| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Esophageal Squamous Cell Carcinoma |
| Carcinoma escamoso de esófago irresecable |
|
| E.1.1.1 | Medical condition in easily understood language |
| Esophageal Squamous Cell Carcinoma |
| Carcinoma escamoso de esófago irresecable |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 25.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10030187 |
| E.1.2 | Term | Oesophageal squamous cell carcinoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10058527 |
| E.1.2 | Term | Oesophageal squamous cell carcinoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 25.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061534 |
| E.1.2 | Term | Oesophageal squamous cell carcinoma |
| 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 compare the overall survival (OS) of sintilimab vs. placebo, in combination with chemotherapy, for first-line treatment in subjects with unresectable, locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC);
- To compare the OS of sintilimab vs. placebo, in combination with chemotherapy, for first-line treatment in subjects with PD-L1 positive, unresectable, locally advanced, recurrent or metastatic ESCC. |
- Comparar la supervivencia global (SG) de sintilimab frente a placebo, en combinación con quimioterapia, para el tratamiento de primera línea en sujetos con carcinoma escamoso de esófago (CEE) irresecable, localmente avanzado, recurrente o metastásico;
-Comparar la SG de sintilimab frente a placebo, en combinación con quimioterapia, para el tratamiento de primera línea en sujetos con CEE positivo para PD-L1 irresecable, localmente avanzado, recurrente o metastásico |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), and duration of response (DoR) between two treatment arms in overall population;
- To compare the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), and duration of response (DoR) between two treatment arms in subjects with PD-L1 positive ESCC.
- To compare the safety between the two treatment arms. |
- Comparar la tasa de respuesta objetiva (TRO), la supervivencia sin progresión (SSP), la tasa de control de la enfermedad (TCE) y la duración de la respuesta (DR) entre dos grupos de tratamiento en la población general;
- Comparar la tasa de respuesta objetiva (TRO), la supervivencia sin progresión (SSP), la tasa de control de la enfermedad (TCE) y la duración de la respuesta (DR) entre dos grupos de tratamiento en sujetos con CEE positivo para PD-L1.
- Comparar la seguridad entre los dos grupos de tratamiento. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histopathologically confirmed unresectable, locally advanced, recurrent or metastatic ESCC (excluding mixed adenosquamous carcinoma and other histological subtypes).
2. Aged ≥ 18.
3. ECOG PS of 0 or 1.
4. Subject must be unsuitable for definitive treatment, such as definitive chemoradiotherapy and/or surgery. For subjects who have received (neo)adjuvant or definitive chemotherapy/radiochemotherapy, time from the completion of last treatment to disease recurrencne must be > 6 months.
5. Could provide archival or fresh tissues for PD-L1 expression analysis with obtainable results.
6. Have at least one measurable lesion as per RECIST v1.1.
7. Adequate organs and bone marrow functions, as defined below:
1) Complete blood count: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet (PLT) count ≥ 100 × 109/L, hemoglobin (HGB) ≥ 9.0 g/dL. Note: Subjects cannot receive blood transfusion, erythropoietin (EPO), or Granulocyte-colony stimulating factor (GSF) within 7 days prior to the blood collection.
2) Hepatic function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN in subjects without hepatic metastasis; TBIL ≤ 1.5 × ULN, ALT and AST ≤ 5 × ULN in subjects with hepatic metastasis.
3) Renal function: urine protein < 2+ from random sample or < 1 g from 24-hour urine collection, and creatinine clearance rate (Ccr) ≥ 60 mL/min by Cockcroft-Gault formula.
The calculations of Ccr for one subject must use the same formula throughout the entire study.
4) Adequate coagulation function, defined as international normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × ULN; if the subject is receiving anticoagulant therapy, the results of coagulation tests need to be within the acceptable range for anticoagulants.
8. Expected survival ≥ 12 weeks.
9. Subject (female subjects of childbearing age or male subjects whose partners are of childbearing age) must take effective contraceptive measures during the entire course of the trial and until 180 days after the last dose.
10. Signed the informed consent form (ICF) and be able to comply with the scheduled follow-up visits and related procedures required in the protocol. |
1. CEE irresecable, localmente avanzado, recurrente o metastásico (excepto carcinoma adenoescamoso mixto y otros subtipos histológicos) con confirmación histopatológica.
