| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Muscle-Invasive Urothelial Carcinoma (NMIBC) of the Bladder |
| Cáncer de vejiga urotelial 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 | LLT |
| E.1.2 | Classification code | 10046714 |
| E.1.2 | Term | Urothelial carcinoma bladder |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10046720 |
| E.1.2 | Term | Urothelial carcinoma bladder stage II |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10046721 |
| E.1.2 | Term | Urothelial carcinoma bladder stage III |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10046722 |
| E.1.2 | Term | Urothelial carcinoma bladder stage IV |
| 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 |
| To evaluate the overall Complete Response (CR) rate in participants treated with TAR-200 in combination with cetrelimab (Cohort 1), or TAR-200 alone (Cohort 2), or cetrelimab alone (Cohort 3) with Carcinoma in Situ (CIS), with or without concomitant high-grade Ta or T1 papillary disease. |
| Evaluar la tasa de respuesta completa (RC) global en participantes tratados con TAR-200 en combinación con cetrelimab (cohorte 1) o con TAR-200 en monoterapia (cohorte 2) o con cetrelimab en monoterapia (cohorte 3) con carcinoma in situ (CIS), con o sin enfermedad papilar concomitante de grado alto Ta o T1. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the durability of CR in participants treated with TAR-200 in combination with cetrelimab (Cohort 1), or TAR-200 alone (Cohort 2), or cetrelimab alone (Cohort 3) with CIS (with or without concomitant Ta or T1 papillary disease) who achieve a CR.
- To determine the overall survival (OS) in all participants.
- To evaluate the pharmacokinetics (PK) of gemcitabine and major metabolite 2’,2’-difluorodeoxyuridine (dFdU) in urine and plasma in TAR-200 in
combination with cetrelimab (Cohort 1), or TAR-200 alone (Cohort 2).
- To evaluate the PK and immunogenicity of cetrelimab in serum in combination with TAR-200 (Cohort 1), or cetrelimab alone (Cohort 3).
- To evaluate health-related quality of life (HRQoL) in all participants.
- To assess the safety and tolerability of participants receiving TAR-200 in combination with cetrelimab (Cohort 1), or TAR-200 alone (Cohort 2), or cetrelimab alone (Cohort 3). |
-Evaluar la durabilidad de la RC en participantes tratados con TAR-200 en combinación con cetrelimab (cohorte 1) o con TAR-200 en monoterapia (cohorte 2) o con cetrelimab en monoterapia (cohorte 3) con CIS (con o sin enfermedad papilar concomitante Ta o T1) que alcancen una RC
-Determinar la supervivencia global (SG) en todos los participantes
-Evaluar la farmacocinética (FC) de gemcitabina y el metabolito grande 2´, 2´-difluorodeoxiuridina (dFdU) en orina y plasma en TAR-200 en combinación con cetrelimab (cohorte 1) o TAR-200 solo (cohorte 2)
-Evaluar la farmacocinética (FC) e immunogenicidad de cetrelimab en suero en combinación con TAR-200 (cohorte 1), TAR-200 solo (cohorte 2) o cetrelimab solo (cohorte 3). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥18 years male or female (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.
2. Histologically confirmed diagnosis of high-risk, non-muscle invasive urothelial carcinoma in situ (CIS; Tis) [AJCC, 2017], with or without papillary disease (T1, high-grade Ta) within 12 months of completion of adequate BCG therapy.
3. Visible papillary disease must be fully resected (absent) prior to randomization (residual CIS acceptable) and documented at screening cystoscopy.
4. Participants must be willing to undergo all study procedures (e.g., multiple cystoscopies from Screening through the end of study and TURBT/bladder biopsy for assessment of recurrence/progression).
5. Participants must be ineligible for or have elected not to undergo radical cystectomy.
6. BCG-unresponsive high-risk NMIBC after treatment with adequate BCG therapy defined as a minimum of 5 of 6 doses of an induction course (adequate induction) plus 2 of 3 doses of a maintenance course, or 2 of 6 doses of a second induction course.
7. All adverse events associated with any prior surgery and/or intravesical therapy must have resolved to CTCAE version 5.0 Grade <2 prior to screening.
8. Participants must sign the informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study and agree to store samples when applicable.
9. Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2.
10. Thyroid function tests within normal range or stable on hormone supplementation per investigator assessment.
11. Adequate bone marrow, liver, and renal function
12. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.
