| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic BRAF V600 Melanoma |
| Melanoma BRAF V600 localmente avanzado o metastásico |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 assess the anti-tumor activity of LGX818/MEK162 in combination with targeted agents after progression on LGX818/MEK162 combination therapy |
| El objetivo principal de este estudio es evaluar la actividad antitumoral de LGX818/MEK162 en combinación con terceros agentes diana después de progresión con la terapia de combinación con LGX818/MEK162. |
|
| E.2.2 | Secondary objectives of the trial |
- To characterize the safety and tolerability of LGX818/MEK162 in combination with targeted agents
- To estimate the MTD/RP2D of triple combinations after progression on LGX818/MEK162 therapy
- To further assess anti-tumor activity of LGX818/MEK162 combination, and in combination with targeted agents after progression on LGX818/MEK162 combination
- To characterize genomic alterations in tumor tissue at baseline and at tumor progression
- To determine the PK profiles of LGX818, MEK162 and the third agents when given in combination and to assess drug-drug interaction |
Estimar la DMT/DRF2 de combinaciones triples después de progresión con tratamiento con LGX818/MEK162
Caracterizar la seguridad y la tolerabilidad de LGX818/MEK162 en combinación con agentes diana
Evaluar más la actividad antitumoral de la combinación LGX818/MEK162 y en combinación con agentes diana después de progresión con la combinación LGX818/MEK162
Caracterizar las alteraciones genómicas en tejido tumoral en la visita basal y en la progresión del tumor.
Determinar el perfil PK de LGX818, MEK162 y los terceros agentes cuando se administran en combinación y evaluar la interacción entre fármacos |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients (males and females) age ? 18 years
Histologically confirmed diagnosis of unresectable stage III or metastatic melanoma (stage IIIC to IV per American Joint Committee on Cancer [AJCC])
Documented evidence of BRAF V600 mutation.
Newly obtained tumor biopsy at baseline, and patient agrees to a mandatory biopsy at the time of progression, if not medically contraindicated.
Evidence of measurable disease, as determined by RECIST v1.1.
Inclusion criteria for triple combinations:
Progressive disease following prior treatment with LGX818/MEK162 combination.
A pre-LGX818/MEK162 combination archival tumor sample must be available |
Pacientes (hombres y mujeres) con Edad ? 18 años
Diagnóstico confirmado histológicamente de melanoma metastásico o de estadio III inextirpable (estadio IIIC a IV según el American Joint Committee on Cancer [AJCC])
? Evidencia documentada de mutación BRAF V600.
? Biopsia tumoral obtenida recientemente en la visita basal y aceptación por parte del paciente de una biopsia obligatoria en el momento de la progresión, si no está contraindicado desde el punto de vista médico.
? Evidencia de enfermedad medible, según determinación por RECIST v1.1.
Enfermedad progresiva después de tratamiento previo con la combinación LGX818/MEK162.
Se debe disponer de una muestra tumoral de archivo previa a la combinación LGX818/MEK162 |
|
| E.4 | Principal exclusion criteria |
Symptomatic or untreated leptomeningeal disease
Symptomatic brain metastases. Patients previously treated or untreated for brain metastases that are asymptomatic in the absence of corticosteroid therapy or on a stable dose of steroids for four weeks are allowed to enroll. Brain metastases must be stable at least 4 weeks with verification by imaging (e.g. brain MRI completed at screening demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs.
Known acute or chronic pancreatitis.
History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes);
Clinically significant cardiac disease including any of the following:
CHF requiring treatment (NYH grade ? 2),
LVEF < 50% as determined by MUGA scan or ECHO
History or presence of clinically significant ventricular arrhythmias or atrial fibrillation
Clinically significant resting bradycardia
Unstable angina pectoris ? 3 months prior to starting study drug
Acute Myocardial Infarction (AMI) ? 3 months prior to starting study drug,
QTcF > 480 msec.
