9.1CAS number 1218778-77-8
    D.3.9.2Current sponsor codeLDE225
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    locally advanced or metastatic basal cell carcinoma
    carcinoma a cellule basali in stadio localmente avanzato o metastatico
    E.1.1.1Medical condition in easily understood language
    A type of skin cancer in an advanced stage
    Un tipo di tumore della pelle in uno stadio avanzato
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10066495
    E.1.2Term Basal cell carcinoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of LDE225 as measured by Objective Response Rate (ORR) in patients with locally advanced or metastatic basal cell carcinoma.
    Valutare l`€™efficacia di LDE225, somministrato una volta al giorno, misurando il tasso di risposta obiettiva (ORR), in base ai criteri RECIST 1.1 (vedi Appendice 1, Linee-guida di Novartis, basate sui criteri RECIST), in pazienti con carcinoma a cellule basali in stadio localmente avanzato o metastatico.
    E.2.2Secondary objectives of the trial
    1. To asses the time to tumor response (TTR) i.e. partial response (PR) or complete response (CR) associated with 800 mg and 200 mg dose LDE225 therapy. 2. To assess duration of overall response (DoR), i.e. partial response (PR) or complete response (CR) associated with 800 mg and 200 mg dose LDE225 therapy. 3. To assess the effect of LDE225 therapy on progression-free survival (PFS). 4. To assess the effect of LDE225 therapy on overall survival (OS). 5. To characterize the safety of LDE225 therapy. 6. To further characterize the pharmacokinetics of LDE225 by measuring trough (Cmin) plasma concentrations of LDE225.
    •Valutare il tempo alla risposta tumorale (TTR) ossia il tempo alla risposta parziale (PR) o completa (CR) associata alla terapia con LDE225. •Valutare la durata della risposta globale (DoR) ossia la durata della risposta parziale (PR) o completa (CR) associata alla terapia con LDE225. •Valutare l`€™effetto della terapia con LDE225 sulla sopravvivenza libera da progressione (PFS). •Valutare la sopravvivenza globale (OS) associata alla terapia con LDE225. •Caratterizzare ulteriormente la sicurezza della terapia con LDE225. •Caratterizzare ulteriormente la farmacocinetica di LDE225 misurando le concentrazioni plasmatiche trough (Cmin) di LDE225.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age 18 years or older 2. Patient with locally advanced BCC or metastatic BCC 3. WHO performance status `‰¤ 2 4. Patients with adequate bone marrow, liver and renal function 5. Written informed consent obtained prior to any screening procedures Other protocol defined inclusion criteria may apply
    1.Pazienti di eta' &gt; 18 anni. 2.Pazienti con BCC in stadio localmente avanzato o BCC metastatico: oPazienti con diagnosi confermata istologicamente di BCC in stadio localmente avanzato che non siano canditati alla radioterapia o all`€™intervento chirurgico curativo. I pazienti con BCC in stadio localmente avanzato devono presentare malattia misurabile, definita dalla presenza di almeno una lesione che puo' essere misurata in modo accurato in almeno una dimensione (&gt; 10 mm) alla RMN o mediante fotografie a colori. oI pazienti con diagnosi confermata istologicamente di BCC metastatico devono presentare malattia misurabile, definita dalla presenza di almeno una lesione non nodulare che puo' essere misurata in modo accurato in almeno una dimensione (non inferiore al doppio dello spessore della sezione o a 10 mm) alla TAC spirale o alla RMN oppure una lesione nodulare (ad es: linfonodo) &gt; 15 mm nell`€™asse breve misurata mediante TAC o RMN (indipendentemente dallo spessore della sezione). Le lesioni ossee litiche o le lesioni miste litiche-blastiche con componente di tessuto molle identificabile che possono essere valutate mediante TAC/RMN possono essere considerate lesioni misurabili. Nota: Le lesioni in aree precedentemente irradiate possono solo essere considerate misurabili se hanno mostrato chiara evidenza di progressione dal momento della radioterapia, come documentato nella cartella clinica. 3.WHO performance status &lt; 2. 4.Funzionalita' del midollo osseo, epatica e renale adeguata definita da: oANC &gt; 1,5 x 109/L oEmoglobina &gt; 9 g/dL oPiastrine &gt; 80 x 109/L oBilirubina totale &lt; 1,5 x ULN oALT/SGOT &lt; 2,5 x ULN o &lt; 5 x ULN se sono presenti metastasi epatiche oCreatinfosfochinasi (CPK) &lt; 1,5 x ULN oCreatininemia &lt; 1,5 x ULN oppure clearance della creatinina delle 24 ore &gt; 50 ml/min. 5.Consenso informato scritto ottenuto prima di qualsiasi procedura di screening.
