| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BRAF V600E-mutant Non-small Cell Lung Cancer |
| Carcinoma polmonare non a piccole cellule positivo alla mutazione BRAFV600E |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-small Cell Lung Cancer |
| Carcinoma polmonare non a piccole cellule |
|
| 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 | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 encorafenib + binimetinib in patients with BRAFV600-mutant NSCLC as measured by ORR |
| Valutare l'efficacia di encorafenib + binimetinib in pazienti con NSCLC positivo alla mutazione BRAFV600 misurata tramite ORR |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of encorafenib + binimetinib in patients with BRAFV600E-mutant NSCLC as measured by DOR, DCR and PFS
- To evaluate the efficacy of encorafenib + binimetinib with respect to OS
- To evaluate the safety and tolerability of encorafenib + binimetinib in patients with BRAFV600E-mutant NSCLC, Although very rare in NSCLC, patients with other V600 Class 1 BRAF mutations (e.g., K or D) are also allowed |
-Valutare l'efficacia di encorafenib + binimetinib in pazienti con NSCLC positivo alla mutazione BRAFV600E misurata tramite DOR (Duration Of Response), DCR (Disease Control Rate) e PFS (Progression-Free Survival)
-Valutare l’efficacia di encorafenib + binimetinib rispetto all’OS (Overall Survival)
-Valutare la sicurezza e la tollerabilità di encorafenib + binimetinib in pazienti con NSCLC positivo alla mutazione BRAFV600E, Benché molto rari nel NSCLC, sono ammessi anche pazienti con altre mutazioni BRAF V600 di Classe 1 (ad es. K o D). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to provide written informed consent. Adult patients under guardianship may participate with the consent of their legally authorized guardian if permitted by local regulations.
2. Age = 18 years at the time of informed consent.
3. Histologically confirmed diagnosis of NSCLC that is currently Stage IV (M1a, M1b or M1c - AJCC 8th edition).
4. Presence of a BRAFV600E mutation in tumor tissue or blood (e.g.,ctDNA genetic testing) as determined by a local laboratory assay, Other Class 1 BRAFv600 mutations (e.g., K or D) will be permitted with prior discussion with the Array Medical Monitor.
5. The Investigator must obtain prior to enrollment that the patient has adequate tumor tissue for submission to a central laboratory for confirmation of BRAFV600 mutation status
6. Patients who are either treatment-naïve (e.g., no prior systemic therapy for advanced/metastatic disease), OR who have received 1) first-line platinum-based chemotherapy OR 2) first-line treatment with an anti-PD-1/PD-L1 inhibitor platinum-based chemotherapy, or in combination with immunotherapy (e.g., ipilimumab) with or without given alone or in combination with platinum-based chemotherapy.given alone or in combination with platinum-based chemotherapy.
7. Presence of measurable disease based on RECIST v1.1.
8. ECOG performance status of 0 or 1.
9. Adequate bone marrow function characterized by the following at screening: a. ANC = 1.5 × 109/L;
b. Platelets = 100 × 109/L;
c. Hemoglobin = 8.5 g/dL (with or without blood transfusions).
10. Adequate hepatic and renal function characterized by the following at screening: a. Total bilirubin = 1.5 × ULN ; b. ALT and AST = 2.5 × ULN, or = 5 × ULN in presence of liver metastases; c. Serum creatinine = 1.5 × ULN; or calculated creatinine clearance >= 50 mL/min by Cockcroft-Gault formula; or estimated glomerular filtration rate > 50 mL/min/1.73m2.
11. Able to swallow, retain and absorb oral medications.
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
13. Female patients of childbearing potential as described in Appendix 1, must have a negative serum ß-HCG test result. 14. Female patients of childbearing potential must agree to use methods of contraception that are highly effective or acceptable, as described in Appendix 1, and to not donate ova from Screening until 30 days after the last dose of study treatment.
14. Female patients of childbearing potential must agree to use methods of contraception that are highly effective or acceptable, as described in Appendix 1, and to not donate ova from Screening until 30 days after the last dose of study treatment.
