E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
EGFR mutated, T790M negative NSCLC |
Cáncer de pulmón no microcítico (NSCLC) EGFR mutado, T790M negativo |
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E.1.1.1 | Medical condition in easily understood language |
Type of lung cancer, called non-small cell lung cancer (NSCLC) with certain genetic alterations (called mutations) of a gene called epidermal growth factor receptor (EGFR) |
Tipo de cáncer de pulmón llamado cáncer de pulmón no microcítico (NSCLC) con ciertas alteraciones genéticas (llamadas mutaciones) de un gen llamado receptor del factor de crecimiento epidérmico (EGFR) |
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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 | 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) |
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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 |
Run-in part: to confirm the recommended dose of capmatinib in combination with osimertinib for the randomized part
Randomized part: to compare the progression-free survival (PFS) of capmatinib in combination with osimertinib versus platinum-based doublet chemotherapy |
Parte de preinclusion: Confirmar la dosis recomendada de capmatinib en combinación con osimertinib para la parte aleatorizada. Parte aleatorizada: Comparación de la supervivencia libre de progresión (PFS) de capmatinib en combinación con osimertinib en comparación con platino y pemetrexed. |
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E.2.2 | Secondary objectives of the trial |
Key secondary objective:
To compare the Overall Response Rate (ORR) of capmatinib in combination with osimertinib
To compare the overall intracranial response rate (OIRR) of capmatinib in combination with osimertinib
Other secondary objectives:
To characterize the safety and tolerability of capmatinib in combination with osimertinib
To characterize the pharmacokinetics of capmatinib, osimertinib, and osimertinib's active metabolites (AZ5104 and AZ7550)
To assess the tumor response of capmatinib in combination with osimertinib
To assess PFS2 (PFS after next-line of treatment)
To evaluate association between MET amplification status as measured in ctDNA at baseline with PFS and ORR
To evaluate overall survillance in participants treated with capmatinib in combination with osimertinib
To evaluate the safety profile of capmatinib in combination with osimertinib
To assess intracranial anti-tumor activity of capmatinib in combination with osimertinib |
Secundarios principales: Comparar la tasa de respuesta global (TRG) de capmatinib en combinación con osimertinib Comparar la tasa de respuesta intracraneal global (TRIG) de capmatinib en combinación con osimertinib Otros objetivos secundarios: Caracterizar la seguridad y tolerabilidad de capmatinib en combinación con osimertinib Caracterizar la farmacocinética de capmatinib, osimertinib y los metabolitos activos de osimertinib (AZ5104 y AZ7550). Evaluar la respuesta tumoral de capmatinib en combinación con osimertinib Evaluar la PFS2 (PFS después de la siguiente línea de tratamiento) Evaluar la asociación entre la amplificación de MET medida en el ADNtc (ADN tumoral circulante) en la basal y la PFS y la ORR Evaluar la supervivencia global en participantes tratados con capmatinib en combinación con osimertinib Evaluar la actividad antitumoral intracraneal de capmatinib en combinación con osimertinib |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent must be obtained prior to participation in the study.
2. Adult > or = 18 years old at the time of informed consent.
3. Stage IIIB/IIIC (not amenable to curative surgery or radiation) or IV NSCLC at the time of study entry.
4. Histologically or cytologically confirmed diagnosis of NSCLC with EGFR mutations known to be associated with EGFR TKI sensitivity, T790M negative, and MET gene amplification defined as Gene Copy Number (GCN) > or = 5 per central Novartis laboratory
5. Mandatory provision of a formalin-fixed, paraffin embedded tumor tissue sample (a newly obtained tumor sample, or archival tumor block/slides taken after progression on prior line of EGFR TKI.
6. Participants must have failed maximum one prior line of therapy (either to 1st/2nd generation EGFR TKIs or osimertinib) for advanced/metastatic disease and must be candidates for platinum (cisplatin or carboplatin) - pemetrexed doublet based chemotherapy.
