| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic melanoma |
| Melanoma metastatico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic melanoma, a type of skin cancer |
| Melanoma metastatico, un tipo di tumore della pelle |
|
| 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 | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| 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 establish the superiority of dabrafenib and trametinib combination therapy with vemurafenib monotherapy with respect to overall survival (OS) for subjects with advanced/metastatic BRAF V600E/K mutationpositive cutaneous melanoma. |
| L’obiettivo primario di questo studio a due bracci di trattamento e' dimostrare la superiorita' della terapia di associazione dabrafenib-trametinib rispetto alla terapia con vemurafenib per quanto riguarda la sopravvivenza globale (OS) nei soggetti con melanoma cutaneo avanzato/metastatico positivo per la mutazione BRAF V600E/K. |
|
| E.2.2 | Secondary objectives of the trial |
| • To compare dabrafenib and trametinib combination therapy over vemurafenib monotherapy with respect to progression-free survival (PFS) for subjects with advanced/metastatic BRAF V600E/K mutationpositive cutaneous melanoma. • To compare dabrafenib and trametinib combination therapy over vemurafenib monotherapy with respect to overall response rate (ORR). • To compare dabrafenib and trametinib combination therapy over vemurafenib monotherapy with respect to duration of response • To characterize the safety of dabrafenib and trametinib combination therapy, including incidences of squamous cell carcinoma (SCC) and other proliferative cutaneous lesions; |
| •Valutare e confrontare la terapia di associazione dabrafenib-trametinib versus vemurafenib in termini di sopravvivenza libera da progressione (PFS),tasso globale di risposta (ORR) e durata della risposta;•Determinare la sicurezza della terapia di associazione dabrafenib-trametinib,compresa l’incidenza di carcinoma a cellule squamose (SCC) e di altre patologie dermoproliferative |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Subjects eligible for enrolment in the study must meet all of the following criteria: 1. ≥ 18 years of age. 2. Signed written informed consent. 3. Histologically confirmed cutaneous melanoma that is either Stage IIIC XML File Identifier: PaOVXzSLcR9K+4UsEWL0NAFeSdU= Page 26/41 (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID™ BRAF Assay. The assay will be tested in a central reference laboratory. Subjects with ocular or mucosal melanoma are not eligible. 4. Measurable disease (i.e., present with at least one measurable lesion per RECIST, version 1.1. Refer to Section 7.2.3.1 of the Protocol for the definition of a measurable lesion. 5. All prior anti-cancer treatment-related toxicities (except alopecia) must be ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; National Cancer Institute ( NCI) 2009) at the time of randomization. 6. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. 7. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception, as defined in Section 7.3.3 of the Protocol, throughout the treatment period, and for 30 days after the last dose of study treatment. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in Section 7.3.3 of the protocol from 14 days prior to administration of the first dose of study treatment, throughout the treatment period, and for 16 weeks after the last dose of study treatment. 8. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 [Oken 1982]. Refer to Appendix 1 of the protocol for details. 9. Adequate baseline organ function as defined in Table 2 (see inclusion criteria within the Protocol). 10. Subjects enrolled in France: In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category. |
| 3. Eta' 18 anni. Consenso informato scritto firmato. Diagnosi istologica di melanoma cutaneo allo stadio IIIC (non resecabile) o allo stadio IV (metastatico) e con positivita' per le mutazioni BRAF V600E/K, determinata con il saggio bioMerieux (bMx) per uso esclusivamente sperimentale (investigational use only, IUO) THxID BRAF Assay (IDE: G120011). Il saggio diagnostico delle mutazioni tumorali sara' effettuato da un laboratorio di riferimento centralizzato. Non sono eleggibili i soggetti con melanoma oculare o mucoso. Malattia misurabile (≥1 lesione misurabile secondo i criteri RECIST, versione 1.1). Alla randomizzazione, eventuali effetti tossici di pregresse terapie antineoplastiche (tranne l’alopecia) devono essere di Grado CTCAE 1 (Common Terminology Criteria for Adverse Events, versione 4.0; Il paziente deve essere