13. A woman of childbearing potential must have a negative pregnancy test (β-hCG) (serum)
within the Screening period. |
1. Hombre o mujer ≥18 años (o la edad legal del consentimiento en la jurisdicción en la que se esté realizando el estudio) en el momento del consentimiento informado
2. Diagnóstico confirmado histológicamente de carcinoma in situ (CIS) urotelial invasivo no muscular de alto riesgo (Tis) [AJCC, 2017], con o sin enfermedad papilar (T1, Ta de alto grado) en los 12 meses posteriores a la finalización del tratamiento adecuado con BCG
3. La enfermedad papilar visible debe estar totalmente resecada (ausente) antes de la aleatorización (CIS residual aceptable) y documentarse en la cistoscopia de selección
4. Los participantes deben estar dispuestos a someterse a todos los procedimientos del estudio (p. ej., múltiples cistoscopias desde la selección hasta el final del estudio y la biopsia de TURBT/vejiga para evaluar la recidiva/progresión)
5. Los participantes no deben ser aptos para una cistectomía radical o haber elegido no someterse a ella
6. Presentar NMIBC de alto riesgo sin respuesta al BCG después del tratamiento con un tratamiento adecuado con BCG definido como un mínimo de 5 de 6 dosis de un ciclo de inducción (inducción adecuada) más 2 de 3 dosis de un ciclo de mantenimiento, o 2 de 6 dosis de un segundo ciclo de inducción
7. Todos los acontecimientos adversos asociados a una intervención quirúrgica y/o a tratamiento intravesical previo deben haberse resuelto a un grado <2 según la versión 5.0 de CTCAE antes de la selección
8. Los participantes deben firmar el formulario de consentimiento informado (FCI) indicando que entienden el propósito y los procedimientos requeridos para el estudio y que están dispuestos a participar en el estudio y aceptan almacenar las muestras cuando corresponda
9. Estado funcional del Grupo Oncológico Cooperativo del Este (ECOG) de 0, 1 o 2
10. Pruebas de función tiroidea dentro del intervalo normal o estable con suplementos hormonales según la evaluación del investigador.
11. Funcionamiento de la médula ósea, hepático y renal adecuado
12. El uso de anticonceptivos por parte de hombres o mujeres debe cumplir con las normativas locales sobre el uso de métodos anticonceptivos para los participantes de estudios clínicos
13. Una mujer con capacidad de concebir debe tener un resultado negativo en la prueba de embarazo (ß-hCG) en el periodo de selección |
|
| E.4 | Principal exclusion criteria |
1. Histologically confirmed, muscle-invasive, locally advanced, nonresectable, or metastatic urothelial carcinoma (i.e., T2, T3, T4, and/or Stage IV).
2. Concurrent extra-vesical (i.e., urethra, ureter, or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium.
3. Active malignancies (i.e., progressing or requiring treatment change in the last 24 months) other than the disease being treated under study.
4. Presence of any bladder or urethral anatomic feature that, in the opinion of the Investigator, may prevent the safe placement, indwelling use, or removal of TAR-200.
5. Evidence of bladder perforation during diagnostic cystoscopy.
6. Bladder post-void residual (PVR) volume > 350mL at Screening after second voided urine.
7. Participants should not have a history of acute ischemic heart disease within 30 days of cohort assignment, or history of uncontrolled cardiovascular disease.
8. A history of clinically significant polyuria with recorded 24-hour urine volumes greater than 4000 mL.
9. Participants with an active, known or suspected autoimmune disease. Participants with autoimmune disorders not requiring systemic treatment (e.g. skin conditions such as vitiligo, psoriasis, alopecia) or conditions requiring hormonal replacement therapies such as type 1 diabetes mellitus or hypothyroidism are permitted to enroll.
10. Received a live virus vaccine within 30 days of planned start of study treatment.
11. Active infection requiring systemic therapy.
12. Has had an allogeneic tissue/solid organ transplant.
13. Currently participating or has participated in a study of an investigational agent and received study therapy or investigational device within 4 weeks prior to screening.
14. Indwelling catheters are not permitted; however, intermittent catheterization is acceptable.
15. Received intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy/Transurethral Resection of Bladder Tumor (TURBT) to starting study treatment. Immediate post-operative intravesical chemotherapy prior to signing the ICF is allowed per local standard of care.
16. Prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-ligand 2 (L2) agent, or with an agent directed to another co-inhibitory T-cell receptor.
17. Participants with a history of Grade ≥3 toxic effects when using anti-TNF or anti-IL-6 agents are excluded.
18. Not recovered from toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration).
19. Participants who require immunosuppressive medications including but not limited to systemic corticosteroid at doses >10 mg/day of prednisone or its equivalence, methotrexate, cyclosporine, azathioprine, and TNF α blockers.
20. Participants must not have clinically significant liver disease that precludes participant treatment regimens prescribed on the study.