2. Edad ≥18.
3. EF del ECOG de 0 o 1.
4. El sujeto debe ser apto para el tratamiento definitivo, como quimiorradioterapia y/o cirugía definitivas. Para los sujetos que han recibido quimioterapia/quimiorradioterapia (neo)adyuvante o definitiva, el tiempo transcurrido desde la finalización del último tratamiento hasta la recurrencia de la enfermedad debe ser >6 meses.
5. Podría proporcionar tejidos de archivo o frescos para el análisis de expresión de PD-L1 con resultados alcanzables.
6. Tener al menos 1 lesión medible según los criterios RECIST v1.1.
7. Tener funciones orgánicas y de médula ósea adecuadas, lo que se define como:
1) Hemograma completo: recuento absoluto de neutrófilos (RAN) ≥1,5 x 109/l, recuento de plaquetas (PLT) ≥100 x 109/l, hemoglobina (HGB) ≥9,0 g/dl. Nota: los sujetos no pueden recibir una transfusión de sangre, eritropoyetina (EPO) o factor estimulador de colonias de granulocitos (GSF) en el plazo de 7 días antes de la extracción de sangre.
2) Función hepática: bilirrubina total (TBIL) ≤1,5 veces el límite superior de la normalidad (LSN), alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) ≤2,5 x LSN en sujetos sin metástasis hepáticas; TBIL ≤1,5 veces el LSN, ALT y AST ≤5 × LSN en sujetos con metástasis hepáticas.
3) Función renal: proteína en orina <2+ de una muestra aleatoria o <1 g de la recogida de orina de 24 horas y tasa de aclaramiento de creatinina (Ccr) ≥60 ml/min según la fórmula de Cockcroft-Gault:
Los cálculos de Ccr de un sujeto debe usar la misma fórmula durante todo el estudio.
4) Función de coagulación adecuada, definida como un índice internacional normalizado (INR) ≤1,5 o tiempo de protrombina (TP) ≤1,5 veces el LSN; si el sujeto está recibiendo tratamiento anticoagulante, los resultados de las pruebas de coagulación deben estar dentro del intervalo aceptable para anticoagulantes.
8. Supervivencia esperada ≥12 semanas.
9. El sujeto (mujeres en edad fértil u hombres cuyas parejas estén en edad fértil) deberá usar métodos anticonceptivos eficaces durante todo el ensayo y hasta 180 días después de la última dosis.
10. Haber firmado el formulario de consentimiento informado (FCI) y ser capaz de cumplir con las visitas de seguimiento programadas y los procedimientos requeridos en el protocolo. |
|
| E.4 | Principal exclusion criteria |
1. ESCC with endoscopy-confirmed near-complete obstruction requiring interventional therapy.
2. Post stent implantation in the esophagus or trachea with risks of perforation.
3. Received systemic treatment for advanced or metastatic ESCC.
4. Received a Cumulative dose of cisplatin > 300 mg/m2within 12 months to randomization.
5. High risk of hemorrhage or perforations due to tumor invasion in adjacent organs (aorta or trachea), or have fistula formation.
6. Load of hepatic metastasis > 50% of the total liver volume.
7. Received treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug that specifically targets T-cell co-stimulation or immune checkpoint pathways.
8. Enrolled in another interventional clinical study, unless only involved in an observational study (non-interventional) or in the follow-up phase of an interventional study.
9. Received palliative therapy for local lesion within 2 weeks prior to the first dose.
10. Received systemic treatment with Chinese traditional medicines with anti-cancer indications or immunomodulators (including thymosins, interferons, and interleukins) within 2 weeks prior to the first dose of study treatment.
11. Received systemic immunosuppressants within 2 weeks prior to randomization, excluding local use of glucocorticoids administered by nasal, inhaled, or other routes, and systemic glucocorticoids at physiological doses (no more than 10 mg/day of prednisone or equivalents), or glucocorticoids to prevent allergies to contrast media.
12. Received a live attenuated vaccine within 4 weeks prior to the first dose of study treatment or be scheduled to receive live attenuated vaccine during the study period.
Note: Seasonal inactivated influenza virus vaccines within 4 weeks prior to the first dose of study treatment are permitted, but attenuated influenza vaccines are not.
13. Received major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose of study treatment or is scheduled to receive major surgery during the course of the trial.