    E.4Principal exclusion criteria
    1. Patients who have had major surgery within 4 weeks of initiation of study medication. 2. Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data. 3. Patients unable to take oral drugs or with lack of physical integrity of the upper gastrointestinal tract or known malabsorption syndromes. 4. Patients who have previously been treated with systemic LDE225 or with other Hh pathway inhibitors.5. a) Patients who have neuromuscular disorders or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis and that cannot be discontinued at least 2 weeks prior to starting LDE225 treatment. b) Patients who are planning on embarking on a new strenuous exercise regimen after initiation of study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided whilst on LDE225 treatment. 6. Patients who have taken part in an experimental drug study within 4 weeks of initiating treatment with LDE225. 7. Patients who are receiving other anti-neoplastic therapy concurrently or within 2 weeks of starting treatment with LDE225. 8. Patients who are receiving treatment with medications known to be moderate and strong inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have narrow therapeutic index, and that cannot be discontinued before starting treatment with LDE225. Medications that are strong CYP3A4/5 inhibitors should be discontinued at least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to starting treatment with LDE225. 9. Pregnant or nursing (lactating) women 10. Women of child-bearing potential unless they are using two forms of highly effective contraception 11. Fertile males not willing to use condoms. 12. Patients unwilling or unable to comply with the protocol. Other protocol defined exclusion criteria may apply
    1.Pazienti sottoposti a intervento chirurgico maggiore nelle 4 settimane precedenti l`€™inizio della somministrazione del trattamento in studio. 2.Qualsiasi condizione medica concomitante non controllata che possa interferire con la partecipazione del paziente allo studio o influire sull`€™interpretazione dei risultati. 3.Pazienti che non possono assumere farmaci per via orale o con patologie del tratto gastrointestinale superiore o sindrome da malassorbimento nota. 4. Pazienti sottoposti a trattamento precedente con LDE225 o altri inibitori della via di segnalazione Hedgehog. 5.A) Pazienti con disturbi neuromuscolari (ad es: miopatie infiammatorie, distrofia muscolare, sclerosi laterale amiotrofica, atrofia muscolare spinale) o in trattamento concomitante con farmaci noti per causare rabdomiolisi, quali: inibitori di HMG-CoA reduttasi (statine), clofibrato e gemfibrozil e che non possono sospendere tale trattamento almeno 2 settimane prima dell`€™inizio della somministrazione di LDE225. Se fosse necessario per il paziente proseguire il trattamento con statine per il controllo dell`€™iperlipidemia (vedi Sezione 5.1.7.5 del protocollo per maggiori dettagli), puo' essere usata solo la pravastatina, ma con estrema cautela. B) Pazienti che intendono sottoporsi a esercizio fisico intenso dopo l`€™inizio del trattamento in studio. NB: Le attivita' muscolari come l`€™esercizio fisico intenso, possono determinare aumenti rilevanti dei livelli plasmatici di CPK, pertanto devono essere evitate durante il trattamento con LDE225. 6.Pazienti sottoposti a terapia con farmaci sperimentali nelle 4 settimane precedenti l`€™inizio della somministrazione del trattamento con LDE225. 7.Pazienti in trattamento con altra terapia antineoplastica (ad es: chemioterapia, terapie mirate o radioterapia) o sottoposti a tale trattamento nelle 2 settimane precedenti l`€™inizio della somministrazione del trattamento con LDE225. 8.Pazienti in trattamento con forti inibitori o induttori noti del CYP3A4/5 o che sono metabolizzati dal CYP2B6 e dal CYP2C9 e che hanno un basso indice terapeutico e non possono essere sospesi prima di iniziare il trattamento con LDE225 (vedi Sezione 5.1.7 del protocollo per maggiori dettagli). I farmaci forti inibitori del CYP3A4/5 devono essere sospesi almeno 7 giorni prima dell`€™inizio del trattamento con LDE225, mentre i farmaci forti induttori del CYP3A/5 devono essere sospesi almeno 2 settimane prima. 