| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Muscle Invasive Bladder Cancer (NMIBC) |
| Cáncer de vejiga no músculo-invasivo (CVNMI) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Bladder Cancer |
| Cáncer de vejiga |
|
| 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 | 10005003 |
| E.1.2 | Term | Bladder 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 |
In:
Cohort A – Subjects with CIS at baseline (CIS only, Ta+CIS, or T1+CIS)
And
Cohort B – Subjects without CIS at baseline (High Grade Ta or Any Grade T1)
And
Cohort C - Subjects with CIS at baseline (CIS only, Ta+CIS, or T1+CIS)
The study is considered to have met its primary objective if the primary hypothesis for either Cohort A or Cohort B is successful.
To evaluate anti-tumor activity of pembrolizumab (MK-3475) by evaluating the absence of high risk NMIBC or progressive disease, as determined by cystoscopy, cytology, biopsy (if applicable), and radiologic imaging by central pathology and radiology review.
To evaluate anti-tumor activity of MK-7684A and MK-4280 by 12-month complete response (CR) rate of high-risk NMIBC, as determined by cystoscopy, cytology, biopsy and radiologic imaging by central pathology and radiology review. |
En:
Cohorte A - Sujetos con CIS en el momento basal (solo CIS, Ta+CIS o T1+CIS)
Y
Cohorte B - Sujetos sin CIS en el momento basal (Ta de grado alto o T1 de cualquier grado)Y
Cohorte C - Sujetos con CIS en el momento basal (solo CIS, Ta+CIS o T1+CIS)
Se considerará que el estudio ha cumplido su objetivo principal si la hipótesis principal en relación con la cohorte A o la cohorte B es satisfactoria.
Determinar la actividad antitumoral de pembrolizumab (MK-3475) mediante una evaluación de la ausencia de CVNMI de alto riesgo o progresión de la enfermedad mediante cistoscopia, citología, biopsia (si procede) y estudios de imagen según una evaluación anatomopatológica y radiológica centralizada.
Determinar la actividad antitumoral de MK-7684A y MK-4280A mediante la tasa de respuesta completa (RC) a los 12 meses del CVNMI de alto riesgo, por medio de cistoscopia, citología, biopsia y estudios de imagen según una evaluación anatomopatológica y radiológica centralizada. |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate anti-tumor activity by:
Cohort A -CIS at baseline
- CR rate of any disease
- DOR of high risk NMIBC and any disease (resp only)
- in PD-L1+ subjects by CR rate of high risk NMIBC and any disease
- in PD-L1+ subjects by DOR of high risk NMIBC and any disease (resp only)
- in study population & PD-L1+ subjects by:
a. DOR rate at specific time points of both high risk NMIBC and any disease (resp only)
Cohort B -no CIS at baseline
- by DFS rate of any disease
- in PD-L1 + subjects by 12-month DFS rate of high risk NMIBC and any disease
- in the study population and in PD-L1+ subjects by:
a. Overall DFS and 3-month/6-month DFS rates of high risk NMIBC and any disease
Cohort C - CIS at baseline
- DOR of high-risk NMIBC (responders only)
- CR rate at 3 months, CR rates at 6 months, overall CR rate
All cohorts:
- PFS, to worsening of grade or stage or death
- PFS, to muscle-invasive or metastatic disease or death; or
- OS |
Cohorte A-CIS momento basal
-tasa RC de enfermedad cualquier tipo
-DR del CVNMI y de enfermedad cualquier tipo (solo con respuesta)
-En sujetos con PD-L1+ tasa RC del CVNMI y de enfermedad cualquier tipo
-En sujetos con PD-L1+ DR del CVNMI y de enfermedad cualquier tipo (solo con respuesta)
-En la población del estudio y sujetos con PD-L1+ por:
a.Tasa de DR del CVNMI y de enfermedad cualquier tipo (solo con respuesta)
Cohorte B: sujetos sin CIS momento basal
-tasa SSE de enfermedad cualquier tipo
-En sujetos con PD-L1+ por la tasa SSE a los 12 meses del CVNMI y de enfermedad cualquier tipo
-En la población del estudio y sujetos con PD-L1+ por:
a.Tasas de SSE global y SSE a los 3/6 meses de CVNMI y de
enfermedad cualquier tipo
Cohorte C-CIS momento basal
-DR del CVNMI (solo con respuesta)
-Tasa RC a los 3, 6 meses y global
Todas las cohortes:
-SSP hasta empeoramiento del grado o estadio o la muerte
-SSP a enfermedad músculo-invasiva o metastásica o la muerte; o
-SG |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have a histologically-confirmed diagnosis of high risk non-muscle-invasive (T1, High Grade Ta and/or CIS) transitional cell carcinoma of the bladder.
