| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early stage localized Renal Cell Carcinoma |
| Carcinoma de células renales localizado en estadio precoz |
|
| E.1.1.1 | Medical condition in easily understood language |
| Early stage localized renal cancer |
| Cáncer renal localizado en estadio precoz |
|
| 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 | 10038395 |
| E.1.2 | Term | Renal carcinoma |
| E.1.2 | System Organ Class | 100000056053 |
|
| 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 compare disease-free survival (DFS) per Blinded Independent Central Review (BICR) of nivolumab combined with
ipilimumab versus placebo infusions in participants with localized renal cell carcinoma, with a predominantly clear cell histology, who have undergone a nephrectomy. |
| Comparar la supervivencia libre de enfermedad (SLE) determinada por un comité revisor central independiente y ciego (BICR) de nivolumab combinado con ipilimumab versus placebo en participantes con carcinoma de células renales localizado, con histología predominante de células claras que se hayan sometido a una nefrectomía. |
|
| E.2.2 | Secondary objectives of the trial |
1) To compare overall survival (OS), including the 5-year OS rates, of nivolumab combined with ipilimumab vs placebo infusions in participants with localized renal cell carcinoma with a predominantly clear cell histology who have undergone a nephrectomy
2) To describe the safety and tolerability of nivolumab combined with ipilimumab |
1) Comparar la supervivencia global (SG), incluidas las tasas de SG a 5 años, de nivolumab combinado con ipilimumab vs placebo en participantes con carcinoma de células renales localizado con histología predominante de células claras que se hayan sometido a una nefrectomía
2) Describir la seguridad y tolerabilidad de nivolumab combinado con ipilimumab |
|
| 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 |
Additional research is optional for all study participants, except where retention and/or collection is prohibited by local laws or regulations, ethics committees, or institutional requirements.
This collection for additional research is intended to expand the translational R&D capability at Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our understanding of disease and options for treatment. It may also be used to support health authority requests for analysis, and advancement of pharmacodiagnostic development to better target drugs to the right patients. This may also include genetic/genomic exploration aimed at exploring disease pathways, progression and response to treatment etc. |
| La investigación adicional es opcional para todos los participantes del estudio, excepto donde la retención y/o recogida está prohibida por legislación local, comités éticos o requerimientos institucionales. Esta recogida para la investigación adicional tiene como objetivo expandir la capacidad translacional de I+D en Bristol-Myers Squibb, y apoyará objetivos de investigación aún no definidos que fomentarán nuestra comprensión de la enfermedad y las opciones de tratamiento. También se podrá utilizar para apoyar las solicitudes de análisis de las autoridades sanitarias, y el avance del desarrollo farmacodiagnóstico para orientar mejor los fármacos hacia los pacientes adecuados. Esto también puede incluir la exploración genética/genómica dirigida a explorar las vías de la enfermedad, la progresión y la respuesta al tratamiento, etc. |
|
| E.3 | Principal inclusion criteria |
a) Kidney tumor has been completely resected, and the nephrectomy must occur no less than 4 weeks and less or equal to 12 weeks prior to randomization. Partial nephrectomy is allowed provided all inclusion criteria are met and negative surgical margins are obtained.
b) Post-nephrectomy tumor shows RCC with a predominately clear cell histology, including participants with sarcomatoid features.
c) Pathological TNM staging per AJCC staging version 2010:
i) pT2a, G3 or G4, N0M0
ii) pT2b, G any, N0M0
iii) pT3, G any, N0M0
iv) pT4, G any, N0M0
v) pT any, G any, N1M0
d) Participants must have no clinical or radiological evidence of macroscopic residual disease or distant metastases (M0) after nephrectomy
i) Baseline tumor assessment, performed 4 to approximately 12 weeks after nephrectomy, shows no metastasis or residual tumor lesions per local review and as confirmed by Blinded Independent Central Review (BICR). Results of BICR of the baseline tumor assessment confirming absence of metastasis or residual tumor lesions must be received before randomization.
Note: participants with one or more regional lymph nodes identified with short axis more or equal to 15 mm on the baseline tumor assessments are considered to have gross residual disease and are therefore ineligible.
e) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1.
f) Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, obtained within 3 months prior to enrollment, preferably from nephrectomy, with an associated pathology report, must be submitted to the central laboratory prior to randomization. FFPE block or 20 unstained slides is ideal, but a minimum of 10 unstained
slides will be acceptable if tumor tissue is limited. Biopsy should be excisional, incisional, or core needle. Fine needle aspiration is unacceptable for submission. |
a) El tumor renal se ha resecado completamente y la nefrectomía debe producirse no menos de 4 semanas y ≤ 12 semanas antes de la aleatorización. Se permite la nefrectomía parcial siempre que se cumplan todos los criterios de inclusión y se obtengan márgenes quirúrgicos negativos.
b) Muestra tumoral posnefrectomía muestra CCR con una histología predominantemente de células claras, incluidos participantes con tumores con rasgos sarcomatoides.
