| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal cancer |
| Cáncer colorrectal metastásico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Colorectal cancer |
| Cáncer colorrectal |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Parts 1, and 1A (no EU subjects):
- To characterize the safety and tolerability of combination therapies
- To establish recommended dosing regimen for the combination (nivolumab plus ipilimumab plus trametinib OR nivolumab plus trametinib)
Parts 1B and 2:
- To evaluate the ORR in all participants treated with nivolumab plus ipilimumab and trametinib in the 2L and 3L setting (Parts 1B and 2) and regorafenib in 3L (Part 2 only) |
Partes 1, y 1A (sujetos no Europeos):
- Caracterizar la seguridad y tolerabilidad de los tratamientos de combinación.
- Establecer el régimen de dosis recomendado para la combinación (nivolumab más ipilimumab más trametinib O nivolumab más trametinib).
Partes 1B y 2:
Evaluar la TRO en todos los participantes tratados con nivolumab más ipilimumab y trametinib en el contexto de 2L y 3L (Partes 1B y 2) y regorafenib en 3L (Parte 2 exclusivamente). |
|
| E.2.2 | Secondary objectives of the trial |
Parts 1, and 1A (no EU subjects):
- To evaluate preliminary efficacy
Parts 1B and 2:
- To evaluate efficacy in all participants treated with nivolumab plus ipilimumab and trametinib in the 2L and 3L setting (Parts 1B and 2); and regorafenib in 3L (Part 2 only)
- To evaluate efficacy in subgroups of CMS in 3L MSS CRC patients treated with nivolumab plus ipilimumab and trametinib vs. regorafenib (Part 2), as well as explore efficacy in relation to CMS
subgroups in 2L MSS CRC patients (Part 1B)
- To characterize the safety and tolerability of combination therapies |
Partes 1, y 1A (sujetos no Europeos):
Evaluar la eficacia preliminar
Partes 1B y 2:
Evaluar la eficacia en todos los participantes tratados con nivolumab más ipilimumab y trametinib en el contexto de 2L y 3L (Partes 1B y 2) y regorafenib en 3L (Parte 2 exclusivamente).
Evaluar la eficacia en subgrupos de CMS en pacientes con CCR MSS en 3L tratados con nivolumab más ipilimumab y trametinib frente a regorafenib (Parte 2), así como explorar la eficacia en relación con los subgrupos de CMS en pacientes con CCR MSS en 2L (Parte 1B).
Caracterizar la seguridad y la tolerabilidad de los tratamientos de combinación. |
|
| 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 |
For non-US Sites
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 research and development (R&D) capability at BMS, 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. |
Para no USA:
La investigación adicional es opcional para rodos los participantes en el ensayo, except donde la retención y/o recogida de muestras estñe prohibida por la ley,
Comités éticos o requerimientos institucionales.
La recogida de muestras para investigaciones adicionales etiene como objetivo expandir la capacidad de la investigación traslacional y el desarrollo (R&D) en BMS, y soportará la todavía investigación indefinida que permitirá avanzar nuestro conocimiento de la enfermedad y opciones de tratamiento. También puede utilizarse para justificar las peticiones de las Autoridades Sanitarias para análisis, y avances del desarrollo farmacodiagnóstico para dirigir los mejores tratamientos a los pacientes más adecuados. Esto también podría incluir exploración genetica/genomica que ayide a explorer las vias de la enfermedad, progresión y respuesta sl tratamiento etc. |
|
| E.3 | Principal inclusion criteria |
• Age ≥ 18, signed written informed consent
• Histological or cytological confirmed diagnosis of previously treated mCRC with adenocarcinoma histology and in Stage IV per AJCC
• Confirmed microsatellite status: only participants with pMMR/MSS mCRC are eligible
• Verified KRAS, NRAS (extended RAS) and BRAF mutation status: BRAF V600 mutant are not eligible
• Measurable disease per RECIST 1.1
• Provide Tumor Tissue sample at screening.
• ECOG Performance Status of 0-1 |
• Edad ≥ 18, consentimiento informado escrito, firmado
• Diagnóstico confirmado histlógica o citológicamente de Cáncer Colorrectal metastásico previamente tratado, con histología de adenocarcinoma y en estadío IV por AJCC
• Estatus de microsatélites confirmado: solo pacientes con pMMR/MSS mCRC son elegibles
• Estatus de mutaciones verificado: KRAS, NRAS (RAS extendido ) y BRAF: los pacientes con mutación BRAF V600 no son elef¡gibles
• Enfermedad medible por RECIST 1.1
• Aportar muestra de tejido tumoral en el screening.
