E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with Previously Untreated, Unresectable or Metastatic Melanoma
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Melanoma metastatico non precedentemente trattato e non resecabile |
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E.1.1.1 | Medical condition in easily understood language |
Melanoma |
Melanoma metastatico |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025671 |
E.1.2 | Term | Malignant melanoma stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025670 |
E.1.2 | Term | Malignant melanoma stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to compare the incidence of drug-related Grade 3 - 5 AEs of nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg to nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg in treatmentnaive subjects with unresectable or metastatic melanoma. |
L¿obiettivo principale ¿ confrontare l¿incidenza di eventi avversi di Grado 3 - 5 correlati al farmaco di nivolumab 3 mg/kg in combinazione con ipilimumab 1 mg/kg con nivolumab 1 mg/kg in combinazione con ipilimumab 3 mg/kg in soggetti na¿ve al trattamento affetti da melanoma non resecabile o metastatico |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the objective response rate (ORR), as determined by investigators, of nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg and nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg in treatment-naive subjects with unresectable or metastatic melanoma. -To evaluate progression free survival (PFS) of nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg and nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg in treatment-naive subjects with unresectable or metastatic melanoma. -To assess overall survival (OS) -To assess Health Related Quality of Life (HRQoL) using the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30). |
Valutare il tasso di risposta oggettiva (objective response rate, ORR), come determinato dagli sperimentatori, di nivolumab 3 mg/kg in combinazione con ipilimumab 1 mg/kg e nivolumab 1 mg/kg in combinazione con ipilimumab 3 mg/kg in soggetti na¿ve al trattamento affetti da melanoma non resecabile o metastatico. ¿ Valutare la sopravvivenza libera da progressione (progression-free survival, PFS) di nivolumab 3 mg/kg in combinazione con ipilimumab 1 mg/kg e nivolumab 1 mg/kg in combinazione con ipilimumab 3 mg/kg in soggetti na¿ve al trattamento affetti da melanoma non resecabile o metastatico. ¿ Valutare la sopravvivenza globale (overall survival, OS). ¿ Valutare la qualit¿ di vita correlata alla salute (Health Related Quality of Life, HRQoL) tramite il questionario sulla qualit¿ della vita dell¿Organizzazione europea per la ricerca e il trattamento del cancro (European Organisation for Research and Treatment of Cancer Quality of life questionnaire ¿ EORTC QLQ-C30).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Adult subjects (>=18 years) with histologically confirmed unresectable Stage III or Stage IV Melanoma as per AJCC staging system. -Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 -No prior systemic anticancer therapy for unresectable or metastatic melanoma. Prior adjuvant or neoadjuvant melanoma therapy ispermitted if it was completed at least 6 weeks prior to date of first dose, and all related adverse events have either returned to baseline or stabilized. -Measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST) criteria -Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. In order to be randomized, a subject must be classified as PD-L1 positive, PD-L1 negative, or PD-L1 indeterminate. If an insufficient amount of tumor tissue from an unresectable or metastatic site is available prior to the start of the screening phase, subjects must consent to allow the acquisition of additional tumor tissue for performance of biomarker analyses. -Known BRAF V600 mutation status as determined by local institutional standard or subject to consent to BRAF V600 mutation testing per local institutional standards during the Screening Period, the results of which must be reported within 3 months of randomization. All BRAF statuses (BRAF wild-type or BRAF 600 mutation positive) are eligible. |
Soggetti adulti (18 anni) con melanoma non resecabile istologicamente confermato allo stadio III o stadio IV, come determinato dal sistema di stadiazione dell’AJCC. • Stato della performance secondo la scala del Gruppo Cooperativo Orientale dell’Oncologia (Eastern Cooperative Oncology Group, ECOG) pari a 0 o 1. • Nessuna precedente terapia antitumorale sistemica per il melanoma non resecabile o metastatico. È consentita una precedente terapia adiuvante o neoadiuvante per il trattamento del melanoma, sempre che sia stata completata almeno nelle 6 settimane precedenti alla data della prima dose e tutti i correlati eventi avversi siano ritornati ai livelli basali oppure si siano stabilizzati. • Malattia misurabile secondo i criteri di valutazione della risposta nei tumori solidi (RECIST) versione 1.1. • Deve essere fornito del tessuto tumorale dal sito di malattia non resecabile o metastatico per le analisi sui biomarcatori. Al fine di essere randomizzato, un soggetto deve essere classificato come PD-L1 positivo, PD-L1 negativo o PD-L1 indeterminato. Se è disponibile solo una quantità insufficiente di tessuto tumorale da un sito non resecabile o metastatico prima di iniziare la fase di screening, i soggetti devono fornire il loro consenso per concedere l’acquisizione di tessuto tumorale aggiuntivo, al fine di eseguire le analisi sui biomarcatori. • Stato mutazionale noto di BRAF V600 come determinato dal principio istituzionale locale oppure il soggetto deve dare il consenso all’analisi mutazionale BRAF V600 in accordo ai principi istituzionali locali durante il periodo di screening. I risultati dell’analisi devono essere comunicati entro i 3 mesi successivi alla randomizzazione. Sono idonei tutti gli stati mutazionali BRAF (BRAF wild-type o positività alla mutazione BRAF 600).