2. In subjects who have papillary tumors (Ta and T1), a complete TURBT must have been performed, as characterized by:
- Attainment of a visually complete resection of all papillary tumors (Ta and T1)
-Residual CIS not amenable to complete resection is allowed
-The most recent cystoscopy/TURBT must have been performed within 12 weeks of randomization
-For Cohort C: subjects with T1 disease should have undergone a restaging TURBT procedure within 12 weeks prior to randomization to confirm complete resection.
3. Have been treated with adequate BCG therapy and have developed high risk NMIBC that is unresponsive to BCG therapy.
4. Have elected not to undergo, or are considered ineligible for radical cystectomy, as determined by the treating surgeon.
5. Have provided tissue for biomarker analysis from the most recent cystoscopy/TURBT procedures from which tumor sample is available.
6. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. (Max of 5% ECOG of 2.) (for cohorts A and B only)
7. Have adequate organ function.
8. A female participant is eligible if not pregnant or breastfeeding, and at least one of the following applies:
- Is not a WOCBP; or
- Is a WOCBP and using a contraceptive method as described in the protocol. A WOCBP must have a negative pregnancy test as described in the protocol |
1. Tener un diagnóstico confirmado histológicamente de carcinoma de células de transición de vejiga no músculo-invasivo de alto riesgo (T1, Ta de alto grado y/o CIS).
2. En los sujetos con tumores papilares (Ta y T1) deberá haberse practicado una RTUTV completa, caracterizada por:
• Realización de una resección visualmente completa de todos los tumores papilares (Ta y T1)
• Se permite la presencia de un CIS residual no susceptible de resección completa
• La cistoscopia/RTUTV más reciente tendrá que haberse realizado en las 12 semanas previas a la aleatorización
•En la cohorte C: los sujetos con enfermedad T1 deben haberse sometido a una RTUTV de reestadificación en las 12 semanas previas a la aleatorización para confirmar la resección completa.
3. Recepción de una terapia adecuada con BCG y aparición de un CVNMI de alto riesgo sin respuesta a la terapia con BCG.
4. Haber optado por no someterse a una cistectomía radical, o ser considerado no apto para someterse a ella, según lo determinado por el cirujano responsable del tratamiento.
5. Facilitación de tejido para análisis de biomarcadores a partir de los procedimientos de cistoscopia/RTUTV más recientes de los que se disponga de una muestra tumoral.
6. Presencia de un estado funcional de 0, 1 o 2 según la escala del Eastern Cooperative Oncology Group (ECOG). (Máximo del 5% de sujetos con un estado del ECOG de 2) (Únicamente en las cohortes A y B).
7. Presencia de una función orgánica adecuada.
8. Podrán participar mujeres que no estén embarazadas ni en período de lactancia y que cumplan al menos una de las condiciones siguientes:
• No tener capacidad de procrear.
O
• Tener capacidad de procrear y utilizar un método anticonceptivo muy eficaz según se describe en el protocolo. Las mujeres con capacidad de procrear deberán dar negativo en una prueba de embarazo según se describe en el protocolo. |
|
| E.4 | Principal exclusion criteria |
1. Has centrally-assessed muscle invasive (i.e. T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma.
2. Has centrally-assessed concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium.
3. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
4. Has undergone any intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy/TURBT to starting trial treatment.
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1, Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
6. Has a known additional malignancy that has had progression or has required active treatment in the last three years
7. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks before randomization/study allocation for Cohort C.
8. Has severe hypersensitivity to pembrolizumab (all cohorts), MK-7684A (Cohort C arm 1), MK-4280A (Cohort C Arm 2), and/or any of their excipients.
9. Has an active autoimmune disease that has required systemic treatment in past 2 years.
10. 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 to the first dose of the study intervention. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
11. Has a history of (non-infectious) pneumonitis/or interstitial lung disease that required steroids or has current pneumonitis.
12. Has an active infection requiring systemic therapy, including active or intractable UTI in the last month.
13. Has a history or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation, or is not in the best interest of the subject to participate, in the opinion of the investigator.
14. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL2 agent, or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).
17. Has received previous treatment with another agent targeting the TIGIT and/or LAG3 receptor pathway (Cohort C only).
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
19. Has known active Hepatitis B or Hepatitis C.
20. Has received a live virus vaccine within 30 days of planned start of trial treatment.
21. Has had an allogeneic tissue/solid organ transplant. |
1. Presenta un carcinoma urotelial músculo-invasivo (es decir, T2, T3 o T4), localmente avanzado irresecable o metastásico.
2. Presenta un carcinoma urotelial de células de transición no músculo-invasivo extravesical (es decir, uretra, uréter o pelvis renal) concurrente.
3. Está participando o ha participado en un estudio de un fármaco o dispositivo en investigación y está recibiendo o ha recibido el fármaco o utilizado el dispositivo en investigación en las 4 semanas previas a la primera dosis del tratamiento del ensayo.
4. Ha recibido quimioterapia o inmunoterapia intravesical intermedia entre el momento de la cistoscopia/RTUTV más reciente y el comienzo del tratamiento del ensayo.