21. Known human immunodeficiency virus (HIV) infection, unless the participant has been on a stable anti-retroviral therapy regimen for the last 6 months or more and has had no opportunistic infections and a CD4 count of >350 in the last 6 months.
22. Known active hepatitis B or C infection.
23. Concurrent urinary tract infection (UTI), defined as a symptomatic infection with a positive urine culture with a bacterial count of ≥105 colony forming units (CFU)/mL in urine voided from women, or >104 CFU/mL in urine voided from men, or in straight-catheter urine from women.
24. Participants with a history of allergy to protein-based therapies and participants with a history of any significant drug allergy (such as anaphylaxis, hepatotoxicity, or immune-mediated thrombocytopenia or anemia) are excluded.
25. Known hypersensitivity to any component of the drug formulation for cetrelimab.
26. Known hypersensitivity to gemcitabine (or other drug excipients) or chemically-related drugs.
27. Known hypersensitivity to the device constituent or the (TAR-200) Urinary Placement
Catheter materials.
28. Evidence of interstitial lung disease or active non-infectious pneumonitis
29. Participants must not have active tuberculosis.
30. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
31. Major surgery within 4 weeks before screening (TURBT is not considered major
surgery).
32. Any condition for which, in the opinion of the investigator, participation would not be
in the best interest of the participants (e.g., compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments.
33. The participant is unable to comply with the requirements of this protocol, including
any factors that are likely to affect the participant’s return for scheduled visits and
follow-up. |
1. Carcinoma urotelial no resecable, metastásico, localmente avanzado, con invasión muscular y confirmado mediante histología (es decir, T2, T3, T4 y/o estadio IV)
2. Carcinoma del urotelio de células transicionales sin invasión muscular extravesical concomitante
3. Neoplasias malignas activas distintas de la enfermedad que se está tratando en el estudio
4. Presencia de cualquier característica anatómica vesical o uretral que, en opinión del investigador, impida la colocación segura, el uso permanente o la retirada de TAR-200
5. Indicios de perforación vesical durante la cistoscopia diagnóstica
6. Volumen residual de la vejiga posterior a la micción >350 ml en la selección después de la segunda micción
7. Antecedentes de cardiopatía isquémica aguda en los 30 días previos a la asignación de la cohorte ni antecedentes de enfermedad cardiovascular no controlada
8. Antecedentes de poliuria clínicamente significativa con un volumen de orina de 24 horas registrado superior a 4000 ml
9. Enfermedad autoinmunitaria activa, conocida o sospechada. Pueden inscribirse participantes con trastornos autoinmunitarios que no requieran tratamiento sistémico o afecciones que requieran tratamiento hormonal restitutivo como diabetes mellitus tipo 1 o hipotiroidismo
10. Recepción de una vacuna con virus activos en los 30 días previos al inicio previsto del tratamiento del estudio
11. Presencia de una infección activa que requiera tratamiento sistémico
12. Haber recibido un alotrasplante de tejidos/órganos sólidos
13. Participación en ese momento o haber participado en un estudio de un producto en fase de investigación y haber recibido el tratamiento del estudio o un dispositivo en investigación en las 4 semanas previas a la selección
14. Catéteres permanentes; sin embargo, se acepta un cateterismo intermitente
15. Quimioterapia intravesical o inmunoterapia desde el momento de la cistoscopia/resección transuretral del tumor de vejiga (TURBT) más reciente hasta comenzar el tratamiento del estudio. Se permite la quimioterapia intravesical inmediata después de la operación antes de la firma del FCI conforme a la práctica clínica habitual local
16. Tratamiento previo con un fármaco contra la muerte celular programada 1 (PD-1) y el ligando 2 anti-PD (L2) o con un fármaco dirigido a otro receptor de linfocitos T coinhibidor
17. Antecedentes de efectos tóxicos de grado ≥3 al usar fármacos anti-TNF o anti-IL-6
18. No recuperado de la toxicidad del tratamiento antineoplásico anterior (excepto toxicidades que no son clínicamente significativas, como alopecia, decoloración de la piel)
19. Medicamentos inmunosupresores, entre otros, corticoesteroides sistémicos a dosis >10 mg/día de prednisona o su equivalente, metotrexato, ciclosporina, azatioprina y bloqueantes del TNF-α
20. Hepatopatía clínicamente significativa que impida las pautas de tratamiento del participante prescritas en el estudio
21. Infección conocida por el virus de la inmunodeficiencia humana (VIH), a menos que el participante haya estado recibiendo tratamiento antirretrovírico estable durante los últimos 6 meses o más, y no presente infecciones oportunistas y un recuento de CD4 >350 en los últimos 6 meses
22. Infección activa conocida por hepatitis B o C
23. Infección urinaria concomitante, definida como una infección sintomática con un cultivo de orina positivo con un recuento bacteriano ≥105 unidades formadoras de colonias (UFC)/ml en orina de mujeres o >104 UFC/ml en orina de hombres o en orina de catéter recto de mujeres