c) Estadificación TNM patológica según la estadificación del AJCC versión 2010:
i) pT2a, G3 o G4, N0M0
ii) pT2b, G cualquiera, N0M0
iii) pT3, G cualquiera, N0M0
iv) pT4, G cualquiera, N0M0
v) pT cualquiera, G cualquiera, N1M0
d) Los participantes no deben tener pruebas clínicas o radiológicas de enfermedad residual macroscópica o metástasis a distancia (M0) después de la nefrectomía.
i) La evaluación tumoral basal, realizada de 4 a aproximadamente 12 semanas después de la nefrectomía, no muestra metástasis ni lesiones tumorales residuales según la revisión local y confirmado por un comité revisor central independiente y ciego (BICR). Deben haberse recibido resultados del BICR de la evaluación tumoral basal que confirmen la ausencia de metástasis o lesiones tumorales residuales antes de la aleatorización.
Nota: a los participantes con uno o más ganglios linfáticos regionales identificados con un eje corto ≥ 15 mm en las evaluaciones tumorales basales se les considera con enfermedad residual macroscópica y, por tanto, no son elegibles.
e) Estado funcional (PS, Performance Status) del Eastern Cooperative Oncology Group (ECOG) de 0-1 (Apéndice 5).
f) Previo a la aleatorización, debe enviarse al laboratorio central bien un bloque de tejido fijado en formol e incluido en parafina (FFIP) o secciones tumorales no teñidas, obtenido dentro de los 3 meses previos al reclutamiento, preferiblemente obtenido a partir de la nefrectomía, con un informe de anatomía patológica asociado. Es ideal el bloque FFIP o 20 secciones tumorales no teñidas, pero será aceptable un mínimo de 10 secciones tumorales no teñidas si el tejido tumoral disponible es limitado. La biopsia debe ser escisional, incisional o con aguja gruesa. Es inaceptable enviar aspiración con aguja fina. |
|
| E.4 | Principal exclusion criteria |
a) Any severe or serious, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration including ongoing or active infection requiring parental antibiotics
b) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Topical, ocular, intra-articular, intranasal, inhaled steroids, and adrenal replacement steroid doses > 10 mg daily prednisone or the
equivalent are permitted in the absence of active immune disease.
c) Uncontrolled adrenal insufficiency
d) Participants with an active known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. |
a) Cualquier enfermedad médica o psiquiátrica intensa o grave, aguda o crónica, que pueda aumentar el riesgo asociado con la participación en el estudio o con la administración del fármaco del estudio, incluidas infecciones que se mantienen o activas que precisen antibióticos parenterales
b) Participantes con una condición médica que precise tratamiento sistémico con corticosteroides (> 10 mg al día de prednisona o equivalente) u otra medicación inmunosupresora dentro de los 14 días previos a la primera dosis del fármaco del estudio. Se permiten esteroides tópicos, oculares, intraarticulares, intranasales, inhalados y dosis de esteroides de sustitución suprarrenal > 10 mg al día de prednisona o equivalente en ausencia de enfermedad inmunitaria activa.
c) Insuficiencia suprarrenal no controlada
d) Participantes con una enfermedad autoinmunitaria activa, conocida o de sospecha. Se permite la inclusión de participantes con diabetes mellitus de tipo I, hipotiroidismo que solo precise sustitución hormonal, trastornos cutáneos (como vitíligo, psoriasis o alopecia) que no precisen tratamiento sistémico o condiciones médicas que no se espere que recurran en ausencia de un desencadenante externo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is DFS (disease-free survival). |
| El criterio de valoración principal es SLE (supervivencia libre de enfermedad). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint of DFS will be programmatically determined based on the disease recurrence date provided by the BICR. DFS is defined as the time from randomization to development of local disease recurrence (ie, recurrence of primary tumor in situ or occurrence of a secondary RCC primary cancer), distance metastasis, or death, whichever came first. |
| El criterio de valoración principal de SLE se determinará programáticamente de acuerdo con la fecha de recidiva de la enfermedad facilitada por el BICR. La SLE se define como el tiempo desde la aleatorización hasta el desarrollo de recidiva local de la enfermedad (esto es, recidiva del tumor primario in situ o aparición de un segundo cáncer primario de tipo CCR), metástasis a distancia o muerte, lo que suceda antes. |
|
| E.5.2 | Secondary end point(s) |
| Overall survival OS |
| Supervivencia global SG |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| OS, defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the participants were known to be alive. |
| SG, definida como el tiempo entre la fecha de la aleatorización y la fecha de la muerte. Para los participantes sin documentación de la muerte, la SG se censará en la última fecha en la que se supo que los participantes estaban vivos. |
|
| 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 | Yes |
| 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) | 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 | 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 | 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 | 5 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Mexico |
| Netherlands |
| Peru |
| Poland |
| Russian Federation |
| Singapore |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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
|
| End of trial is defined as the last participant’s last study visit or phone call. |
| El fin del ensayo se define como la última visita o llamada de teléfono del último participante. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 11 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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