7. At least one measurable lesion as defined by RECIST 1.1.
8. ECOG performance status (PS) of 0 or 1. |
1. Se deberá obtener el consentimiento informado firmado antes de la participación en el estudio. 2. Adultos > or = 18 años de edad en el momento de la firma del consentimiento informado. 3. NSCLC en estadio IIIB/IIIC (no susceptible de cirugía curativa o radiación ) o IV en el momento de la inclusión en el estudio. 4. Diagnóstico de NSCLC confirmado histológica o citológicamente con mutaciones de EGFR asociadas a la sensibilidad a TKI del EGFR, T790M negativa y amplificación del gen MET definida como número de copias del gen (GCN) > or = 5 según el laboratorio central de Novartis. 5. Presentación obligatoria de una muestra de tejido tumoral fijada en formalina y embebida en parafina (una muestra tumoral obtenida recientemente o bloque/cortes tumorales de archivo extraídos después de la progresión con una línea previa de TKI. 6. Fracaso como máximo a una línea previa de tratamiento (TKI del EGFR de 1ª/2ª generación u osimertinib) para la enfermedad avanzada/metastásica y los pacientes deben ser candidatos para quimioterapia basada en doblete de platino (cisplatino o carboplatino) y pemetrexed. 7. Al menos una lesión medible según RECIST 1.1. 8. Estado funcional (PS) del ECOG de 0 o 1. |
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E.4 | Principal exclusion criteria |
1. Prior treatment with any MET inhibitor or HGF-targeting therapy.
2. Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms
3. Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention)
4. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome
5. Treatment with a prior 1st or 2nd generation EGFR TKIs (e.g. erlotinib, gefitinib, afatinib, dacomitinib) or osimertinib within 14 days or approximately 5x half-life, whichever is shorter, of the first dose of study treatment
6. Unable or unwilling to swallow tablets as per dosing schedule |
1. Tratamiento previo con cualquier inhibidor de MET o terapia dirigida al factor de crecimiento hepatocítico (HGF). 2. Participantes con metástasis sintomáticas en el sistema nervioso central (SNC) neurológicamente inestables o que requieran un aumento de la dosis de esteroides durante las dos semanas anteriores a su inclusión en el estudio para tratar los síntomas del SNC. 3. Presencia o antecedentes de enfermedad pulmonar intersticial o neumonitis intersticial, incluida neumonitis por radiación clínicamente significativa (es decir, que afecte a actividades de la vida diaria o que requiera tratamiento). 4. Síndrome de QT largo, antecedentes familiares de muerte súbita idiopática o síndrome del QT largo congénito. 5. Tratamiento previo con TKI del EGFR de 1ª/2ª generación (p. ej., erlotinib, gefitinib, afatinib o dacomitinib) u osimertinib en los 14 días o aproximadamente 5 vidas medias, aquel periodo que sea más corto, antes de la primera dosis del tratamiento del estudio. 6. No poder o no estar dispuesto a tragar comprimidos según la pauta posológica. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Run-in: Incidence of Dose Limiting Toxicities (DLT) during cycle 1 Randomized part: Progression-free survival (PFS) by BIRC as per RECIST 1.1 |
Para la fase de preinclusión: Incidencia de toxicidad limitante de dosis (DLT) durante el ciclo 1. Parte aleatorizada: supervivencia libre de progresión (PFS) por (BIRC) según RECIST 1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The interim analysis (IA) for futility is planned for PFS in this study when approximately 65 events have occurred (40% of total PFS events) at approximately 18.5 months from the date of first participant randomized in the randomized part of the study. A final analysis will be performed at the end of the study. |
El análisis intermedio (IA) para la futilidad está planeado para la PFS en este estudio cuando ocurran aproximadamente 65 eventos (40% del total de eventos PFS) aproximadamente a los 18.5 meses desde la fecha del primer participante aleatorizado en la parte aleatorizada del estudio. Se realizará un análisis final al final del estudio. |
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E.5.2 | Secondary end point(s) |
Run-in Part: • Safety: Incidence, type, and severity of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 5.00 including changes in laboratory values, vital signs, liver assessments and cardiac assessments; Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all drug components • Plasma PK concentrations and derived PK parameters • All calculated per RECIST 1.1 by investigator: Overall response rate (ORR), Duration of response (DOR), Time to response (TTR), Disease control rate (DCR), Progression free survival (PFS)