9.Gravidanza e allattamento. La gravidanza viene definita dal momento successivo al concepimento fino al termine della gestazione, confermata dalla presenza di positivita' del test hCG nel siero (&gt; 5 mIU/mL). 10. Donne potenzialmente fertili comprese le donne il cui orientamento sessuale non precluda un rapporto sessuale con un partner maschile e donne i cui partner siano stati sottoposti a sterilizzazione mediante vasectomia o altri metodi, a meno che non usino due forme di contraccezione di efficacia elevata per l`€™intera durata dello studio e nei 3 mesi successivi alla somministrazione dell`€™ultima dose del trattamento in studio. Inoltre, l`€™astinenza totale dai rapporti sessuali deve essere considerata un metodo contraccettivo di efficacia elevata. 11. Pazienti di sesso maschile fertili che non desiderano utilizzare il preservativo per l`€™intera durata dello studio e nei 3 mesi successivi alla somministrazione dell`€™ultima dose del trattamento in studio. 12. Pazienti che non possono o non desiderano aderire alle procedure in studio. Per maggiori dettagli consultare le Sezioni 4.1 e 4.2 del protocollo originale.
    E.5 End points
    E.5.1Primary end point(s)
    Objective response rate (ORR) according to RECIST 1.1
    •L`€™endpoint primario dello studio e' il tasso di risposta obiettiva (ORR) valutato in base ai criteri RECIST 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary analysis will occur when all patients have been treated for 24 weeks or have discontinued
    L`€™analisi primaria per la valutazione dell`€™efficacia del trattamento con LDE225 si basera' sul tasso di risposta obiettiva ORR in tutti i pazienti che sono stati trattati per 24 settimane o hanno interrotto il trattamento
    E.5.2Secondary end point(s)
    Time to tumor response (TTR) Duration of overall response (DoR) Progression-free survival (PFS) Overall survival (OS) Frequency and severity of adverse events, new or worsened laboratory results and other safety data from other tests (e.g. electrocardiogram or vital signs) PK (Cmin, steady-state trough concentration)
    •Tempo alla risposta del tumore (TTR). •Durata della risposta del tumore (DoR) •Sopravvivenza libera da progressione (PFS) •Sopravvivenza globale (OS) •Incidenza e gravita' degli eventi avversi, valori degli esami di laboratorio e di altri dati di sicurezza (ECG o segni vitali) alterati o peggioramento rispetto alle misurazioni precedenti. •Concentrazione trough allo steady state (Cmin).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Analysis will occur when all patients have been treated for 24 weeks or have discontinued
    L`analisi degli end-point secondari e' prevista quando tutti i pazienti sono stati trattati per 24 settimane o hanoo
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    - Stesso farmaco ad altro dosaggio
    - same IMP used at different dosage
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    Switzerland
    United States
    E.8.7Trial has a data monitoring committee Yes
    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
    LPLS
    LPLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months30
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months30
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 85
    F.4.2.2In the whole clinical trial 120
    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)
    Expected normal treatment of that condition
    Trattamento secondo quanto previsto per questa condizione
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-11-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-07-25
    P. End of Trial
    P.End of Trial StatusCompleted
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