| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable locally advanced or metastatic melanoma |
| MELANOMA METASTATICO O LOCALMENTE AVANZATO NON RESECABILE, |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced melanoma |
| melanoma avanzato |
|
| 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 | 10025669 |
| E.1.2 | Term | Malignant melanoma stage II |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of atezo + cob+ vem compared with placebo +cobi +vem |
| valutare l'efficacia di atezo + cob+ vem rispetto a placebo +cobi +vem |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of atezo+ cobi +vem compared with placebo+ cobi +vem using objective response rate, duration of response, overall survival, change in quality of life, health reported outcomes and global health status.
To evaluate the safety of atezolizumab + cobimetinib + vemurafenib compared to placebo + cobimetinib + vemurafenib.
To evaluate the pharmacokinetics of atezolizumab, cobimetinib and vemurafenib and cobimetinib and vemurafenib when administered together. |
valutare l'efficacia di atezo + cob+ vem rispetto a placebo +cobi +vem usando il tasso di risposta obiettiva, durata della risposta, sopravvivenza globale, cambiamento di qualità di vita, risultati riferiti sulla salute e stato di salute globale.
Per valutare la sicurezza di atezolizumab + cobimetinib + vemurafenib rispetto al placebo + cobimetinib + vemurafenib.
Per valutare la farmacocinetica di atezolizumab, cobimetinib e vemurafenib e cobimetinib e vemurafenib quando somministrati insieme. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Signed informed consent form
- Women and men, age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma, as defined by the American Joint
Committee on Cancer, 7th revised edition
- Measurable disease, according to response evaluation criteria in solid tumours (RECIST), v1.1
- Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first dose of study drug treatment, with the exception of amylase, lipase, and LDH where
up to 28 days is acceptable (using central laboratory result)
– Amylase and lipase <= 1.5 x ULN
–Absolute neutrophil count (ANC) >= 1.5 × 10 exp9/L
–Platelet count >= 100 × 10 exp9/L
–Hemoglobin >= 9 gram (g)/decilitre (dL)
–Albumin >= 2.5 g/dL
–Bilirubin <= 1.5 × the upper limit of normal (ULN)
- AST and ALT = 2.0×ULN
- ALP = 2.5×ULN or, for patients with documented liver or bone metastases, ALP = 5×ULN
-Patients with documented liver or bone metastases: alkaline phosphatase <= 5 × ULN
–Serum creatinine <= 1.5 × ULN or creatinine clearance (CrCl) >= 40 mL/min on the basis of measured CrCl from a 24-hour urine collection or
Cockroft-Gault glomerular filtration rate estimation: (140-age) x (weight in kg) x (0.85 if female) 72 x (serum creatinine in milligram/dL)
- Ability and capacity to comply with the study and follow-up procedure
- For patients not receiving therapeutic anticoagulation: INR or aPTT =
1.5×ULN within 28 days prior to initiation of study treatment
- For patients receiving therapeutic anticoagulation: stable anticoagulant
regimen and stable INR during the 28 days immediately preceding initiation of study treatment
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method
with a failure rate of <1% per year during the treatment period and for 6 months after the last dose of study treatment. Women must refrain from
donating eggs during this same period.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm |
• Firma del modulo di consenso informato
• Uomini e donne di età >= 18 anni
• Performance status sulla scala ECOG (Eastern Cooperative Oncology Group) 0 o 1
• Melanoma di stadio IV (metastatico) o stadio IIIc non resecabile (localmente avanzato) confermato istologicamente, secondo la definizione dell’American Joint Committee on Cancer, 7a edizione
• Malattia misurabile in base ai criteri RECIST v1.1
• Adeguata funzione ematologica, epatica e renale, definita in base ai valori degli esami di laboratorio riportati di seguito ottenuti nei 14 giorni precedenti l’inizio del trattamento in studio, con l’eccezione di amilasi, lipasi e LDH dove è accettabile un risultato fino a 28 giorni prima ( utilizzando gli esiti del laboratorio centralizzato )
– Amilasi e lipasi <= 1,5 x ULN
– ANC >= 1.5 × 10 exp9/L
– Conta piastrinica >= 100 × 10 exp9/L
– Emoglobina >= 9 gram (g)/decilitre (dL)
– Albumina sierica >= 2.5 g/dL
