| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer Stage I or IIA |
| cáncer de pulmón no microcítico en estadio I o IIA |
|
| E.1.1.1 | Medical condition in easily understood language |
| Early stage non-small cell lung cancer in patients who cannot have surgery due to other medical conditions |
| Estadios tempranos de cáncer de pulmón no microcítico en pacientes medicamente inoperables debido a otras condiciones medicas |
|
| 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 | 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 |
1.To compare the Event Free Survival (EFS).
2.To compare Overall Survival (OS). |
1- Comparar la supervivencia sin episodios (SSE).
2- Comparar la supervivencia global (SG). |
|
| E.2.2 | Secondary objectives of the trial |
1.To compare the time to death or distant metastases (TDDM).
2.To evaluate the safety and tolerability of Stereotactic Body Radiotherapy (SBRT) + pembrolizumab (MK-3475).
3.To compare the change from baseline scores in global health status/quality of life (QoL), cough, chest pain, dyspnea, and physical functioning scale. |
1- Comparar el tiempo hasta la muerte o la aparición de metástasis a distancia.
2- : Evaluar la seguridad y la tolerabilidad de RTCE + pembrolizumab ( MK-3475)
3- Comparar la variación con respecto a las puntuaciones basales en las escalas de estado de salud general/calidad de vida, tos, dolor torácico, disnea y función física. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (blood and saliva) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
| El promotor llevará a cabo investigaciones biomédicas futuras de ADN ( sangre y saliva) |
|
| E.3 | Principal inclusion criteria |
A participant will be eligible for inclusion in the study if the participant:
1. Has NSCLC diagnosed by histology or cytology and confirmed as Stage I or IIA NSCLC (AJCC 8th edition) by chest CT and PET scan. Prospective participants with mediastinal lymph nodes measured on chest CT as >1 cm in the short axis or PET avid lymph nodes may be eligible if the lymph node(s) in question is biopsied and is histologically benign.
2. Cannot undergo thoracic surgery due to existing medical illness(es) as determined by the participant’s treating physician in consultation with the site’s multi-disciplinary tumor board. The recommendation from the tumor board as well as the reason(s) for declaring the patient medically inoperable must be included in the participant’s study documents in order to be eligible for KEYNOTE-867. Patients, who are able to withstand thoracic surgery, but choose to pursue non-operative therapy, are not eligible. If there is no tumor board, then this decision will be made by the investigator in consultation with a thoracic surgeon and a radiation oncologist if the investigator is not a radiation oncologist.
3. Has a ECOG Performance Status of 0, 1, or 2.
4. Is able to receive SBRT.
5. Has adequate organ function. Specimens must be collected within 7 days prior to the start of study intervention.
6. Is male or female ≥18 years of age, at the time of signing the informed consent.
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
7. A female is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a) not a women of childbearing potential (WOCBP) OR b) A WOCBP who agrees to follow the contraceptive guidance during the treatment interval and for at least 120 days (corresponding to time needed to eliminate any study treatment (pembrolizumab).
8. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research. |
En este estudio podrán participar pacientes que cumplan todos los criterios siguientes:
1-Presencia de un CPNM diagnosticado mediante histología o citología y confirmado como CPNM en estadio I o IIA (criterios AJCC, 8ª edición) mediante TC de tórax y PET. Podrán participar pacientes prospectivos con ganglios linfáticos mediastínicos > 1 cm de eje menor medidos en la TC de tórax o con ganglios linfáticos con avidez en la PET si se biopsian los ganglios en cuestión y son histológicamente benignos
2-Imposibilidad de someterse a cirugía torácica debido a enfermedades existentes, según lo determinado por el médico responsable del tratamiento del participante en consulta con el comité multidisciplinario de tumores del centro. La recomendación del comité de tumores y los motivos para declarar que el paciente es médicamente inoperable deberán incluirse en los documentos del estudio del participante para que pueda participar en el estudio KEYNOTE-867. No podrán participar pacientes que puedan soportar la cirugía torácica, pero que decidan recibir un tratamiento no quirúrgico. Ante la ausencia de un comité de tumores, el investigador tomará esta decisión en consulta con un cirujano torácico y un radioterapeuta en caso de que el investigador no sea radioterapeuta.
3.Estado funcional de 0, 1 o 2 en la escala del ECOG.
4.Capacidad de recibir RTCE.
5.Presencia de una función orgánica adecuada.Se obtendrán muestras en los siete días previos al comienzo del tratamiento del estudio.
6.Participante de cualquier sexo con una edad mínima de 18 años en el momento de firmar el consentimiento informado
Varones participantes
El uso de anticonceptivos por los varones deberá cumplir la normativa local sobre métodos anticonceptivos para los participantes en estudios clínicos.
Mujeres participantes
El uso de anticonceptivos por las mujeres deberá cumplir la normativa local sobre métodos anticonceptivos para los participantes en estudios clínicos.
7.Podrán participar mujeres que no estén embarazadas (véase el apéndice 10.5) ni en período de lactancia y que cumplan al menos una de las condiciones siguientes: a) no ser una mujer en edad fértil (MEF) según se define en el apéndice 10.5. O b) Ser una MEF que se compromete a seguir las normas relativas a métodos anticonceptivos recogidas en el apéndice 10.5 durante el intervalo de tratamiento y un mínimo de 120 días después (correspondiente al tiempo necesario para eliminar cualquier tratamiento del estudio [pembrolizumab]).
8.El participante (o su representante legal cuando proceda) otorga su consentimiento/asentimiento informado por escrito para el estudio. El participante también podrá otorgar su consentimiento/asentimiento para las investigaciones biomédicas futuras. No obstante, se podrá participar en el estudio principal sin necesidad de hacerlo en las investigaciones biomédicas futuras |
|
| E.4 | Principal exclusion criteria |
The participant must be excluded from the study if the participant:
1. Is a WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or treatment allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
3. Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or breast. Participants receiving radiotherapy to the contralateral breast at least 5 years prior to randomization may still be eligible.
4. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines are allowed.
5. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
7. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
8. Has a known hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
9. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
10. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
11. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). However, replacement therapy (eg thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency), while systemic, will be permitted for study eligibility.
12. Has an active infection requiring systemic therapy.
13. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
14. Has a known history of active tuberculosis (TB; Bacillus tuberculosis). No TB testing is required unless mandated by local health authority.
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
16. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
17. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention.
18. Has had an allogenic tissue/solid organ transplant. |
Se excluirá de participar en el estudio a todo candidato que cumpla alguno de los criterios siguientes:
1.Mujer en edad fértil que dé positivo en una prueba de embarazo en orina realizada en las 72 horas previas a la aleatorización o asignación del tratamiento (véase el apéndice 10,5). Cuando el resultado de la prueba en orina sea positivo o no pueda confirmarse que es negativo, será necesario hacer una prueba de embarazo en suero.
2.Tratamiento previo con un fármaco anti-PD-1, anti-PD-L1 o anti-PD-L2 o con un fármaco dirigido contra otro receptor de los linfocitos T estimulador o coinhibidor (como CTLA-4, OX-40 o CD137).
3.Recepción previa de radioterapia torácica, incluida radioterapia sobre el esófago, el mediastino o la mama. Podrán participar pacientes que hayan recibido radioterapia sobre la mama contralateral un mínimo de cinco años antes de la aleatorización.
4.Recepción de una vacuna de microorganismos vivos en los 30 días previos a la administración de la primera dosis del fármaco del estudio. Algunos ejemplos de vacunas de microorganismos vivos son, entre otros, los siguientes: vacuna contra el sarampión, antiparotídica, antirrubeólica, contra la varicela/zóster, contra la fiebre amarilla, antirrábica, bacilo de Calmette-Guérin (BCG) y antitifoidea. Las vacunas inyectables contra la gripe estacional contienen, por lo general, virus muertos y están permitidas; en cambio, las vacunas antigripales intranasales (p. ej., FluMist®) son vacunas de virus vivos atenuados y no están permitidas.
5.Participación activa o pasada en un estudio de un fármaco en investigación o uso de un dispositivo en investigación en las cuatro semanas previas a la administración de la primera dosis de la intervención del estudio.
6.Diagnóstico de inmunodeficiencia o recepción de tratamiento sistémico crónico con esteroides (en dosis superiores a 10 mg diarios de prednisona o un equivalente) o cualquier otra forma de tratamiento inmunodepresor en los siete días previos a la primera dosis del fármaco del estudio.
7.Presencia de otra neoplasia maligna conocida que esté en progresión o que haya necesitado tratamiento activo en los últimos tres años.
8.Presencia de hipersensibilidad conocida (grado ≥ 3) a pembrolizumab y/o a cualquiera de sus excipientes.
9.Antecedentes de neumonitis (no infecciosa) que haya precisado la administración de esteroides o presencia de una neumonitis activa.
10.Antecedentes de infección por el virus de la hepatitis B (reactividad del antígeno de superficie del virus de la hepatitis B [HBsAg]) o de infección activa por el virus de la hepatitis C (definida como detección de ARN del virus de la hepatitis C [VHC] [cualitativo]).
11.Presencia de una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico (es decir, fármacos modificadores de la enfermedad, corticoides o inmunodepresores) en los dos últimos años. Sin embargo, para poder participar en el estudio se permitirá el tratamiento de reposición (por ejemplo, tiroxina, insulina o corticoides en dosis fisiológicas por insuficiencia suprarrenal o hipofisaria), aunque sea por vía sistémica.
12.Infección activa con necesidad de tratamiento sistémico.
13.Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH). No será necesario realizar pruebas de VIH a menos que lo exijan las autoridades sanitarias locales.
14.Antecedentes de tuberculosis activa (Bacillus tuberculosis). No será necesario realizar pruebas de tuberculosis a menos que lo exijan las autoridades sanitarias locales.
15.Antecedentes o datos presentes de cualquier proceso, tratamiento o anomalía analítica que, en opinión del investigador responsable del tratamiento, podría confundir los resultados del estudio, dificultar la participación durante la totalidad del estudio o motivar que la participación no sea lo más conveniente para el posible participante.
16.Presencia de un trastorno psiquiátrico o por abuso de sustancias que podría dificultar la capacidad del participante para colaborar en el cumplimiento de los requisitos del estudio.
17.Embarazo, período de lactancia o intención de concebir o engendrar un hijo durante el período previsto del estudio, desde la visita de selección hasta 120 días después de la última dosis de la intervención del estudio.
18.Recepción de un alotrasplante de órgano sólido o tejidos |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Event-Free Survival (EFS)
2. Overall Survival (OS) |
1-la supervivencia sin episodios (SSE).
2- supervivencia global (SG). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 6 years
2. Up to approximately 6 years |
1- aproximadamente hasta 6 años
2- aproximadamente hasta 6 años |
|
| E.5.2 | Secondary end point(s) |
1. Time to Death or Distant Metastases (TDDM)
2. Number of Participants Who Experience an Adverse Event (AE)
3. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
4. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Score
5. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Cough (Item 1) Score
6. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Chest Pain (Item 10) Score
7. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Dyspnea (Item 8) Score
8. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Physical Functioning (Items 1-5) Score |
1- Tiempo hasta la muerte o la aparición de metástasis a distancia
2-Porcentaje de participantes que experimentan un acontecimiento adversos (AA).
3-Porcentaje de participantes que se retiran del tratamiento del estudio debido a un EA.).
4-Cambio desde el momento basal en las puntuaciones t6otales y de las subescalas del Cuestionario de calidad de vida-Core 30 (QLQ-C30) de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC).
5-Cambio desde el momento basal de la puntuación de la escala del módulo de carcinoma hepatocelular del QLQ de la EORTC (EORTC QLQ-HCC18).
6-Tiempo hasta el deterioro (THD) de la puntuación global y de la subescala del EORTC-QLQ-C30.
7-Tiempo hasta el deterioro (THD) de la puntuación global y de la subescala del EORTC-QLQ-C30.
8-Cambio desde el momento basal de la puntuación de utilidades de la salud del cuestionario de 5 dimensiones y 5 niveles (EQ-5D-5L) de calidad de vida europeo (EuroQol) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 6 years
2. Up to approximately 6 years
3. Up to approximately 6 years
4. Baseline and up to approximately 52 weeks
5. Baseline and up to approximately 52 weeks
6. Baseline and up to approximately 52 weeks
7. Baseline and up to approximately 52 weeks
8. Baseline and up to approximately 52 weeks |
1.aproximadamente hasta 6 años
2.aproximadamente hasta 6 años
3.aproximadamente hasta 6 años
4.Momento basal y hasta 52 semanas aproximadamente.
5.Momento basal y hasta 52 semanas aproximadamente.
6.Momento basal y hasta 52 semanas aproximadamente.
7.Momento basal y hasta 52 semanas aproximadamente.
8.Momento basal y hasta 52 semanas aproximadamente. |
|
| 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 | No |
| 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 53 |
| 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 |
| Austria |
| Brazil |
| Canada |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| New Zealand |
| Norway |
| Poland |
| Russian Federation |
| Spain |
| Switzerland |
| Turkey |
| Ukraine |
| United Kingdom |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| 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 | 7 |
| 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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