in grado di assumere (deglutire e trattenere) farmaci orali e non presentare alterazioni gastroenteriche significative che possano compromettere l’assorbimento (ad es. sindrome da malassorbimento o importanti resezioni gastriche o intestinali). Le donne in eta' fertile devono presentare un test di gravidanza negativo, eseguito nei 14 giorni precedenti la randomizzazione, e accettare di utilizzare un metodo contraccettivo efficace per tutta la durata della terapia dello studio e per i 30 giorni successivi all’assunzione dell’ultima dose. Anche gli uomini con partner femminili in eta' fertile, se non vasectomizzati, devono accettare di utilizzare un metodo contraccettivo efficace, iniziando 14 giorni prima della randomizzazione e continuando per tutta la durata della terapia dello studio e per 16 settimane dopo l’ultima dose. Performance status ECOG (Eastern Cooperative Oncology Group) pari a 0 o 1. Si veda all’Appendice 1 del protocollo per i dettagli. Funzionalita' adeguata dei vari organi al basale. |
|
| E.4 | Principal exclusion criteria |
| Subjects meeting any of the following criteria must not be enrolled in the study: 1. Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119). 2. Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed. (Note: Ipilimumab treatment must end at least 8 weeks prior to randomization.) 3. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomization. 4. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomization. 5. Current use of a prohibited medication as described in Section 6.2 of Protocol. 6. History of another malignancy. Exception: Subjects who have been disease-free for 3 years, (i.e. subjects with second malignancies that are indolent or definitively treated at least 3 years ago) or subjects with a history of completely XML File Identifier: PaOVXzSLcR9K+4UsEWL0NAFeSdU= Page 27/41 resected non-melanoma skin cancer. 7. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures. 8. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed). 9. A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency. 10. Brain metastasis are excluded unless: a. All known lesions were previously treated with surgery or stereotactic surgery (whole-brain radiation is not allowed unless given after definitive treatment with surgery or stereotactic surgery), AND b. Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for ≥ 12 weeks prior to randomization (stability must be confirmed with two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, AND c. Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to randomization, AND d. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to randomization In addition, for subjects that had brain metastases but currently have no evidence of disease (NED), NED for ≥12 weeks is required and must be confirmed by two consecutive scans, separated by ≥6 weeks, prior to randomization. 11. A history or evidence of cardiovascular risk including any of the following: |
| Terapie pregresse con BRAF-inibitori o MEK-inibitori -Pregresse terapie antineoplastiche sistemiche per il melanoma di stadio IIIC (non resecabile) o di stadio IV(metastatico). Sono consentite pregresse terapie adiuvanti sistemiche. -Interventi chirurgici maggiori, radioterapia estesa, chemioterapia a tox ritardata, farmaci biologici o immunoterapia nei 21 giorni precedenti la randomizzazione, e/o chemioterapia quotidiana o settimanale senza potenziale tox ritardata, nei 14 giorni precedenti la rand. -Assunzione di un farmaco sperimentale nei 28 giorni precedenti la randomizzazione o entro un periodo di 5 emivite del farmaco prima della randomizzazione -Terapia in atto con farmaci non consentiti dal protocollo. -Anamnesi positiva per altre neoplasie. -Patologie internistiche preesistenti gravi o instabili, patologie psichiatriche o altre condizioni che possono compromettere la sicurezza del soggetto, la firma del consenso informato o l’aderenza alle procedure dello studio. -Infezione diagnosticata da virus dell’ HIV, virus HBV o HCV -Deficit da G6PD -Le metastasi cerebrali sono motivo di esclusione tranne nei seguenti casi: a.Lesioni note asportate chirurgicamente o mediante chirurgia stereotassica b.Lesioni cerebrali, se ancora presenti, che si siano confermate stabili per ≥12 settimane prima della randomizzazione c.Lesioni asintomatiche che non richiedono la terapia corticosteroidea per ≥4 settimane prima della randomizzazione; d.Nessuna terapia anticonvulsivante che causi induzione enzimatica per ≥4 settimane prima della randomizzazione -Anamnesi positiva o evidenze di rischio cardiovascolare -Anamnesi positiva o segni clinici/rischio