E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with advanced melanoma who have received one prior immunotherapy systemic regimen for advanced disease, for whom vemurafenib/cobimetinib treatment has been scheduled by the treating physician. |
Pazienti affetti da melanoma avanzato trattati con precedente immunoterapia sistemica per patologia avanzata, ai quali la terapia con vemurafenib/cobimetinib era stata programmata dal medico curante. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with advanced melanoma who have received one prior immunotherapy systemic regimen for advanced disease, for whom vemurafenib/cobimetinib treatment has been scheduled by the treating physician |
Pazienti affetti da melanoma avanzato trattati con precedente immunoterapia sistemica per patologia avanzata, ai quali la terapia con vemurafenib/cobimetinib era stata programmata dal medico curante. |
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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 | LLT |
E.1.2 | Classification code | 10053571 |
E.1.2 | Term | Melanoma |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To evaluate the efficacy and safety profile of vemurafenib in combination with cobimetinib in advanced melanoma patients treated in the second-line setting after treatment with first-line systemic immunotherapy. The efficacy is measured as 1-year OS rate. |
Valutazione dell'efficacia e della sicurezza del trattamento di seconda linea con associazione di vemurafenib e cobimetinib nei pazienti con melanoma avanzato dopo trattamento di prima linea con immunoterapia sistemica. L'efficacia viene misurata con il tasso di OS ad 1 anno. |
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E.2.2 | Secondary objectives of the trial |
¿ PFS ¿ Objective Response Rate (ORR) ¿ Safety and toxicity of the investigational medicinal products (IMPs) ¿ Health Related Quality of Life (HRQoL) as assessed by the European Organisation for Research and Treatment of Care (EORTC) QLQ-C30 |
¿ PFS ¿ Percentuale di risposta obiettiva (ORR) ¿ Sicurezza e tossicit¿ dei prodotti medicinali in sperimentazione (IMPs) ¿ Qualit¿ della vita associata alla salute (HRQoL) secondo la valutazione dell'Organizzazione Europea per la Ricerca e la Cura del Cancro (EORTC) QLQ-C30
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Patients must have histologically confirmed, unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist 2) Patients with advanced melanoma who have received one prior immunotherapy systemic regimen for advanced disease, for whom vemurafenib/cobimetinib treatment has been scheduled by the treating physician. 3) Adjuvant treatment is allowed, except for anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 agents 4) Patients must be naïve to treatment for locally advanced unresectable or metastatic with BRAF/MEK inhibitors 5) Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue BRAF V600 mutation test 6) At least one measurable lesion according to disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria 7) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0- 2 8) Male or female patient aged = 18 years 9) Able to participate and willing to give written informed consent prior to performance of any study-related procedures and to comply with the study protocol 10) Life expectancy = 12 weeks
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1) Pazienti con melanoma metastatico di stadio IIIc o IV non resecabile confermato istologicamente secondo la definizione dell'American Joint Committee on Cancer 7ma edizione. La non resecabilità della malattia di stadio IIIc deve essere stata confermata da un chirurgo oncologo 2) Pazienti affetti da melanoma avanzato trattati con precedente immunoterapia sistemica per patologia avanzata, per i quali la terapia con vemurafenib/covimetinib era stata programmata dal medico curante. 3) Pazienti trattati con terapia adiuvante con esclusione degli agenti anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 o anti-CTLA-4. 4) Pazienti naive al trattamento con inibitori BRAF/MEK per melanoma localmente avanzato non resecabile o metastatico 5) Mutazione BRAFV600 positiva documentata nel tessuto tumorale del melanoma con l'analisi mutazionale del gene BRAF V600 6) Almeno una lesione misurabile secondo i criteri RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 7) Indice della qualità della vita secondo l'Eastern Cooperative Oncology Group (ECOG) da 0 a 2 8) Maschi o femmine di età = 18 anni 9) In grado di partecipare e di firmare il consenso informato prima che venga effettuata qualsiasi procedura collegata allo studio e che osservino il protocollo dello studio 10) Aspettativa di vita = 12 settimane |
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E.4 | Principal exclusion criteria |