– Bilirubina totale <= 1.5 × ULN
– AST e ALT <= 2.0 x ULN
- ALP <= 2,5 ¿ ULN o, per i pazienti con metastasi epatiche o ossee documentate, ALP ¿ 5 ¿ ULN
- pazienti con metastasi epatiche o ossee documentate, ALP ¿ 5 ¿ ULN
– Creatinina sierica <= 1.5 × ULN o clearance della creatinina (CrCl) >= 40 ml/min sulla base della CrCl misurata con la raccolta delle urine nelle 24 ore o con la stima della velocità di filtrazione glomerulare determinata con la formula di Cockcroft-Gault: CrCl= (140 - età) x (peso in kg) x (0.85 per le donne) /72 x (creatinina sierica in mg/dl)
• Capacità di seguire il protocollo dello studio secondo il giudizio dello sperimentatore
• Per i pazienti non sottoposti a terapia anticoagulante: INR o aPTT <= 1,5 x ULN nei 28 giorni precedenti l’inizio del trattamento in studio
• Per i pazienti sottoposti a terapia anticoagulante: regime anticoagulante stabile e INR stabile nei 28 giorni immediatamente precedenti l’inizio del trattamento in studio
• Per donne in età fertile: accettazione a praticare l’astinenza (astenersi dai rapporti eterosessuali) o a utilizzare metodi contraccettivi con un tasso di insuccesso < 1% per anno, durante il periodo di trattamento e per 6 mesi dopo l’ultima dose del trattamento in studio. Le donne devono astenersi dal donare le uova durante lo stesso periodo.
• Per gli uomini: accettazione a praticare l’astinenza (astenersi dai rapporti eterosessuali) o a utilizzare metodi contraccettivi e accettazione ad astenersi dalla donazione di sperma |
|
| E.4 | Principal exclusion criteria |
• Major surgical procedure other than for diagnosis within 4 weeks prior
to initiation of study treatment, or anticipation of need for a major
surgical procedure during the course of the study
• Traumatic injury within 2 weeks prior to initiation of study treatment
• Palliative radiotherapy within 14 days prior to initiation of study
treatment
• Active malignancy (other than BRAFV600 mutation-positive
melanoma) or malignancy within 3 years prior to screening are
excluded, with the exception of resected melanoma, resected basal cell
carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC),
resected carcinoma in situ of the cervix, resected carcinoma in situ of
the breast, in situ prostate cancer, limited-stage bladder cancer, or any
other curatively treated malignancies from which the patient has been
disease-free for at least 3 years
• History of or evidence of retinal pathology on ophthalmologic
examination that is considered a risk factor for neurosensory retinal
detachment, central serous chorioretinopathy, retinal vein occlusion
(RVO), or neovascular macular degeneration
• History of clinically significant cardiac dysfunction, including the
following:
-Poorly controlled hypertension, defined as sustained, uncontrolled,
nonepisodic baseline hypertension consistently above 159/99 mmHg
despite |
•Intervento di chirurgia maggiore per scopi diversi da quelli diagnostici nelle 4 sett precedenti la randomizzazione o previsione della necessità di una procedura chirurgica maggiore durante lo studio
•Lesione traumatica nelle 2 sett precedenti l’inizio del trattamento in studio•Radioterapia palliativa nei 14 gg precedenti l’inizio del trattamento in studio •Neoplasia maligna attiva (diversa dal melanoma positivo alla mutazione BRAFV600) o neoplasia maligna nei 3 anni precedenti lo screening sono esclusi, ad eccezione del melanoma resecato, del basalioma resecato, del carcinoma squamoso della pelle resecato, del carcinoma in situ della cervice uterina resecato, del carcinoma in situ della mammella resecato, del carcinoma prostatico in situ, del carcinoma della vescica in stadio limitato o ogni altra neoplasie maligne trattate in modo curativo per la quale il paziente è libero dalla malattia per almeno 3 anni •Positività anamnestica per patologia retinica o sua evidenza all’esame oculistico, che sia considerata un fattore di rischio per il distacco della retina neurosensoriale, per la corioretinopatia sierosa centrale, per l’occlusione della vena retinica (RVO) o per la degenerazione maculare neovascolare
•Positività anamnestica per disfunzione cardiaca clinicamente significativa, compresi:
- Ipertensione controllata male, definita come sostenuta, incontrollata, l'ipertensione non basale della linea basale a livelli superiori a 159/99 mmHg
nonostante la gestione medica ottimale
