| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed medulloblastoma characterised by Hedgehog (Hh)-pathway activation |
| Medulloblastoma in recidiva con via di segnalazione di Hedgehog (Hh) attivata |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed medulloblastoma characterised by Hedgehog (Hh)-pathway activation |
| Medulloblastoma in recidiva con via di segnalazione di Hedgehog (Hh) attivata |
|
| 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 | 10066594 |
| E.1.2 | Term | Medulloblastoma recurrent |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess efficacy of LDE225 with respect to the Overall Response Rate (ORR) according to independent central review (ICR) |
| Confrontare l’efficacia di LDE225 versus TMZ rispetto al tasso di risposta globale (ORR) in base a una revisione centralizzata indipendente (ICR). |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the efficacy of LDE225 with respect to: - ORR according to local investigator assessment - Progression free survival (PFS) according to both ICR and local investigator assessment - Duration of response (DoR) according to both ICR and local investigator assessment - Overall survival (OS) To further characterize the safety and tolerability of LDE225 treatment To further characterize the pharmacokinetics of LDE225 and any relevant metabolites |
| •Confrontare l’efficacia di LDE225 versus TMZ rispetto al ORR e alla PFS in base alla ICR e alla valutazione locale da parte dello sperimentatore •Valutare l’efficacia di ciascun trattamento sulla durata della risposta (DoR) in base alla ICR e alla valutazione locale da parte dello sperimentatore Valutare l’effetto di ciascun trattamento sulla sopravvivenza globale (OS). •Caratterizzare ulteriormente la sicurezza d’impiego e la tollerabilità di ciascun trattamento •Caratterizzare ulteriormente la farmacocinetica di LDE225 e di qualsiasi metabolita rilevante |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| - Patients aged >= 4 months - Patients with histologically confirmed diagnosis of MB, who have experienced relapse or progression - Only patients with a test result, using the 5-gene Hh signature assay, indicating Hh-pathway activated MB are eligible for this study. - At least one measurable lesion - Adequate renal function - Adequate liver function - Adequate bone marrow function - Serum CK <= 1.5 ULN Other protocol defined inclusion criteria may apply. |
| - Pazienti di età > 4 mesi. - Pazienti con diagnosi istologica confermata di medulloblastoma che ha manifestato recidiva o progressione dopo terapia standard. - Solo i pazienti che, utilizzando il test “5-gene Hh signature”, presentano un risultato indicativo di medulloblastoma con via di Hh attivata sono eleggibili. - Presenza di almeno una lesione misurabile - Funzionalità renale adeguata - Funzionalità renale adeguata - Funzionalità midollare adeguata - Livelli sierici di CK < 1,5 x ULN. Altri criteri di inclusione applicabili sono listati nel protocollo |
|
| E.4 | Principal exclusion criteria |
| - Systemic anticancer treatment within 2 weeks before first dose of study treatment - Focal radiation therapy within 4 weeks before first dose of study treatment, or full spinal radiotherapy within 3 months before first dose of study treatment. - Patients who have neuromuscular disorders that are associated with elevated CK - Any concurrent severe and/or uncontrolled medical conditions that in the investigator's opinion could put the patient at greater risk for treatment-related toxicities or confound the interpretation of clinical outcomes. - Impaired cardiac function - Clinically significant heart disease - Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B or C - Impairment of GI function or GI disease - Major surgery, serious illness, or traumatic injury within 2 weeks of first dose of study treatment. - Unresolved toxicity greater than CTCAE grade 1 from previous anticancer therapy - Patients anticipated to require major surgery within the first 8 weeks of treatment - Patients who require a nasogastric tube for drug administration - Patients on concomitant treatment with drugs that are recognized to cause rhabdomyolysis - Patients receiving treatment with medications that are known to be strong inhibitors or inducers of CYP3A4/5 or are metabolized by CYP2B6 and CYP2C9. - Patients receiving unstable or increasing doses of corticosteroids - Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be discontinued at least 2 weeks before first dose of study treatment, and for the duration of the study - Investigational agents within 4 weeks or ≤ 5 x t1/2 (whichever is longer) before first dose of study treatment. - Pregnant females. - Patients who are not willing to apply highly effective contraception. - Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. Other protocol defined exclusion criteria may apply. |