14. Any toxicity (excluding alopecia, events that are not clinically significant, or asymptomatic laboratory abnormalities) due to prior anti-tumor therapy that has not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 grade 0 or 1 prior to the first dose of study treatment.
15. Known symptomatic central nervous system (CNS) metastasis or carcinomatous meningitis.
16. Clinically significant ascites, including ascites that could be detected on physical examination, has been treated with a prior procedure, or currently requires treatment. Asymptomatic subjects with a small amount of ascitic fluid demonstrated by imaging can be enrolled.
17. Moderate bilateral pleural effusion or large unilateral pleural effusion, or effusion resulting in respiratory dysfunction and requiring drainage.
18. Subjects with bone metastases at risk of paraplegia.
19. Known active autoimmune disease requiring treatment or previous disease history within 2 years (subjects with vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic treatment, hypothyroidism only requiring thyroid replacement, or type I diabetes only requiring insulin can be enrolled).
20. Known history of primary immunodeficiency diseases.
21. Known active pulmonary tuberculosis.
22. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
23. Known allergy to any monoclonal antibody or any formulation or excipient of chemotherapy agents (e.g. paclitaxel, fluorouracil, or cisplatin) in that the subjects is inappropriate to receive TP or CF regimen.
24. HIV-infected subjects (positive anti-HIV antibody).
25. Active or poorly controlled serious infections.
26. Symptomatic congestive heart failure (NYHA Class II–IV) or symptomatic or poorly controlled arrhythmia.
27. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) despite of standard treatment.
28. Any arterial thromboembolic event within 6 months prior to enrollment, including myocardial infarction, unstable angina, cerebrovascular accident, or transient cerebral ischemic attack.
29. Significant malnutrition, such as those requiring continuous parenteral nutrition ≥7 days; excluding those having received intravenous treatment for malnutrition for more than 4 weeks before the first dose of study treatment.
30. History of deep venous thrombosis, pulmonary embolism, or other serious thromboembolic events within 3 months prior to enrollment (implantable port or catheter-related thrombosis, or superficial venous thrombosis are not considered as "serious" thromboembolisms).
For a complete overview of the exclusion criteria refer to the protocol. |
1. CEE con obstrucción casi completa confirmada con endoscopia que requiera un tratamiento intervencionista.
2. Implante posterior al stent en el esófago o la tráquea con riesgo de perforación.
3. Haber recibido tratamiento sistémico para el CEE avanzado o metastásico.
4. Haber recibido una dosis acumulada de cisplatino de >300 mg/m2 en el plazo de 12 meses antes de la aleatorización.
5. Alto riesgo de hemorragia o perforaciones debido a la invasión del tumor en órganos adyacentes (aorta o tráquea) o formación de fístulas.
6. Metástasis hepática >50 % del volumen hepático total.
7. Haber recibido un tratamiento con anticuerpos anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 o anti-CTLA-4, o cualquier otro anticuerpo o fármaco que actúa específicamente sobre la estimulación conjunta de los linfocitos T o las vías de los puntos de control inmunitario.
8. Estar inscrito en otro estudio clínico intervencionista, a menos que solo participe en un estudio observacional (no intervencionista) o en la fase de seguimiento de un estudio intervencionista.
9. Haber recibido tratamiento paliativo para una lesión local en el plazo de 2 semanas antes de la primera dosis.
10. Haber recibido tratamiento sistémico con medicina tradicional china con indicaciones antineoplásicas o inmunomoduladoras (incluidas timosinas, interferones e interleucinas) en las 2 semanas anteriores a la primera dosis del tratamiento del estudio.
11. Haber recibido inmunodepresores sistémicos en el plazo de 2 semanas antes de la aleatorización, excepto el uso local de glucocorticoides administrados por vía nasal, inhalados, o por otras vías y glucocorticoides sistémicos a dosis fisiológicas (no más de 10 mg/día de prednisona o equivalente) o glucocorticoides para prevenir alergias a los medios de contraste.
12. Haber recibido una vacuna viva atenuada en las 4 semanas anteriores a la primera dosis del tratamiento del estudio o tener previsto recibir una vacuna viva atenuada durante el periodo del estudio.
Nota: se permiten las vacunas inactivadas contra la gripe estacional en las 4 semanas previas a la primera dosis del tratamiento del estudio, pero no las vacunas atenuadas contra la gripe.