• ECOG estado functional de 0-1 |
|
| E.4 | Principal exclusion criteria |
1) Target Disease Exceptions
a) Participants with BRAF V600 mutant colorectal cancer are NOT eligible for this study in Part 1, 1A, and 1B only.
2) Medical History and Concurrent Diseases
a) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results.
b) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate/cervix/breast.
c) Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders not requiring systemic treatment, or conditions not
expected to recur in the absence of an external trigger are permitted to enroll.
d) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.
e) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents.
f) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE [current version]) or baseline before administration of study drug.
g) Toxicities from the prior anti-cancer treatment have not been resolved to Grade 1 (NCI CTCAE current version) at the time of study entry
h) Current use of a prohibited medication. Treatment with botanical preparations (eg, herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to first dose of study treatment
i) Prior treatment with any MEK inhibitor
j) History of interstitial lung disease or pneumonitis.
k) Inability to take oral medication or significant nausea and vomiting, malabsorption, external biliary shunt, significant bowel resection that would preclude adequate absorption of oral medication.
l) Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule.
m) Additional criteria for Part 2 only:
i) Prior treatment with regorafenib or TAS-102
ii) Severe hepatic impairment (Child-Pugh C)
iii) Any evidence of active bleeding, or hemorrhage or bleeding event ≥ NCI-CTCAE Grade 3 within 4 weeks prior to the start of study medication
iv) Prior or current gastrointestinal perforation or fistula
v) Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis, or pulmonary embolism within 6 months before the start of study medication
vi) Non-healing wound, non-healing ulcer, or non-healing bone fracture
vii) Active infection (ie, body temperature ≥ 38°C due to infection)
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100×103/μL
d) Hemoglobin < 9.0 g/dL
e) PT/INR and PTT > 1.5 ×ULN
f) Serum creatinine > 1.5 ×ULN, unless creatinine clearance > 50 mL/min (measured or calculated using the Cockcroft-Gault formula)
g) AST and/or ALT: > 3.0 ×ULN
i) Part 2 ONLY: Participants with documented liver metastases with AST and ALT > 5.0 ×ULN will be excluded.
h) Total bilirubin > 1.5 ×ULN
i) Participants with Gilbert’s Syndrome who have a total bilirubin level of > 3.0 ×ULN will be excluded.
i) Albumin < 3.0 g/dL
j) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody positive (except if HCV-RNA negative).
k) History or evidence of cardiovascular risk
n) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
o) Participants with serous retinopathy or retinal vein occlusion noted on ophthalmological evaluation, or participants with a history of serous retinopathy/retinal vein occlusion.
4) Allergies/Adverse Drug Reaction
a) History of allergy/hypersensitivity to study drug components.
b) History of severe hypersensitivity reaction to any monoclonal antibody.
c) Have a known immediate or delayed hypersensitivity reaction/idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide.
5) Other Exclusion Criteria
a) Prisoners/participants who are involuntarily incarcerated.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical illness |
1) Excepciones de enfermedades diana
a) Pacientes con CRC con mutación RAF V600 NO son elegibles para la parte 1, 1A, y 1B.
2) Historial Médico y enfermedades concurrentes
a) cualquier alteración médica grave o incontrolada en opinión del investigador pueda aumentar el riesgo asociado con la participación en el ensayo o con la administración del fármaco, disminuya la capacidad del paciente de recibir el tto. del protocolo o interfiera con la interpretación de resultados.
b) Malignidad previa activa, en los 3 años previos excepto cánceres curables locamente que aparentemente hayan sido curados, como cáncer de piel de células basales o escamosas, cáncer de vejiga superficial, o carcinoma in situ de prostata/cervix/mama.
c) Se permite reclutar pacientes con enfermedad autoinmune activa, conocida o sospechada, pacientes con diabetes melitus tipo I, hipotiroidismo solo si no requieran sustitución hormonal, alteraciones de la piel que no requieren tto. sistémico, o condiciones no esperadas que les hiciese recurrir en ausencia de algo externo
d) Pacientes con una condición que requiera tto. sistémico con corticosteroides (> 10 mg de prednisona o equivalente al día) u otra medicación inmunosupresora en los 14 d siguientes al tratamiento del ensayo.
e) Tto. previo con anti-PD-1, anti-PD-L1, anti-PD-L2, anticuerpos anti-CTLA-4, o cualquier otro anticuerpo o medicamento dirigido a la coestimulación de células T o vias de punto de control inmunitario, incluyendo tto. previo con vacunas antitumorales o agentes anti tumorales.
f) Todas las toxicidades atribuidas a ttos. previos anti cancerosos que no sean alopecia y fatiga deben haberse resuelto hasta Grado 1 (NCI CTCAE) o al estado basal antes de la administración del medicamento del ensayo.