di occlusione venosa retinica (retinal vein occlusion, RVO) o CSR, -Fattori predisponenti per RVO o CSR -Patologie retiniche visibili diagnosticate mediante oftalmoscopia e considerate fattori di rischio per RVO o CSR -Ipersensibilita' nota, immediata o ritardata, o allergia a farmaci chimicamente correlati ai farmaci dello studio, ai loro eccipienti e/o al dimetil-sulfossido (DMSO). -Allattamento al seno |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • To establish the superiority of dabrafenib and trametinib combination therapy with vemurafenib monotherapy with respect to overall survival (OS) for subjects with advanced/metastatic BRAF V600E/K mutationpositive cutaneous melanoma. |
| L’obiettivo primario di questo studio a due bracci di trattamento e' dimostrare la superiorita' della terapia di associazione dabrafenib-trametinib rispetto alla terapia con vemurafenib per quanto riguarda la sopravvivenza globale (OS) nei soggetti con melanoma cutaneo avanzato/metastatico positivo per la mutazione BRAF V600E/K. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| •Overall survival (OS; defined as the time from randomization until death due to any cause). |
| sopravvivenza globale; definito come l’intervallo intercorso tra la randomizzazione e la morte per tutte le cause |
|
| E.5.2 | Secondary end point(s) |
| •To evaluate and compare dabrafenib and trametinib combination therapy versus vemurafenib with respect to progression-free survival (PFS), overall response rate (ORR) and duration of response; • To characterize the safety of dabrafenib and trametinib combination therapy, including incidences of squamous cell carcinoma (SCC) and other proliferative skin diseases; Safety parameters to be measured: • Safety as measured by clinical assessments including vital signs and physical examinations, 12-lead electrocardiograms (ECG), echocardiogram (ECHO), chemistry and hematology laboratory values, and adverse events (AEs). |
| • Confrontare la terapia di associazione dabrafenib-trametinib rispetto alla monoterapia con vemurafenib in termini di sopravvivenza libera da progressione (PFS), per soggetti con melanoma cutaneo metastatico/avanzato BRAF positivo. • Valutare la terapia di combinazione dabrafenib e trametinib rispetto alla monoterapia con vemurafenib • Confrontare la terapia di associazione dabrafenib-trametinib rispetto alla monoterapia con vemurafenib in termini di durata della risposta. • Determinare la sicurezza dell’associazione dabrafenib-trametinib, compresa l’incidenza di carcinoma a cellule squamose (SCC) e di altre lesioni dermoproliferative; |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| • Progression-free survival (PFS; defined as the time from randomization until the earliest date of disease progression or death due to any cause) • Overall response rate (ORR; defined as the percentage of subjects with a confirmed or unconfirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], • Duration of response (defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among subjects who achieve an overall response [i.e., confirmed or unconfirmed CR or PR]). |
| • sopravvivenza libera da progressione (PFS; definita come tempo intercorso tra la randomizzazione e la prima data di progressione di malattia o la morte per tutte le cause) • Tasso globale di risposta (ORR; definito come % soggetti con risposta completa [complete response, CR] confermata o non confermata, o risposta parziale [partial response, PR], valutata in qualsiasi momento secondo i criteri RECIST [Response Evaluation Criteria in Solid Tumors], versione 1.1 [Eisenhauer, 2009]). • Durata della risposta (definita come tempo intercorso tra la prima evidenza documentata di CR o PR fino alla progressione di malattia o alla morte per tutte le cause nei soggetti che hanno ottenuto una risposta globale [CR o PR confermata o non confermata]). |
|
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarker testing |
| Test dei biomarcatori |
|
| 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 | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| . |
| vemurafenib (Zelboraf®) |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Israel |
| Korea, Democratic People's Republic of |
| Korea, Republic of |
| New Zealand |
| Russian Federation |
| Ukraine |
| United States |
|
| E.8.7 | Trial 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
|
| Last Subject Last Visit |
| Ultima visita dell'ultimo paziente |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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 |
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