13. Haber recibido cirugía mayor (craneotomía, toracotomía o laparotomía) en las 4 semanas anteriores a la primera dosis del tratamiento del estudio o tener prevista una cirugía mayor durante el transcurso del ensayo.
14. Cualquier toxicidad (excepto la alopecia, los acontecimientos que no son clínicamente significativos o las anomalías analíticas asintomáticas) debida al tratamiento antineoplásico previo que aún no se ha resuelto a grado 0 o 1 según la v5.0 de los Criterios Terminológicos Comunes para Acontecimientos Adversos del Instituto Nacional del Cáncer (CTCAE del NCI) antes de la primera dosis del tratamiento del estudio.
15. Metástasis sintomáticas conocidas en el sistema nervioso central (SNC) o meningitis carcinomatosa.
16. Ascitis clínicamente significativa, incluida la ascitis que podría ser detectada en la exploración física, que se ha tratado con un procedimiento previo, o que actualmente requiere tratamiento. Puede incluirse a sujetos asintomáticos con una pequeña cantidad de líquido ascítico según lo demostrado por estudios de imagen.
17. Derrame pleural bilateral moderado o derrame pleural unilateral extenso, o derrame que provoque disfunción respiratoria y que requiera drenaje.
18. Sujetos con metástasis óseas en riesgo de paraplejia.
19. Enfermedad autoinmunitaria activa conocida que requiera tratamiento o antecedentes de enfermedad en los 2 años anteriores (pueden incluirse los sujetos con vitíligo, psoriasis, alopecia o enfermedad de Graves que no requieran tratamiento sistémico, hipotiroidismo que solo requiera sustitución tiroidea, o diabetes de tipo I que solo requiere insulina).
20. Antecedentes conocidos de enfermedades de inmunodeficiencia primaria.
21. Tuberculosis pulmonar activa conocida.
22. Antecedentes conocidos de alotrasplante de órganos o de alotrasplante de células madre hematopoyéticas.
23. Alergia conocida a cualquier anticuerpo monoclonal o a cualquier formulación o excipiente de los fármacos de quimioterapia (p. ej., paclitaxel, fluorouracilo o cisplatino) en la que los sujetos no son adecuados para recibir la pauta de TP o CF.
24. Pacientes con infección por VIH (anticuerpo contra el VIH positivo).
25. Infecciones graves activas o mal controladas.
26. Insuficiencia cardíaca congestiva sintomática (clase II-IV de la NYHA) o arritmia sintomática o mal controlada.
27. Hipertensión no controlada (presión arterial sistólica ≥160 mmHg o presión arterial diastólica ≥100 mm Hg) a pesar de recibir tratamiento de referencia.
.
Para una revisión completa de los criterios de exclusión, véase el protocolo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- OS (Overall survival) in the ITT population;
- OS in PD-L1 positive subjects in the ITT population. |
- SG (Supervivencia global) en la población IDT;
- SG en sujetos positivos para PD-L1 en la población IDT. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assessments will be performed at timepoints described in the protocol. |
| Las evaluaciones se realizarán en los momentos descritos en el protocolo |
|
| E.5.2 | Secondary end point(s) |
- Key secondary endpoints:
-ORR (Objective response rate), PFS (Progression free survival) in the ITT population;
-ORR. PFS in PD-L1 positive subjects in the ITT population.
- Other secondary endpoints:
- DCR (Disease control rate), DoR (Duration of response)in the ITT population;
- DCR, DoR in PD-L1 positive subjects in the ITT population. |
- Criterios de valoración secundarios clave:
- TRO (Tasa de respuesta objetiva), SSP (Supervivencia sin progresión) en la población IDT;
- TRO. SSP en sujetos positivos para PD-L1 en la población IDT.
- Otros criterios de valoración secundarios:
- TCE (Tasa de control de la enfermedad), DR (Duración de la respuesta) en la población IDT;
- TCE, DR en los sujetos positivos para PD-L1 en la población IDT. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assessments will be performed at timepoints described in the protocol. |
| Las evaluaciones se realizarán en los momentos descritos en el protocolo |
|
| 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 | No |
| 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) | 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 | 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) | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
| China |
| United States |
| Belgium |
| France |
| Hungary |
| Romania |
| Spain |
|
| 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 end of the study at 24 months after last patient enrolment. |
| La finalización del estudio 24 meses después de la inscripción del último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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