Patients with any of the following laboratory values at Screening/baseline:
Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L]
Platelets < 100,000/mm3 [100 x 109/L]
Hemoglobin < 9.0 g/dL
Serum creatinine >1.5 x ULN or calculated or directly measured CrCl < 50% LLN (lower limit of normal)
Serum total bilirubin >1.5 x ULN
AST/SGOT or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present
Additional exclusion criteria for the triple combinations:
Patients who have developed brain metastases during Part I of the study may continue to Part II upon discussion with Sponsor Medical Monitor. The brain metastasis must be either asymptomatic or treated and stable for at least 4 weeks and on a stable or tapering dose of steroids for at least 2 weeks
Additional exclusion criteria for the triple combinations:
LGX818/MEK162/BKM120:
Patients with fasting glucose > 120 mg/dL or 6.7 mmol/L, and HbA1c > 8 %.
Patient has any of the following mood disorders as judged by the Investigator or a Psychiatrist:
Patient has a score ? 12 on the PHQ-9 questionnaire
Patient has ? CTCAE grade 3 anxiety
LGX818/MEK162/BGJ398:
History and/or current evidence of significant ectopic mineralization/ calcification with the exception of calcified lymph nodes and asymptomatic vascular calcification.
Current evidence of corneal disorder/ keratopathy incl. but not limited to bullous/ band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits etc., confirmed by ophthalmologic examination
LGX818/MEK162/LEE011:
Patients with uncontrolled hypertension (please refer to WHO-ISH guidelines) are excluded from study.
QTcF >450 ms for males and >470 ms for females Congenital long QT syndrome or family history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade ? 3 and magnesium levels below the clinically relevant lower limits at study entry
Current evidence of brain metastasis or brain metastasis detected by mandatory CT/MRI at screening
PT/INR or aPTT > 1.5xULN
Asymptomatic serum amylase > CTCAE Grade 2 (1.5-2.0xULN). Patients with Grade 1 or Grade 2 serum amylase at the beginning of the study
must be confirmed to have no signs or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging
findings of pancreas, etc.)
Serum lipase > ULN |
Enfermedad leptomeníngea sintomática o no tratada.
Metástasis cerebrales sintomáticas. Se permite el reclutamiento de pacientes previamente tratados o no tratados por metástasis cerebrales que están asintomáticos en ausencia de terapia con corticoesteroides o con una dosis estable de corticoesteroides durante cuatro semanas. Las metástasis cerebrales deben ser estables al menos 4 semanas, con verificación por pruebas de imagen (p. ej., RM cerebral realizada en la visita de selección que no ponga de manifiesto evidencia actual de metástasis cerebrales progresivas). No se permite que los pacientes reciban antiepilépticos inductores enzimáticos.
Pancreatitis aguda o crónica conocida.
Antecedentes o evidencia actual de oclusión venosa retiniana (OVR) o factores actuales de riesgo de OVR (p. ej. glaucoma o hipertensión ocular no controlada, antecedentes de hiperviscosidad o síndromes de hipercoagulabilidad);
Cardiopatía clínicamente significativa incluida cualquiera de las siguientes:
ICC que requiera tratamiento (grado ? 2 NYH),
FEVI < 50% determinada mediante MUGA o ECO
Antecedentes o presencia de arritmia ventricular clínicamente significativa o fibrilación auricular
Bradicardia en reposo clínicamente significativa
Angina de pecho inestable ? 3 meses antes del inicio del fármaco de estudio
Infarto agudo de miocardio (IAM) ? 3 meses antes del inicio del fármaco de estudio
QTcF > 480 ms
Pacientes con cualquiera de los siguientes valores de laboratorio en la visita de Selección/Visita basal:
Recuento absoluto de neutrófilos (ANC) <1.500/mm3 [1,5 x 109/l]
Plaquetas <100.000/mm3 [100 x 109/l]
Hemoglobina < 9,0 g/dl
Creatinina sérica >1,5 x LSN o aclaramiento de creatinina calculado o medido directamente < 50% LIN (límite inferior de normalidad) Bilirrubina sérica total >1,5 x LSN
AST/SGOT o ALT/SGPT >2,5 x LSN o >5 x LSN si hay metástasis hepáticas
Criterios adicionales para la triple combinación
Pacientes que han desarrollado metástasis cerebrales durante la parte I del estudio, pueden continuar con la Parte II tras discusión con el monitor clínico del promotor. Las metástasis cerebrales deberán ser asintomáticas o tratadas y estables durante por lo menos 4 semanas y con una dosis estable o reducida de esteroides durante por lo menos 2 semanas.