15. Male patients must agree to use methods of contraception that are highly effective or acceptable, as described in Appendix 1, and to not donate sperm from Screening until 90 days after the last dose of study drug. |
1. Capacità di fornire il consenso informato scritto. I pazienti adulti sotto tutela possono partecipare previo consenso del proprio tutore legale autorizzato, se consentito dalle normative locali.
2. Età = 18 anni al momento dell’ottenimento del consenso informato.
3. Diagnosi di NSCLC attualmente in Stadio IV (M1a, M1b, M1c secondo il manuale AJCC 8a edizione) confermata istologicamente.
4. Presenza di una mutazione BRAFV600E nel tessuto tumorale o nel sangue (ad es. test genetico su ctDNA) confermata mediante analisi di laboratorio locale. Altre mutazioni BRAFv600 di Classe 1 (ad es. K o D) saranno consentite previa discussione con il medical monitor di Array.
5. Lo Sperimentatore dovrà ottenere, prima dell'arruolamento, del tessuto tumorale adeguato da inviare a un laboratorio centrale per la conferma dello stato mutazionale di BRAFV600.
6. Pazienti naïve al trattamento (ovvero che non hanno ricevuto nessuna precedente terapia sistemica per malattia in stadio avanzato/metastatica) O che hanno ricevuto 1) chemioterapia di prima linea a base di platino O 2) trattamento di prima linea con un inibitore anti-PD-1/PD-L1 somministrato in monoterapia o in combinazione con chemioterapia a base di platino o in combinazione con l’immunoterapia (ad es. ipilimumab) con o senza chemioterapia a base di platino..
7. Presenza di malattia misurabile in base ai criteri RECIST v1.1.
8. Stato di performance ECOG 0 o 1.
9. Funzionalità del midollo osseo adeguata caratterizzata allo screening da:
a. ANC = 1,5 × 109/l;
b. Piastrine = 100 × 109/l;
c. Emoglobina = 8,5 g/dl (con o senza trasfusioni di sangue).
10. Funzionalità epatica e renale adeguate caratterizzate allo screening da:
a. Bilirubina totale = 1,5 × ULN
b. ALT e AST = 2,5 × ULN o = 5 × ULN in presenza di metastasi epatiche;
c. Creatinina sierica = 1,5 × ULN; o clearance della creatinina calcolata mediante formula di Cockcroft-Gault >= 50 ml/min; o velocità di filtrazione glomerulare stimata
> 50 ml/min/1,73 m2.
11. Capacità di deglutire, trattenere e assorbire farmaci orali.
12. Volontà e capacità di attenersi alle visite programmate, al programma di trattamento, ai test di laboratorio e alle altre procedure dello studio.
13. Le pazienti di sesso femminile in età fertile, come descritto nell'Appendice 1, devono ottenere un risultato negativo al test ß-HCG su siero.
La lista completa dei criteri di inclusione è visibile sul protocollo |
|
| E.4 | Principal exclusion criteria |
1. Patients who have documentation of any of the following: EGFR mutation, ALK fusion oncogene or ROS1 rearrangement.
2. Patients who have received more than 1 prior line of systemic therapy in the advanced/metastatic setting.
3. Previous treatment with any BRAF inhibitor (e.g., dabrafenib, vemurafenib, XL281/BMS-908662, etc.), or any MEK inhibitor (e.g., trametinib, cobimetinib, selumetinib, RDEA119, etc.) prior to screening and enrollment.
4. Receipt of anticancer medications or investigational drugs within the following intervals before the first administration of study treatment: a. = 14 days for chemotherapy, targeted small-molecule therapy, radiation therapy, immunotherapy, or antineoplastic biologic therapy (e.g., erlotinib, crizotinib, bevacizumab, etc.). b. = 14 days or 5 half-lives (minimum of 14 days) for investigational agents or devices. For investigational agents with long half-lives (e.g., > 5 days), enrollment before the fifth half-life requires medical monitor approval.
c. Palliative radiation therapy must be complete 7 days prior to the first dose of study treatment.
5. Patients who have had major surgery (e.g., inpatient procedure with regional or general anesthesia) = 6 weeks prior to start of study treatment.
6. Patient has not recovered to = Grade 1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting study treatment.
7. Current use of a prohibited medication (including herbal medications, supplements or foods), as described in Section 6.5.2, or use of a prohibited medication = 1 week prior to the start of study treatment.