1) History of any prior systemic treatment for unresectable stage IIIc or stage IV melanoma (prior anti RAF or MEK agents) other than one prior first-line immunotherapy 2) Palliative radiotherapy within 14 days prior to the first dose of study treatment 3) Major surgery or traumatic injury within 14 days prior to first dose of study treatment 4) Patients with active malignancy (other than BRAF- mutated melanoma) or a previous malignancy within the past 3 years are excluded; except for patients with resected melanoma, resected BCC, resected cutaneous SCC, resected melanoma in-situ, resected carcinoma in-situ of the cervix, and resected carcinoma in-situ of the breast Exclusion Criteria Based on Organ Function Ocular: 5) History of, or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serouschorioretinopathy (CSCR), retinal vein occlusion (RVO) or neovascularmacular degeneration 6) The risk factors for RVO are listed below. Patients will be excluded if they currently have the following conditions: a. Uncontrolled glaucoma with intra-ocular pressures =21 mmHg. b. Serum cholesterol =Grade 2 c. Hypertriglyceridemia = Grade 2 d. Hyperglycemia (fasting) =Grade 2 Cardiac: 7) History of clinically significant cardiac dysfunction, including the following: a. Current unstable angina b. Symptomatic congestive heart failure of New York Heart Association class 2 or higher c. History of congenital long QT syndrome or mean (average of triplicate measurements) QTcF = 450 msec at baseline or uncorrectable abnormalities inserum electrolytes (sodium, potassium, calcium, magnesium, phosphorus) d. Uncontrolled hypertension= Grade 2 (patients with a history hypertension controlled with anti-hypertensives to = Grade 1 are eligible). e. Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower Central Nervous System: 8) Patients with active/symptomatic CNS lesions are excluded
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1) Storia precedente di trattamento sistemico per melanoma non resecabile di stadio IIIc o IV (agenti anti RAF o MEK) diversi dall'immunoterapia di prima linea 2) Radioterapia palliativa nei 14 giorni precedenti la prima dose della terapia oggetto dello studio 3) Intervento chirurgico maggiore o danni da trauma nei 14 giorni precedenti la prima dose della terapia oggetto dello studio 4) Pazienti affetti da altri tumori maligni (diversi dal melanoma con BRAF mutato) o da un tumore maligno insorto nei 3 anni precedenti lo studio; sono inclusi i pazienti con melanoma resecato, carcinoma basocellulare (BCC) resecato, carcinoma della pelle a cellule squamose (SCC) resecato, melanoma in situ resecato, carcinoma della cervice in situ resecato, e carcinoma della mammella in situ resecato Criteri di esclusione in base alla funzionalità degli organi Occhio: 5) Storia di, o evidenza di patologie retiniche all'esame oftalmico che possono essere ritenute fattori di rischio per un distacco di retina/corioretinopatia sierosa centrale (CSCR), occlusione venosa retinica (RVO) o degenerazione maculare neovascolare 6) Qui di seguito la lista dei fattori di rischio per RVO Saranno esclusi i pazienti che presentano le condizioni seguenti: a. Glaucoma non controllato con pressione intraoculare =21 mmHg. b. Colesterolo sierico =Grado 2 c. Ipertrigliceridemia = Grado 2 d. Iperglicemia (a digiuno) =Grado 2 Cuore: 7) Storia di cardiopatie clinicamente significative che includono: a. Presenza di angina instabile b. Insufficienza cardiaca congestizia di classe 2 o superiore secondo la New York Heart Association c. Storia di sindrome congenita del QT lungo o media basale (media di tre misurazioni) del QTcF = 450 msec o elettroliti sierici anormali non correggibili (sodio, potassio, calcio, magnesio, fosforo) d. Ipertensione non controllata = Grado 2 (pazienti con storia di ipertensione controllata con antiipertensivi di Grado =1 sono eleggibili). e. Frazione di eiezione ventricolare sinistra (LVEF) al di sotto del limite inferiore della norma (LLN) o al di sotto del 50%, o comunque più bassa Sistema Nervoso Centrale: 8) Sono esclusi i pazienti con lesioni attive/sintomatiche del SNC |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be 1 year OS, and will be calculated from the first day of treatment. |
L'endpoint primario sarà una OS di 1 anno, che sarà calcolata a partire dal primo giorno di trattamento. |
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E.5.2 | Secondary end point(s) |
¿ PFS ¿ Objective Response Rate (ORR) |
¿ PFS ¿ Percentuale di risposta obiettiva (ORR) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
La percentuale di risposta obiettiva ORR e la percentuale di pazienti in vita con o senza progressione della malattia a 6, 12, 18, 24 mesi |
The objective response rate (ORR) and the percentage of patients alive with or without progression at 6, 12, 18, 24 months |
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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 | No |
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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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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Investigational treatment until progression disease |
Il trattamento è previsto fino a Progressione di Malattia |
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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 | 2 |
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 | 2 |
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 |