•Lesioni a carico del SNC (meningite carcinomatosa) non trattate o in progressione attiva
•Positività anamnestica per metastasi al tronco encefalico, al mesencefalo, al ponte o al midollo oppure nel raggio di 10 mm dall’apparato visivo (nervi ottici e chiasma)
•Positività anamnestica per metastasi leptomeningea |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PFS, defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to
RECIST v1.1, or death from any cause, whichever occurs first |
| •PFS, definita come tempo trascorso dalla randomizzazione alla prima progressione della malattia, determinata dallo sperimentatore con i criteri RECIST v1.1 o al decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| When 300 PFS events have occurred |
| Quando 300 eventi PFS si sono verificati |
|
| E.5.2 | Secondary end point(s) |
| ¿PFS, defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first ¿Objective response, defined as a CR or PR on two consecutive occasions = 4 weeks apart, as determined by the investigator according to RECIST v1.1 ¿DOR, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first ¿OS, defined as the time from randomization to death from any cause ¿2-year landmark survival, defined as survival at 2 years ¿Time to deterioration in global health status, defined as the time from randomization to first observed = 10 point decrease in EORTC QLQ-C30 linearly transformed global health status scale score that is sustained for two consecutive assessments or followed by death while the patient is on treatment Time to deterioration in physical functioning, defined as the time from randomization to first observed =10 point decrease in EORTC QLQ-C30 linearly transformed physical functioning scale score that is sustained for two consecutive assessments or followed by death while the patient is on treatment |
| ¿ PFS, definita come tempo trascorso dalla randomizzazione alla prima progressione della malattia, determinata dall¿IRC secondo i criteri RECIST v1.1 o al decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo ¿ Risposta obiettiva, definita come CR o PR in due occasioni consecutive ¿ a 4 settimane di distanza, determinata dallo sperimentatore con i criteri RECIST v1.1 ¿ DOR, definita come tempo trascorso dalla prima evidenza di risposta obiettiva documentata alla progressione della malattia (determinata dallo sperimentatore secondo i criteri RECIST v1.1) o al decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo ¿ OS, definita come tempo trascorso dalla randomizzazione al decesso per qualsiasi causa ¿ Sopravvivenza a 2 anni, definita come sopravvivenza a 2 anni ¿ Tempo al peggioramento dello stato di salute generale, definito come tempo trascorso dalla randomizzazione alla prima riduzione osservata di >= 10 punti sulla scala EORTC QLQ-C30 mantenuta per due valutazioni consecutive o seguita da decesso mentre il paziente ¿ in trattamento ¿ Tempo al peggioramento delle funzionalit¿ fisiche, definito come tempo trascorso dalla randomizzazione alla prima riduzione osservata >= 10 punti sulla scala EORTC QLQ-C30 funzionalit¿ fisiche trasformata in modo lineare, mantenuta per due valutazioni consecutive o seguita da decesso mentre il paziente ¿ in trattamento |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| OS ¿ analysis will be performed when approximately 385 deaths have occurred |
| OS - l'analisi verr¿ effettuata quando si saranno verificati circa 385 decessi |
|
| 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 | 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 | 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Korea, Republic of |
| New Zealand |
| Russian Federation |
| Austria |
| Belgium |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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
|
| The study will end when all patients enrolled have been followed until death, withdrawal of consent, lost to follow-up, or the Sponsor decides to end the trial, whichever occurs first. see protocol section 3.2 |
| Lo studio terminer¿ quando tutti i pazienti arruolati saranno stati sottoposti a follow-up fino a decesso, ritiro del consenso, perdita al follow-up oppure fino a quando lo sponsor non decida di terminare la sperimentazione, a seconda di quale evento si verifichi per primo, come indicato nella sezione 3.2 del protocollo. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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