8. Impairment of gastrointestinal function or disease which may significantly alter the absorption of oral study treatment (e.g., uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, small bowel resection).
9. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) = 6 months prior to start of study treatment;
b. Congestive heart failure requiring treatment (New York Heart Association Grade = 2);
c. LVEF < 50% as determined by MUGA or ECHO;
d. Uncontrolled hypertension defined as persistent systolic blood pressure = 150 mmHg or diastolic blood pressure = 100 mmHg despite optimal therapy;
e. History or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
f. Triplicate average baseline QTcF interval = 480 ms or a history of prolonged QT syndrome.
10. History of thromboembolic or cerebrovascular events = 12 weeks prior to the first dose of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents,
hemodynamically significant (i.e. massive or sub-massive) deep vein thrombosis or pulmonary emboli.
11. History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease.
12. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
13. Evidence of active, noninfectious pneumonitis
14. Evidence of HBV or HCV infection.
15. Known history of a positive test for HIV or known AIDS. Testing for HIV must be performed at sites where mandated locally.
16. Active infection requiring systemic therapy.
17. Patients with symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases are not eligible.
Please refer to Protocol for full list of exclusion criteria |
1. Pazienti in possesso di documentazione attestante una qualsiasi delle seguenti condizioni: mutazione dell’EGFR, oncogene di fusione di ALK o riarrangiamento di ROS1.
2. Pazienti che hanno ricevuto più di 1 linea di terapia sistemica precedente in un contesto di stadio avanzato/metastatico. Le terapie precedenti possono essere valutate con il medical monitor di Array.
3. Precedente trattamento con qualsiasi inibitore di BRAF (ad es. dabrafenib, vemurafenib, XL281/BMS-908662, ecc.) o qualsiasi altro inibitore di MEK (ad es. trametinib, cobimetinib, selumetinib, RDEA119, ecc.) prima dello screening e dell'arruolamento.
4. Assunzione di farmaci antitumorali o sperimentali entro i seguenti intervalli temporali precedenti la prima somministrazione del trattamento in studio:
a. = 14 giorni per chemioterapia, terapia mirata a piccole molecole, radioterapia, immunoterapia o terapia biologica antineoplastica (ad esempio erlotinib, crizotinib, bevacizumab, ecc.).
b. = 14 giorni o 5 emivite (minimo 14 giorni) per agenti o dispositivi sperimentali. Per gli agenti sperimentali a lunga emivita (ad es. > 5 giorni), l'arruolamento prima della quinta emivita richiede l'approvazione del medical monitor.
c. La radioterapia palliativa deve essere completata nei 7 giorni precedenti la somministrazione della prima dose del trattamento in studio.
5. Pazienti che hanno subito un intervento chirurgico importante (ad es. procedura in regime di ricovero con anestesia locale o generale) = 6 settimane prima dell'inizio del trattamento in studio.
6. Paziente che non mostra remissione a grado = 1 degli effetti tossici della terapia precedente e/o delle complicazioni dell’intervento chirurgico prima dell’inizio del trattamento in studio.
7. Uso attuale di farmaci vietati (inclusi farmaci, integratori o alimenti erboristici), come descritto nella Sezione 6.5.2 o uso di un farmaco vietato entro = 1 settimana prima dell'inizio del trattamento in studio.
8. Compromissione della funzionalità gastrointestinale o malattia che possa alterare significativamente l'assorbimento del trattamento orale in studio (ad esempio nausea, vomito o diarrea non controllati; sindrome da malassorbimento; resezione dell'intestino tenue).