Randomized part: All calculated per RECIST 1.1, both by BIRC and investigator: • Overall response rate (ORR) • Overall intracranial response rate (OIRR) • Duration of response (DOR) • Time to response (TTR) • Disease control rate (DCR)
All calculated by investigator: • PFS2 (PFS after next-line of treatment)
The association between MET amplification status as measured in ctDNA at baseline with PFS and ORR by BIRC using RECIST 1.1 criteria
Characterize the pharmacokinetics of capmatinib, osimertinib, and osimertinib's active metabolites (AZ5104 and AZ7550) by assessing plasma PK concentrations
Overall Survival
Safety profile of capmatinib in combination with osimertinib
Change from baseline in European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13, QLQ-C30, EuroQoL-5 Dimension-5 Level/EQ-5D-5L, and NCCN Fact Brain Symptoms Index questionnaires
Intracranial anti-tumor activity in participants with Central Nervous System (CNS) lesions at baseline (e.g. Duration of intracranial response (DOIR), time to intracranial response (TTIR) and intracranial disease control rate (IDCR), all by BIRC as per RANO-BM criteria). |
Parte pre-inclusión: • Seguridad: incidencia, tipo, y gravedad de los eventos adversos por la CTCAE (Common Terminology Criteria for Adverse Events) version 5.0 incluyendo cambios en valores de laboratorio, signos vitales, evaluaciones hepáticas y cardiacas. Tolerabilidad: interrupciones de dosis, reducciones, intensidad de dosis y duración de la exposición a todos los componentes de la medicación. • Concentraciones plasmáticas de PK y parámetros derivados de PK. • Todo calculado según RECIST 1.1 por el investigador: Tasa de respuesta global (ORR), duración de la respuesta (DOR), tiempo de respuesta (TTR), tasa de control de la enfermedad (DCR), supervivencia libre de progresión (PFS). Parte aleatorizada: Todo calculado según RECIST 1.1 por el investigador y el BIRC: • Tasa de respuesta global (ORR) • Tasa de respuesta intracraneal global (OIRR) • Duración de la respuesta (DOR) • Tiempo para la respuesta (TTR) • Tasa de control de la enfermedad (DCR) Todo calculado por el investigador: • Supervivencia libre de progresión después de la siguiente línea de tratamiento
La asociación entre el estado de amplificación MET medido en el ADNtc (ADN tumoral circulante) en el basal con PFS y ORR por el BIRC usando los criterios RECIST 1.1 Caracterizar la farmacocinética de capmatinib, osimertinib y metabolitos activos de osimertinib (AZ5104 y AZ7550) mediante la evaluación de concentraciones plasmáticas de PK. Supervivencia global. Perfil de seguridad de capmatinib en combinación con osimertinib. Cambios desde el basal en los cuestionarios European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13, QLQ-C30, EuroQoL-5 Dimension-5 Level/EQ-5D-5L y NCCN Fact Brain Symptoms Index. Actividad antitumoral intracraneal en participantes con lesiones en sistema nervioso central (CNS) en el basal (ejemplo: duración de la respuesta intracraneal (DOIR), tiempo hasta la respuesta intracraneal (TTIR) y tasa de control de la enfermedad intracraneal (IDCR), todo por BIRC siguiendo los criterios RANO-BM). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The interim analysis (IA) for futility is planned for PFS in this study when approximately 65 events have occurred (40% of total PFS events) at approximately 18.5 months from the date of first participant randomized in the randomized part of the study. A final analysis will be performed at the end of the study. |
El análisis intermedio (IA) para la futilidad está planeado para PFS en este estudio cuando aproximadamente 65 eventos hayan ocurrido (40% del total de eventos PFS) a aproximadamente 18.5 meses desde la fecha del primer participante aleatorizado en la parte aleatorizada del estudio. Un análisis final será realizado al final del estudio. |
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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 | 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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
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 |
Chile |
China |
Colombia |
Hong Kong |
India |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Russian Federation |
Serbia |
Singapore |
Taiwan |
Thailand |
United States |
Vietnam |
Bulgaria |
Croatia |
France |
Germany |
Hungary |
Italy |
Lithuania |
Netherlands |
Poland |
Portugal |
Romania |
Slovenia |
Spain |
United Kingdom |
Argentina |
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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
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 12 |
E.8.9.2 | In all countries concerned by the trial years | 6 |