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E.4 | Principal exclusion criteria |
- Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated and there is no evidence of progression via magnetic resonance imaging (MRI, except where contraindicated in which CT scan is acceptable) for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. -Ocular melanoma -Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll |
• Metastasi cerebrali o leptomeningee attive. I soggetti con metastasi cerebrali sono idonei se sono stati trattati e non c’è evidenza di progressione tramite risonanza magnetica per imaging (RMI, eccetto se controindicato nel cui caso la TC è accettabile) per almeno 8 settimane dopo il completamento del trattamento ed entro i 28 giorni precedenti la somministrazione della prima dose di farmaco in studio. Non sono neanche richieste dosi elevate di corticosteroidi sistemici che potrebbero comportare immunosoppressione (> 10 mg/die di equivalenti del prednisone) per almeno 2 settimane prima della somministrazione del farmaco in studio. • Melanoma oculare. • Soggetti affetti da malattia autoimmune attiva, nota o sospetta. È consentito l’arruolamento di soggetti con vitiligine, diabete mellito di tipo I, ipotiroidismo residuo dovuto a una condizione autoimmune che richieda soltanto terapia ormonale sostitutiva, psoriasi che non richieda un trattamento sistemico o condizioni di cui non si prevede la recidiva in assenza di un fattore scatenante esterno.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the incidence of drug-related Grade 3 - 5 AEs. |
L’endpoint primario è l’incidenza di eventi avversi di Grado 3 - 5 correlati al farmaco. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 6 months from the first dose of study treatment |
Dopo 6 mesi dalla prima dose di trattamento |
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E.5.2 | Secondary end point(s) |
-To evaluate the objective response rate (ORR), as determined by investigators, of nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg and nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg in treatment-naive subjects with unresectable or metastatic melanoma. -To evaluate progression free survival (PFS) of nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg and nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg in treatment-naive subjects with unresectable or metastatic melanoma. -To assess overall survival (OS) -To assess Health Related Quality of Life (HRQoL) using the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30). |
1) Valutare il tasso di risposta oggettiva (objective response rate, ORR), come determinato dagli sperimentatori, di nivolumab 3 mg/kg in combinazione con ipilimumab 1 mg/kg e nivolumab 1 mg/kg in combinazione con ipilimumab 3 mg/kg in soggetti na¿ve al trattamento affetti da melanoma non resecabile o metastatico. 2) Valutare la sopravvivenza libera da progressione (progression-free survival, PFS) di nivolumab 3 mg/kg in combinazione con ipilimumab 1 mg/kg e nivolumab 1 mg/kg in combinazione con ipilimumab 3 mg/kg in soggetti na¿ve al trattamento affetti da melanoma non resecabile o metastatico. 3) Valutare la sopravvivenza globale (overall survival, OS). 4) Valutare la qualit¿ di vita correlata alla salute (Health Related Quality of Life, HRQoL) tramite il questionario sulla qualit¿ della vita dell¿Organizzazione europea per la ricerca e il trattamento del cancro (European Organisation for Research and Treatment of Cancer Quality of life questionnaire ¿ EORTC QLQ-C30).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-After 6 months from the first dose of study treatment -The first date of documented progression -After 6 months from the first dose of study treatment -After 6 months from the first dose of study treatment |
1) Dopo 6 mesi dalla prima dose di trattamento 2) Prima data di progressione documentata 3) Dopo 6 mesi dalla prima dose di trattamento 4)Dopo 6 mesi dalla prima dose di trattamento
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity Assessments, Biomarker Assessments, Outcomes Research Assessments |
Valutazione di Immunogeneticit¿, dei Biomarker e Valutazioni di Outcome Research |
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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) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Dosaggi differente della stessa combinazione di farmaci |
different dosage of the same combination of drugs |
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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 | 2 |
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 | 45 |
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 | Information not present in EudraCT |
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 |
Canada |
Israel |
Russian Federation |
United States |
Denmark |
France |
Germany |
Italy |
Netherlands |
Poland |
Spain |
United Kingdom |
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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
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Last follow-up visit of the last patient |
L¿ultima visita di follow-up dell¿ultimo paziente |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 9 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |