| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small Cell Lung Cancer |
| cáncer de pulmón no microcítico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Previously Untreated, Locally Advanced/Metastatic Non Small Cell Lung Cancer |
| cáncer de pulmón no microcítico avanzado/metastásico no tratado previamente |
|
| 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 | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| 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 antitumor activity of novel immunotherapy combinations compared with pembrolizumab in participants with PD-L1 high (TC/TPS ≥50%) NSCLC |
| Evaluar la actividad antitumoral de nuevas combinaciones con inmunoterapia en comparación con pembrolizumab en participantes con CPNM con elevada expresión de PD-L1 (CT/TPS ≥50%) |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the dose response relationship of novel immunotherapy combinations across a range of the novel components' dose levels and fixed dostarlimab dose (may not apply to all novel combinations)
• To further assess the clinical activity of novel immunotherapy combinations compared with pembrolizumab in participants with PD-L1 high (TC/TPS ≥50%)
• To evaluate the antitumor activity of novel immunotherapy combinations via treatment arm comparisons for assessment of contribution of components for the combination regimens
• To further characterize the safety of novel immunotherapy combinations
• To determine the immunogenicity of individual agents comprising novel immunotherapy combinations
• To characterize the PK properties of novel immunotherapy combinations |
● Evaluar la relación dosis-respuesta de nuevas combinaciones con inmunoterapia en un rango de niveles de dosis de los nuevos componentes y la dosis fija de dostarlimab (puede no aplicarse a todas las combinaciones nuevas)
● Evaluar más a fondo la actividad clínica de nuevas combinaciones con inmunoterapia comparado con pembrolizumab en participantes con CPNM con elevada expresión de PD-L1 (CT/TPS ≥50%)
● Evaluar la actividad antitumoral de nuevas combinaciones con inmunoterapia mediante comparaciones de los brazos de tratamiento para la evaluación de la contribución de los componentes de las terapias combinadas
● Caracterizar más a fondo la seguridad de nuevas combinaciones con inmunoterapia
● Determinar la inmunogenicidad de cada agente que compone las nuevas combinaciones con inmunoterapia
● Caracterizar las propiedades FC de nuevas combinaciones con inmunoterapia |
|
| 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 |
Substudy 1: dostarlimab + GSK4428859A
Substudy 2: dostarlimab + GSK6097608 + GSK4428859A
Monotherapy arm 1: pembrolizumab,
Monotherapy Arm 2 dostarlimab
date and version are as per the main protocol; objectives are per main protocol.
See Sec 10.3 and 10.4 213824 study protocol. |
|
| E.3 | Principal inclusion criteria |
Key Inclusion Criteria
1. Is capable of giving signed informed consent
2. Is, at the time of signing the ICF, at least 18 years old or the legal age of consent in the jurisdiction in which the study is taking place.
3. Has a histologically or cytologically confirmed diagnosis of locally advanced unresectable NSCLC not eligible for curative surgery and/or definitive radiotherapy with or without chemotherapy or metastatic NSCLC (squamous or nonsquamous). Mixed tumors will be categorized by the predominant cell type; if small cell or neuroendocrine elements are present, the participant is ineligible.
4. Has not received prior systemic therapy for their locally advanced or metastatic NSCLC.
NOTE: Completion of treatment with cytotoxic chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed if therapy was completed at least 6 months prior to the diagnosis of locally advanced or metastatic disease. Prior treatment with neoadjuvant/adjuvant immunotherapy is not permitted.
5. Has a PD-L1-high tumor
6. Has measurable disease based on RECIST 1.1 (Appendix 7), as determined by the investigator.
7. Has an ECOG PS 0 or 1.
8. Has adequate organ function
9. If of childbearing potential, female participants must be willing to use adequate contraception.
Refer protocol for other inclusion criteria |
1. Capacidad de dar consentimiento informado.
2. Tener, al momento de firma del consentimiento informado, al menos 18 años de edad, o la edad legal de dar el consentimiento en la jurisdicción en cual el estudio tiene lugar.
3. Diagnostico citológico o histológico confirmado de CPNM no resecable localmente avanzado, no elegible para cirugía curativa y/o radioterapia definitiva con o sin quimioterapia; o CPNCM metastásico (escamoso o no escamoso). Los tumores mixtos se clasificarán según el tipo celular predominante; si hay elemento microcíticos o neuroendocrinos, el participante no será elegible.
4. No haber recibido tratamiento sistémico anteriormente para la enfermedad localmente avanzada o metastásica de CPNM. Nota: tratamiento completado con quimioterapia citotóxica y/o radiación como parte del tratamiento neoadyuvante/adyuvante está permitido, si la terapia se ha completado al menos 6 meses antes del diagnóstico de la enfermedad localmente avanzada o metastásica. No están permitidos pacientes que hayan recibido anteriormente inmunoterapia en neoadyuvancia/adyuvancia.
5. Estado documentado de expresión de PD‑L1 alta.
6 Enfermedad medible basada en RECIST 1.1 (apéndice 7), a determinación por el investigador.
7. Estado funcional según la escala del ECOG de 0 o 1.
8. Función orgánica adecuada según se define en la tabla 1.
9. Las mujeres potencialmente fértiles deben estar dispuestas a utilizar un adecuado sistema anticonceptivo.
Consulte el protocolo para otros criterios de inclusión. |
|
| E.4 | Principal exclusion criteria |
Key Exclusion criteria
1. Has NSCLC with a tumor that harbors any of the following molecular alterations:
a. EGFR mutations that are sensitive to available targeted inhibitor therapy
b. ALK translocations that are sensitive to available targeted inhibitor therapy.
c. Any other known genomic aberrations or oncogenic driver mutations for which a locally approved targeted therapy is available for first line treatment of locally advanced or metastatic NSCLC.
2. Has had major surgery within 4 weeks of the first dose of study intervention or has received lung radiation therapy of >30 Gy within 6 months of the first dose of study intervention.
3. Has received prior therapy with any immune checkpoint inhibitors, including antibodies or drugs targeting PD-1, PD-L1, CTLA-4, TIGIT, CD96, or other checkpoint pathways.
4. Has never smoked, defined as smoking <100 tobacco cigarettes in a lifetime.
5. Has an invasive malignancy or history of invasive malignancy other than the disease under study within the last 5 years
6. Has known symptomatic, untreated, or actively progressing brain metastases and/or leptomeningeal disease. Participants who have received prior therapy for brain metastases and have stable CNS disease
7. Has autoimmune disease or syndrome (current or history thereof) that required systemic treatment within the past 2 years.
8. Has any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis.
9. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment of these conditions (including therapeutic thoracentesis or paracentesis) is eligible if the participant otherwise meets entry criteria.
10. Has active inflammatory bowel disease, acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or peritoneal carcinomatosis.
11. Has a history or evidence of cardiac abnormalities within the 3 months prior to enrollment
12. QTcF >470 msec, or >480 msec for participants with bundle branch block. QTcF is QT corrected for heart rate according to Fridericia’s formula and can be machine calculated or manually over-read.
13. Has active tuberculosis (i.e., history of exposure or history of positive tuberculosis test, plus presence of clinical symptoms or physical or radiographic findings).
14. Has a known human immunodeficiency virus infection.
15. Has a history of severe hypersensitivity to mAbs or to any of the excipients in the formulations of the components of the study interventions.
16. Has a positive test for the presence of HBsAg at Screening or within 3 months prior to first dose of study intervention.
17. Has a positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study intervention.
NOTE: Participants with a positive hepatitis C antibody test due to prior resolved disease can be enrolled only if a confirmatory negative hepatitis C RNA test is obtained.
18. Has a positive hepatitis C RNA test result at Screening or within 3 months prior to first dose of study intervention.
NOTE: Participants with a negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing.
Refer protocol for other exclusion criteria |
1. CPNM con tumores que contengan cualquiera de las siguientes alteraciones moleculares:
a. Mutaciones EGFR que sean sensibles a terapias disponibles de inhibidores diana.
b. Las traslocaciones ALK que son sensibles a terapias dirigidas disponibles.
c. Cualquier otra aberración genómica conocida o mutación oncogénica dirigida para la cual haya aprobada localmente una terapia diana y esté disponible en primera lía para CPNM localmente avanzado o metastásico
2. Realización de una cirugía mayor en las 4 semanas previas a la primera dosis del estudio o recepción de radioterapia pulmonar >30 Gy en los 6 meses previos a la primera dosis del tratamiento del estudio.
3. Recepción de tratamiento previo con un inhibidor de checkpoint, incluyendo anticuerpo anticuerpos o drogas diana de PD-1, PD L1, ctala-4, TIGIT, CD96, u otros puntos de vías de señalización.
4. No haber fumado (<100 cigarillos en su vida).
5. Neoplasia maligna invasiva o antecedentes de neoplasia maligna invasiva distinta de la enfermedad en estudio en los cinco últimos años.
6. Metástasis cerebrales conocidas sintomáticas, no tratadas, o activamente en progresión y/o enfermedad leptomeníngea. Los sujetos que hayan recibido terapia para las metástasis cerebrales y sean radiológicamente estables a nivel del SNC.
7. Síndrome o enfermedad autoinmunitaria (pasada o presente) que haya requerido tratamiento sistémico en los dos últimos años.
8. Antecedentes de fibrosis pulmonar idiopática, neumonía organizada, neumonitis droga-inducida, neumonitis idiopática o evidencia de neumonitis activa.
9. Ascitis sintomática o derrame pleural. Participantes que se encuentren clínicamente estables tras la terminación del tratamiento (incluyendo toracentesis terapeútica o paracentesis) son elegibles si se cumplen el resto de los criterios.
10. Enfermedad intestinal inflamatoria activa, diverticulitis aguda, absceso intraabdominal, obstrucción gastrointestinal, o carcinomatosis peritoneal.
11. Antecedentes o indicios de anomalías cardíacas en los 3 meses previos a la randomización.
12. QTcF > 470 msec, o >480 msec en participantes con bloqueo de rama. El QTc es el intervalo QT corregido por la frecuencia cardíaca según la fórmula de Fridericia (QTcF), con interpretación del aparato o manual.
13. Tuberculosis activa (por ejemplo, antecedentes de exposición o antecedentes de tuberculosis positiva, y presencia se síntomas clínicos o físicos o hallazgos radiológicos).
14. Infección conocida por el virus de la inmunodeficiencia humana.
15. Antecedentes de hipersensibilidad grave a anticuerpos monoclonales o hipersensibilidad a cualquiera de los tratamientos del estudio o a sus excipientes.
16. Presencia de antígeno de superficie del virus de la hepatitis B (HBsAg) en la visita de selección o en los tres meses previos a la primera dosis de la intervención del estudio.
17. Resultado positivo en análisis de anticuerpos contra la hepatitis C en la visita de selección o en los 3 meses anteriores a la primera dosis de la intervención del estudio.
NOTA: Podrán participar pacientes con anticuerpos contra el virus de la hepatitis C debido a enfermedad resuelta previa solo si se obtiene una prueba de confirmación negativa basada en la determinación del ARN del virus de la hepatitis C.
18. Resultado positivo en el análisis de ARN del virus de la hepatitis C en la visita de selección o en los 3 meses anteriores a la primera dosis del tratamiento del estudio.
NOTA: los participantes con un resultado negativo en el análisis de anticuerpos contra el virus de la hepatitis C no tendrán que someterse a dicho análisis de ARN.
Consulte el protocolo para otros criterios de exclusión. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • ORR per RECIST 1.1 by investigator assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| • every 6 weeks after randomization until week 25, every 9 weeks until week 52, and every 12 weeks thereafter until RECIST 1.1 defined PD." |
|
| E.5.2 | Secondary end point(s) |
• ORR per RECIST v1.1 by investigator assessment at different dose levels
• PFS per RECIST 1.1 by investigator assessment
• OS
• DOR per RECIST 1.1 by investigator assessment
• ORR, PFS, and DOR per RECIST 1.1 by investigator assessment, and OS for assessment of contribution of components for the combination regimens
• Incidence of TEAEs, SAEs and AESI
• Incidence of TEAEs/SAEs leading to dose modifications or study intervention discontinuation
• Incidence of ADA
• Plasma PK parameters |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• ORR: Every 6 weeks after randomization until week 25, every 9 weeks until week 52, and every 12 weeks thereafter until RECIST 1.1 defined PD."
• PFS: The time from the date of randomization to the date of first documented PD per RECIST 1.1 by investigator assessment, or death by any cause, whichever occurs first
• OS: Following treatment discontinuation, survival status will be assessed every 12 weeks after the last dose of study intervention, until death or participant’s withdrawal
• DOR: Time from the date of first documented CR or PR until the date of first documented PD per RECIST 1.1
All SAEs and AESI, Plasma PK parameters, Incidence of ADA will be collected throughout the study as per protocol
Refer protocol for other timepoints |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Platform Study Utilizing a Master Protocol |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Brazil |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| South Africa |
| Thailand |
| United States |
| Finland |
| France |
| Poland |
| Netherlands |
| Spain |
| Germany |
| Greece |
| Italy |
| Belgium |
| Hungary |
| Portugal |
| Russian Federation |
| Turkey |
| United Kingdom |
|
| 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
|
| LVLS |
| última visita del último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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