24. Antecedentes de alergia a tratamientos basados en proteínas y a participantes con antecedentes de alergia farmacológica significativa
25. Hipersensibilidad conocida a cualquier componente de la formulación del fármaco para cetrelimab
26. Hipersensibilidad conocida a gemcitabina (u otros excipientes de fármacos) o a fármacos relacionados con la quimioterapia
27. Hipersensibilidad conocida a los componentes del dispositivo o a los materiales de colocación del catéter urinario (TAR-200)
28. Evidencia de neumopatía intersticial o neumonitis no infecciosa activa
29. Tuberculosis activa
30. Alteración de la capacidad de cicatrización de heridas definida como úlceras cutáneas/por decúbito, úlceras crónicas en las piernas, úlceras gástricas conocidas o incisiones no cicatrizadas
31. Cirugía mayor en las 4 semanas anteriores a la selección (TURBT no se considera cirugía mayor)
32. Cualquier afección para la que, en opinión del investigador, la participación no sea lo mejor para los participantes (p. ej., compromete el bienestar) o que podría impedir, limitar o confundir las evaluaciones especificadas en el protocolo
33. El participante no puede cumplir con los requisitos de este protocolo, incluidos los factores que probablemente puedan afectar al regreso del participante para las visitas programadas y el seguimiento |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall CR rate will be measured by determining the proportion of participants without presence of high-grade disease using results from cystoscopy and centrally read urine cytology at any time point. |
| La tasa global de respuesta completa (RC) se evaluará determinando la proporción de participantes sin presencia de enfermedad de alto grado utilizando los resultados de la citoscopia y lectura central de la citlogía de orina en cualquier momento. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Date of disease progression/death |
| Fecha de la progresión de la enfermedad/fallecimiento |
|
| E.5.2 | Secondary end point(s) |
- Durability of response.
- OS
- Gemcitabine and dFdU concentrations in urine and plasma.
- Serum concentration and incidence of anti-cetrelimab antibodies.
- Change from baseline and time to symptom deterioration in EORTC
QLQ-C30 and EORTC QLQ-NMIBC24.
- Frequency and grade of adverse events (AEs) (according to Common
Terminology Criteria for Adverse Events [CTCAE] version 5).
- Laboratory abnormalities: CTCAE grades comparing baseline to the
worst post-baseline value; other safety data, such as vital signs, will be
considered as appropriate.
- assessment of product quality compliants. |
-Duración de la respuesta
-Supervivencial global
-Concentración de gemcitabina y dFdU en orina y plasma
-Concentración e incidencia de anticuerpos anti cetrelimab en suero
-Cambio de la selección y tiempo hasta empeoramiento de síntomas en EORTC QLQ-C30 y EORTC QLQ-NMIBC24
-Frecuencia y grado de acontecimientos adversos (AAs), conforme a CTCAE versión 5
-Anormalidades en resultados de laboratorio: comparación de los grados CTCAE de selección y el peor valor tras la selección; otros datos de seguridad como constantes vitales se consideraras como apropiados
-Evaluación de quejas sobre la calidad del producto |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- 12 months after achievement of a CR
- date of disease progression/death
- Week 24 and 48 |
-12 meses tras respuesta completa (RC)
-Fecha de progresión de la enfermedad/fallecimiento
-Semana 24 y 18 |
|
| 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 | 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) | 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 | 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) | Yes |
| 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
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 113 |
| 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 |
| Japan |
| Korea, Republic of |
| United States |
| European Union |
| Russian Federation |
| Turkey |
| Ukraine |
|
| 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
|
The study is considered completed with the last follow-up overall survival assessment for the last participant participating in the study, or 5 years after the last participant is randomized. The final data from the study site will be sent to the sponsor (or designee) after completion of the final
participant’s survival assessment at that study site, in the time frame specified in the Clinical Trial Agreement. |
| El estudio se considerará completado con la evaluación del último seguimiento de supervivencia del último paciente del estudio o 5 años después de que el último participante sea aleatorizado. Los datos finales del centro del estudio se enviarán al promotor (o designado) tras haberse completado la evaluación final de supervivencia del participante en el centro del estudio, según lo especificado en el contrato del ensayo clínico. |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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