E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-over-expressing or -mutated, unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC) |
Cáncer de pulmón no microcítico (CPNM) no epidermoide irresecable y/o metastásico con mutación o sobreexpresión de HER2 |
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E.1.1.1 | Medical condition in easily understood language |
Certain types of lung cancer |
Ciertos tipos de cáncer de pulmón |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001246 |
E.1.2 | Term | Adenosquamous cell lung cancer NOS |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029514 |
E.1.2 | Term | Non-small cell lung cancer NOS |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001255 |
E.1.2 | Term | Adenosquamous cell lung cancer stage unspecified |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001253 |
E.1.2 | Term | Adenosquamous cell lung cancer stage IIIB |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001252 |
E.1.2 | Term | Adenosquamous cell lung cancer stage IIIA |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066490 |
E.1.2 | Term | Progression of non-small cell lung cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079440 |
E.1.2 | Term | Non-squamous non-small cell lung cancer |
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 |
The primary objective is to evaluate the objective response rate (ORR) of trastuzumab deruxtecan in HER2-over-expressing and/or –HER2 mutated advanced NSCLC subjects. |
El objetivo principal es evaluar la tasa de respuesta objetiva (TRO) de trastuzumab deruxtecán en sujetos con CPNM avanzado con sobreexpresión o mutación de HER2. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives: The secondary objectives are: • To evaluate duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) • To further evaluate the safety of trastuzumab deruxtecan • To determine the pharmacokinetics (PK) of trastuzumab deruxtecan Exploratory Objective: The exploratory objectives are: • To evaluate time to response (TTR) and best percent change in the sum of the diameters for all target lesions • To evaluate potential biomarkers • To evaluate exposure-response relationships for efficacy and safety endpoints |
Objetivos secundarios: Los objetivos secundarios son: • evaluar la duración de la respuesta (DR), la tasa de control de la enfermedad (TCE), la supervivencia sin progresión (SSP) y la supervivencia general (SG). • evaluar en mayor profundidad la seguridad de trastuzumab deruxtecán. • determinar la farmacocinética (FC) de trastuzumab deruxtecán.
Objetivo exploratorio: Los objetivos exploratorios son: • evaluar el tiempo hasta la respuesta (TR) y el mejor cambio porcentual en la suma de los diámetros de todas las lesiones diana. • evaluar biomarcadores potenciales. • evaluar las relaciones exposición-respuesta de los criterios de valoración de la eficacia y la seguridad. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria: 1. Age ≥20 y old in Japan, ≥18 y old in other countries. 2. Pathologically documented unresectable and/or metastatic non-squamous NSCLC. 3. Has relapsed from or is refractory to standard treatment or for which no standard treatment is available. 4. For Cohort 1 only: HER2-overexpression (IHC 2+ or 3+) status must be assessed and confirmed by Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or equivalent, from an archival tumor sample. 5. For Cohort 2 only: Documented any known activating HER2 mutation from an archival tumor sample analyzed by CLIA laboratory or equivalent, specifically exon 20 insYVMA (Y772_A775dup), insGSP (G778_P780dup), insTGT (G776delinsVC), single base pair substitutions L755S, V777L, or S310F or another HER2 mutation approved by the Principal Investigator and the Sponsor. 6. Presence of at least 1 measurable lesion assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 7. Is willing and able to provide an adequate archival tumor sample. 8. Is willing to undergo a tissue biopsy, after the completion of the most recent treatment regimen. 9. Has Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1. |
Criterios de inclusión: 1. Edad ≥20 años en Japón, ≥18 años en los demás países. 2. CPNM no epidermoide irresecable y/o metastásico anatomopatológicamente documentado. 3. Haber recaído con el tratamiento de referencia o ser resistente al mismo, o no disponer de tratamiento de referencia. 4. Para la cohorte 1 solamente: El estado de sobreexpresión de HER2 (IHQ 2+ o 3+) debe evaluarse y confirmarse por un laboratorio certificado con CLIA (Clinical Laboratory Improvement Amendments) o equivalente, a partir de una muestra tumoral de archivo. 5. Para la cohorte 2 solamente: Se deberá documentar cualquier mutación activadora de HER2 conocida a partir de una muestra tumoral de archivo analizada por el laboratorio CLIA o equivalente, específicamente el exón 20 insYVMA (Y772_A775dup), insGSP (G778_P780dup), insTGT (G776delinsVC), sustituciones de pares de bases únicos L755S, V777L o S310F u otra mutación de HER2 aprobada por el investigador principal y el promotor. 6. Presencia de al menos 1 lesión medible según la evaluación del investigador en base a los Criterios de Evaluación de la Respuesta en Tumores Sólidos (RECIST) versión 1.1. 7. Estar dispuesto a y ser capaz de proporcionar una muestra tumoral de archivo adecuada. 8. Estar dispuesto a someterse a una biopsia de tejido tras la finalización de la pauta de tratamiento más reciente. 9. Presentar un estado funcional (EF) según la escala del Grupo Oncológico Cooperativo del Este (Eastern Cooperative Oncology Group, EF ECOG) de 0 a 1. |
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E.4 | Principal exclusion criteria |