g) Las toxicidades de un tto. anticanceroso previo que no se hayan resuelto a Grado 1 (NCI CTCAE) en el momento de su entrada en el EC
h) Uso actual de medicación prohibida. Tto. con preparaciones botánicas (p. ej. suplementos vegetales o medicinas chinas tradicionales) utilizados como soporte o tto de la enfermedad del EC dentro de las 2 semanas previas a la primera dosis del tto.del EC
i) Tto. previo con inhibidor de MEK
j) Historial de enfermedad pulmonar interesticial o neumonitis.
k) incapacidad para tomar medicación oral o nauseas o vómitos significativos, mala absorción, derivación biliar externa, resección intestinal significativa que impediría la absorción adecuada de la medicación oral.
l) Condiciones psicológicas, familiares o sociológicas que pongan en peligro el cumplimiento del prot. del EC o su seguimiento.
m) Criterios adicionales, parte 2 :
i) Tto. previo con regorafenib o TAS-102
ii) Insuficiencia hepática grave (Child-Pugh C)
iii) Evidencia de sangrado activo, hemorragia o sangrado ≥ NCI-CTCAE Grado 3 en las 4 W previas al comienzo del tto. del EC
iv) Fistula o perforación gastrointestinal previa o actual
v) Acontecimientos trombóticos o embólicos arteriales o venosos como accidentes cerebrovasculares, trombosis venosa profunda, o embolia pulmonar en los 6 meses previos al tto. del EC
vi) Héridas y úlceras que no cicatrizan o fracturas óseas que no sueldan
vii) Infección activa (Tª corporal ≥ 38°C debido a una infección)
3)Resultados de Análisis de laboratorio:
a) Glçobulos blancos < 2000/μL
b) Neutrófilos < 1500/μL
c) Plaquetas < 100×103/μL
d) Hemoglobina < 9.0 g/dL
e) PT/INR and PTT > 1.5 ×ULN
f) Creatinina sérica > 1.5 ×ULN, aclaramiento de creatinina > 50 mL/min (calculados con la formula Cockcroft-Gault)
g) AST y/o ALT: > 3.0 ×ULN
i) Parte2 SOLO: Pacientes con metástasis hepáticas documentadas con AST y ALT > 5.0 ×ULN serán excluidos.
h) Bilirrubina total > 1.5 ×ULN
i) Pacientes con Síndrome de Gilbert con un nivel de bilirrubina total de > 3.0 ×ULN serán excluidos.
i) Albumina < 3.0 g/dL
j) Cualquier resutado positivo en un test de hepatitis B o hepatitis C que indican la presencia de virus, como antígeno de superficie de la Hepatitis B (HBsAg,
antígeno Australia) positivo, o anticuerpos de Hepatitis C positivo (excepto si HCV-RNA es negativo).
k) Historial o evidencia de riesgo cardiovascular
n) Historial de test positivos de HIV o SIDA conocido.
o) Retinopatía grave u oclusión de la vena de la retina detectada por evaluación oftalmológica, o pacientes con historial de retinopatía / oclusión de la vena de la retina.
4) Alergias/Reacciones adversas a medicamentos
a) Historial de alergia/hipersensibilidad a los componentes de la medicación del EC.
b) Historial de hipersensibilidad grave a cualquier anticuerpo monoclonal.
c) Tener una reacción de hipersensibilidad/idiosincrasia inmediata o retardada
a medicamentos químicamente relacionadas con la medicación del EC o
excipientes o al dimetil sulfoxido.
5) Otros criterios de exclusión
a) Presos/pacientes encarcelados involuntariamente.
b) Participantes detenidos involuntariamente detenidos para el tto. de enfermedades psiquiatricas o físicas |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR by investigator |
| TRO por el investigador |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Under current accrual assumption, approximately 12 months from the FPFT. |
| Bajo las actuales asunciones, aproximadamente 12 meses desde FPFT |
|
| E.5.2 | Secondary end point(s) |
| BOR, DCR, DOR, TTR, and PFS by investigator, OS and Safety |
| MTO, DRC, DRO, TTR y SLP por el investigador. SG y seguridad |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Under current accrual assumption, approximately 19 months from the FPFT. |
| Bajo las actuales asunciones, aproximadamente 19 meses desde FPFT |
|
| 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 | Yes |
| 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 | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| It is the first time that subjects will be admnistered Nivo/Tram and Nivo/Ipi/Tram together |
|
| 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 | 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 | 7 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Australia |
| Canada |
| United States |
| Belgium |
| Germany |
| Italy |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 7 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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