Criterios adicionales para la triple combinación
LGX818/MEK162/BKM120:
Pacientes con glucosa en ayunas >120 mg/dl o 6,7 mmol/l y HbA1c >8 %.
Paciente con cualquiera de los siguientes trastornos del estado de ánimo a criterio del investigador o de un psiquiatra:
El paciente tiene una puntuación ? 12 en el cuestionario PHQ-9
El paciente presenta una ansiedad ? grado 3 CTCAE
LGX818/MEK162/BGJ398:
Antecedentes y/o evidencia actual de mineralización/ calcificación ectópica significativa excepto ganglios linfáticos calcificados y calcificación vascular asintomática.
Evidencia actual de trastorno corneal/queratopatía, incluido entre otros, queratopatía ampollosa/en banda, abrasión corneal, inflamación/úlcera, queratoconjuntivitis, confirmado por examen oftalmológico
LGX818/MEK162/LEE011:
Los pacientes con hipertensión no controlada (véanse las guías OMS-ISH) son excluidos del estudio.
QTcF >450 ms en varones y >470 ms en mujeres, síndrome del QT largo congénito o antecedentes familiares de muerte cardíaca súbita inesperada y/o hipopotasemia grado ? 3 CTCAE y nivel de magnesio por debajo del límite inferior clínicamente relevante al incorporarse al estudio
Evidencia actual de metástasis cerebrales o metástasis cerebrales detectadas en la TC/RM obligatoria en la visita de selección
TP/INR o TTPa >1,5 x LSN
Amilasa sérica asintomática > grado 2 de CTCAE (1.5-2.0xULN). Pacientes con grado 1 o 2 de amilasa sérica al comienzo del estudio, deben de ser confirmados que no presentan señales o síntomas de pancreatitis o de daño pancreático (por ej, elevada P-amilasa, imagen anormal del páncreas, etc.)
Lipasa sérica > ULN |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate |
| Tasa de respuesta global |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Incidence and severity of adverse events
- Incidence rate of Dose Limiting Toxicities (DLTs) in Cycle 1 of Combination Part (Part II)
- PFS, DOR, TTR, DCR and OS (Part II only)
- Genomic alteration status(mutation/amplification/expression) of pre-defined markers
- Plasma concentration and derived PK parameters of LGX818/MEK162 and targeted agents |
- La incidencia y gravedad de los acontecimientos adversos
- Tasa de incidencia de la toxicidad limitante de dosis (DLTs) en el Ciclo 1 de Combinación Parte (Parte II)
- PFS, DOR, TTR, DCR y sistema operativo (sólo la parte II)
- Estado de alteración genómica (mutación / amplificación / expresión) de los marcadores pre-definidos
- La concentración plasmática y agentes derivados parámetros farmacocinéticos de LGX818/MEK162 y específicas |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- 24 months
- 24 months
-24 months
-24 months
- baseline, at progression with LGX818/MEK162 up to 24 months |
- 24 meses
- 24 meses
- 24 meses
- 24 meses
- Línea de base, en progresión con LGX818/MEK162 hasta 24 meses |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| 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 | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 |
| Australia |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
| End of study (Last Patient Last Visit [LPLV]) will be upon completion of the safety follow-up, disease progression follow-up and survival follow-up (only for Part II), whichever comes later, for all patients, or if the study is terminated early. Note: the survival follow up will be perfomed until at least 80% of patients enrolled in Part II have died, discontinued, withdrawn consent, or been lost to follow-up |
| Fin del estudio (Última visita del último paciente [UVUP]) será tras la finalización del seguimiento de seguridad, seguimiento de progresión de enfermedad y seguimiento de supervivencia (sólo para Parte II), lo que ocurra más tarde, para todos los pacientes, o si el estudio finaliza prematuramente. Nota: el seguimiento de supervivencia se hará hasta que al menos 80% de pacientes incluidos en la parte II haya muerto, haya discontinuado, haya retirado consentimiento o se haya podido seguir. |
|
| 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 | 10 |
| 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 | 10 |
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