9. Compromissione della funzionalità cardiovascolare o malattie cardiovascolari clinicamente significative, comprese le seguenti:
a. Anamnesi di infarto miocardico acuto, sindromi coronariche acute (tra cui angina instabile, innesto di bypass coronarico, angioplastica coronarica o stenting) = 6 mesi prima dell'inizio del trattamento in studio;
b. Insufficienza cardiaca congestizia che necessita di trattamento (grado della New York Heart Association = 2);
c. LVEF < 50% (Left Ventricular Ejection Fraction) come stabilito mediante scansione MUGA o ECHO;
Fare riferimento al Protocollo per la lista completa dei criteri di esclusione |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR defined as the proportion of patients who have achieved a confirmed best overall response (CR or PR) as determined by Investigator review of radiographic disease assessments per RECIST v1.1 |
| ORR definito come la percentuale di pazienti che hanno ottenuto una migliore risposta globale confermata (CR o PR) come stabilito mediante revisione da parte dello Sperimentatore delle valutazioni radiografiche della malattia secondo i criteri RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the time of review of radiographic disease assessments per RECIST v1.1 |
| Al momento della revisione delle valutazioni radiografiche della malattia secondo RECIST v1.1 |
|
| E.5.2 | Secondary end point(s) |
a) DOR defined as the time from the date of the first documented response (CR or PR) to the earliest date of disease progression, as determined by Investigator review of radiographic disease assessments per RECIST v1.1, or death due to any cause
b) DCR defined as the proportion of patients who have achieved a confirmed best overall response of CR, PR or SD, as determined by Investigator review of radiographic disease assessments per RECIST v1.1
c) PFS defined as the time from the date of first dose of study drug to the earliest date of disease progression, as determined by Investigator review of radiographic disease assessments per RECIST v1.1, or death due to any cause ¿
d) OS defined as the time from the date of first dose of study drug to the date of death due to any cause
e) Incidence and severity of AEs graded according to the NCI CTCAE v4.03 and changes in clinical laboratory
parameters, vital signs, ECGs and ECHO/MUGA scans |
a. DOR definita come il tempo dalla data della prima risposta documentata (CR o PR) fino alla prima data della progressione della malattia, stabilita mediante revisione da parte dello Sperimentatore delle valutazioni radiografiche della malattia secondo i criteri RECIST v1.1, o decesso per qualsiasi causa
b. DCR definito come la percentuale di pazienti che hanno ottenuto una migliore risposta globale confermata di CR, PR o SD, come stabilito mediante revisione da parte dello Sperimentatore delle valutazioni radiografiche della malattia secondo i criteri RECIST v1.1
c. PFS definita come il tempo dalla data della prima dose di farmaco in studio fino alla prima data della progressione della malattia, stabilita mediante revisione da parte dello Sperimentatore delle valutazioni radiografiche della malattia secondo i criteri RECIST v1.1, o decesso per qualsiasi causa
d.OS, definita come il tempo dalla prima dose di farmaco in studio fino alla data di decesso per qualsiasi causa
e. Incidenza e gravità degli AE classificati secondo i criteri CTCAE del NCI v4.03 e variazioni dei parametri clinici di laboratorio, funzioni vitali, ECG e scansioni ECHO/MUGA |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) At the time of review of radiographic disease assessments per RECIST v1.1, or death due to any cause
b) At the time of review of radiographic disease assessments per RECIST v1.1
c) At the time of review of radiographic disease assessments per RECIST v1.1, or death due to any cause
d) date of death due to any cause
|
a) Al momento della revisione delle valutazioni radiografiche della malattia secondo RECIST v1.1, o decesso dovuto a qualsiasi causa
b) Al momento della revisione delle valutazioni radiografiche della malattia secondo RECIST v1.1
c) Al momento della revisione delle valutazioni radiografiche della malattia secondo RECIST v1.1, o decesso dovuto a qualsiasi causa
d) data del decesso dovuto a qualsiasi causa |
|
| 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 | 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| United States |
| Belgium |
| Italy |
| Netherlands |
| Spain |
|
| 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 end of study will occur 2 years after treatment initiation of the last enrolled patient or the point at which all patients have died or withdrawn consent or have been lost to follow up, whichever occurs first. At the end of the study, access to study treatment will be provided in accordance with applicable regulations and requirements to all patients who have not met the protocol-defined criteria for treatment withdrawal. |
La fine dello studio sarà definita come 2 anni dall'inizio del trattamento dell'ultimo paziente arruolato o il momento in cui tutti i pazienti siano deceduti, abbiano ritirato il consenso o siano stati persi al follow-up, a seconda dell'evento che si verifica per primo.
Alla fine dello studio, l’accesso al trattamento in studio verrà fornito secondo i regolamenti e requisiti applicabili a tutti i pazienti che hanno soddisfatto i criteri definiti dal protocollo per il ritiro dal trattamento. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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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