5. Ha recibido quimioterapia, un tratamiento de molécula pequeña dirigido contra dianas moleculares o radioterapia en las 2 semanas previas al día 1 del ciclo 1 o no se ha recuperado (es decir, hasta un grado ≤1 o la situación basal) de acontecimientos adversos debidos a un fármaco administrado anteriormente.
6. Presencia de otra neoplasia maligna conocida que ha mostrado progresión o que ha necesitado tratamiento activo en los 3 últimos años.
7. Presencia o acumulación progresiva de líquido pleural,ascítico o pericárdico con necesidad de drenaje o diuréticos en las 2 semanas previas a la aleatorización/asignación del estudio en la cohorte C.
8. Hipersensibilidad grave a pembrolizumab (todas las cohortes), MK-7684A (grupo 1 de la cohorte C), MK-4280A (grupo 2 de la cohorte C) y/o a cualquiera de sus excipientes.
9. Presencia de una enfermedad autoinmunitaria activa que haya precisado tratamiento sistémico en los 2 últimos años.
10. Diagnóstico de inmunodeficiencia o recepción de tratamiento sistémico crónico con corticoides (en dosis superiores a 10 mg diarios de prednisona o equivalente) o cualquier otra forma de tratamiento inmunodepresor en los 7 días previos a la primera dosis de la intervención del estudio. Se podrá autorizar el uso de dosis fisiológicas de corticoides previa consulta al promotor.
11. Antecedentes de neumonitis (no infecciosa)/neumopatía intersticial con necesidad de corticoides o presencia de neumonitis.
12. Presencia de una infección activa con necesidad de tratamiento sistémico, como una infección urinaria activa o resistente en el último mes.
13. Antecedentes o datos actuales de cualquier trastorno,tratamiento o anomalía analítica que, en opinión del investigador responsable del tratamiento, pueda confundir los resultados del ensayo,afectar a la participación del sujeto durante todo el ensayo o hacer que la participación no sea lo más conveniente para el sujeto.
14. 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.
15. Embarazo o lactancia materna o intención de concebir un hijo durante el período previsto del ensayo, desde la visita de selección hasta 120 días después de la última dosis del tratamiento del ensayo.
16. 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 (p. ej., CTLA-4, OX-40 o CD137).
17. Tratamiento previo con otro fármaco dirigido contra la vía del receptor TIGIT y/o LAG3 (únicamente en la cohorte C).
18. Antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH) (anticuerpos contra el VIH-1 o 2).
19. Presencia de hepatitis B activa demostrada o hepatitis C demostrada.
20. Recepción de una vacuna con virus vivos en los 30 días previos al comienzo previsto del tratamiento del ensayo.
21. Recepción de un alotrasplante de órgano sólido o tejidos. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Cohort A and C: CR rate of high risk NMIBC in the overall population.
Cohort B: 12-month DFS rate of high risk NMIBC in the overall population. |
Cohorte A y C: Tasa de RC de CVNMI de alto riesgo en la población general.
Cohorte B: Tasa de SLE a los 12 meses del CVNMI de alto riesgo en la población general. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim Analysis Proof of Concept (IA POC) = 20 Cohort A subjects @ 12 weeks
Interim Analysis II (IA 2) = 50 Cohort A subjects @ 24 weeks
Final Analysis = Full Enrollment plus 9 months |
Prueba de concepto de análisis provisional (IA POC) = 20 sujetos de la cohorte A a las 12 semanas
Análisis intermedio II (IA 2) = 50 sujetos de la cohorte A a las 24 semanas
Análisis final = reclutamiento completo más 9 meses |
|
| E.5.2 | Secondary end point(s) |
Cohort A and C: CR rate of any disease in the overall population; DOR of high risk NMIBC and any disease.
Cohort B: 12-month DFS rate of any disease in the overall population. |
Cohorte A y C: tasa de RC de cualquier enfermedad en la población general; DOR de CVNMI de alto riesgo y cualquier enfermedad.
Cohorte B: tasa de SLE a 12 meses de cualquier enfermedad en la población general. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Interim Analysis Proof of Concept (IA POC) = 20 Cohort A subjects @ 12 weeks
Interim Analysis II (IA 2) = 50 Cohort A subjects @ 24 weeks
Final Analysis = Full Enrollment plus 9 months |
Prueba de concepto de análisis provisional (IA POC) = 20 sujetos de la cohorte A a las 12 semanas
Análisis intermedio II (IA 2) = 50 sujetos de la cohorte A a las 24 semanas
Análisis final = Inscripción completa más 9 meses |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Brazil |
| Canada |
| Japan |
| Korea, Republic of |
| Puerto Rico |
| Singapore |
| United States |
| Finland |
| France |
| Sweden |
| Netherlands |
| Spain |
| Greece |
| Italy |
| Ireland |
| Russian Federation |
| Turkey |
| 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 | 6 |
| 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 | 6 |
| 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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