Exclusion Criteria: 1. Previously treated with HER2-targeted therapies, except for pan-HER class tyrosine kinase inhibitors. 2. For Cohort 1 only: Has known HER2 mutation. 3. Uncontrolled or significant cardiovascular disease, including any of the following: a. Medical history of myocardial infarction within 6 mo before registration b. Symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV) 28 d prior to registration c. Troponin levels consistent with myocardial infarction (as defined by the Sponsor) 28 d prior to registration d. History of unstable angina, or serious cardiac arrhythmia requiring treatment e. Left ventricular ejection fraction (LVEF) < 50% within 28 d prior to registration f. Has a corrected QT interval (QTcF) prolongation to > 470 ms (females) or >450 ms (males) based on average of the screening triplicate12-lead electrocardiogram (ECG). 4. Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. 5. Has clinically significant corneal disease in the opinion of the Investigator. 6. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 wk must have elapsed between the end of whole brain radiotherapy and study registration. 7. Has multiple primary malignancies within 3 y, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated. |
Criterios de exclusión: 1. Tratamiento previo con terapias dirigidas a HER2, excepto los inhibidores de la tirosina quinasa de clase pan-HER. 2. Para la cohorte 1 solamente: Presentar una mutación de HER2 conocida. 3. Enfermedad cardiovascular no controlada o significativa, incluida cualquiera de las siguientes: a. Antecedentes médicos de infarto de miocardio en los 6 meses anteriores al registro. b. Insuficiencia cardíaca congestiva (ICC) sintomática (clase II a IV según la New York Heart Association) 28 días antes del registro. c. Niveles de troponina indicativos de infarto de miocardio (según determinación del promotor) 28 días antes del registro. d. Antecedentes de angina inestable o arritmia cardíaca grave que requiere tratamiento. e. Fracción de eyección ventricular izquierda (FEVI) < 50 % en los 28 días anteriores al registro. f. Presentar una prolongación del intervalo QT corregido (QTcF) hasta > 470 ms (mujeres) o >450 ms (hombres) en base a la media del electrocardiograma (ECG) de 12 derivaciones realizado por triplicado en la selección. 4. Tener antecedentes de enfermedad pulmonar intersticial (EPI) (no infecciosa)/neumonitis que requiere corticoesteroides, EPI/neumonitis recurrente o sospecha de EPI/neumonitis que no puede descartarse mediante diagnóstico por imagen en la selección. 5. Presentar enfermedad corneal clínicamente significativa, en opinión del investigador. 6. Presentar compresión de la médula espinal o metástasis en el sistema nervioso central clínicamente activas, definidas como no tratadas y sintomáticas, o que requieren tratamiento con corticoesteroides o antiepilépticos para controlar los síntomas asociados. Los sujetos con metástasis cerebrales clínicamente inactivas podrán ser incluidos en el estudio. Los sujetos con metástasis cerebrales tratadas que ya no sean sintomáticas y que no requieran tratamiento con corticoesteroides o antiepilépticos podrán ser incluidos en el estudio si se han recuperado del efecto tóxico agudo de la radioterapia. Deberán haber transcurrido al menos 2 semanas entre el final de la radioterapia total del cerebro y el registro en el estudio. 7. Presentar múltiples neoplasias malignas primarias en los últimos 3 años, excepto el cáncer de piel no melanoma adecuadamente resecado, enfermedad in situ tratada de forma curativa u otros tumores sólidos tratados de forma curativa. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint: The primary efficacy endpoint (primary outcome measure) is ORR assessed by independent central review (ICR) based on RECIST version 1.1 for each cohort. |
Criterio de valoración principal de la eficacia: El criterio de valoración principal de la eficacia (medida de resultado principal) es la TRO evaluada mediante revisión central independiente (RCI) en base a RECIST versión 1.1 para cada cohorte. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
every 6 weeks |
cada 6 semanas |
|
E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints: - DoR based on investigator assessment and ICR - DCR based on investigator assessment and ICR - PFS based on investigator assessment and ICR - OS - ORR based on investigator assessment Secondary outcome measures include: ORR, DoR, and PFS, and OS. |
Criterios de valoración secundarios de la eficacia: - DR en base a la evaluación del investigador y RCI - TCE en base a la evaluación del investigador y RCI - SSP en base a la evaluación del investigador y RCI - SG - TRO en base a la evaluación del investigador Los criterios de valoración secundarios incluyen: TRO, DR, SSP y SG. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
every 6 weeks for efficacy, every 3 months for OS for until death or last contact with subject |
cada 6 semanas para la eficacia, cada 3 meses para SG hasta la muerte o el último contacto con el sujeto |
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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 | 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 | 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.8.3 |
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 | 8 |
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 |
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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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End of OS follow-up |
Fin del seguimiento SG |
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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 | 1 |
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 | 1 |
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 |