| - Trattamento antitumorale sistemico nelle 2 settimane precedenti la somministrazione della prima dose del trattamento in studio _ Radioterapia focale nelle 4 settimane precedenti la somministrazione della prima dose del trattamento in studio o radioterapia spinale completa nei 3 mesi precedenti la somministrazione della prima dose del trattamento in studio. - Pazienti con patologie neuromuscolari associate ad aumento della CK Pazienti con qualsiasi condizione clinica concomitante grave e/o non controllata che, secondo l’opinione dello sperimentatore, possa esporre il paziente a un rischio elevato di sviluppare tossicità correlate al trattamento o compromettere l’interpretazione dei risultati clinici. - Compromissione della funzionalità cardiaca - Diagnosi nota di infezione da virus HIV, virus dell’epatite B o C -- Compromissione della funzionalità gastrointestinale (GI) - Interventi chirurgici maggiori, patologie serie o traumi nelle 2 settimane precedenti la somministrazione della prima dose del trattamento in studio. - Tossicità non risolte di grado CTCAE superiore a 1 della precedente terapia antitumorale o della radioterapia. - Pazienti che debbano sottoporsi a intervento chirurgico maggiore entro prime 8 settimane di trattamento. - Pazienti che necessitano sondino naso-gastrico per la somministrazione del farmaco. - Pazienti in trattamento attuale con farmaci noti per essere forti inibitori o induttori di CYP3A4/5 o che sono metabolizzati da CYP2B6 e CYP2C9 - Pazienti in trattamento con dosi non stabili o incrementali di corticosteroidi - Pazienti in trattamento con qualsiasi antiepilettico induttore enzimatico (Appendice 2) che non può essere sospeso almeno 2 settimane prima della somministrazione della prima dose del trattamento in studio e per tutta la durata dello studio - Farmaci sperimentali entro le 4 settimane o < 5 x t1/2 (qualunque sia più lungo) prima della prima dose del trattamento in studio. - Donne in gravidanza - Pazienti che non sono disposti a utilizzare un metodo contraccettivo di elevata efficacia - Pazienti che hanno intenzione di iniziare attività fisica intensa – dopo la somministrazione della prima dose del trattamento in studio. Altri criteri di inclusione applicabili sono listati nel protocollo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR). |
| ORR definita come la porzione di pazienti con la miglior risposta complessiva (risposta completa o risposta parziale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| every 8 weeks |
| ogni 8 settimane |
|
| E.5.2 | Secondary end point(s) |
| - PFS (progression free survival) - DoR (duration of response) - OS (overall survival) - Adverse and serious adverse events, clinically significant changes in hematology and chemistry values, assessment of physical and/or neurological examinations, vital signs, electrocardiograms, bone x-rays, dental x-rays, and dental exams (as appropriate for age) - PK (Cmin) |
| - PFS (sopravvivenza libera da progressione) - DoR (durata della risposta) - Sopravvivenza complessia - Eventi avversi e eventi avversi gravi, modifiche clinicamente rilevanti dei parametri ematologici e chimici, valutazione delgli esami fisici e/o neurologici, segni vitali, ECG, radiografie ossee e dentali e esami dentali (secondo l'età) - PK (Cmin) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Efficacy endpoint: Every 8 weeks. Adverse events: continuously. PK: every other week during the first 8 weeks of treatment |
Endpoint di efficacia: ogni 8 settimmne
Eventi avversi: continuamente
PK: ogni due settimane durante le prime otto settimane di trattamento |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| Israel |
| Russian Federation |
| Switzerland |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 48 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 48 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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