E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Endometrial cancer, advanced, recurrent or metastatic |
Cáncer de endometrio, avanzado, recurrente o metastásico |
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E.1.1.1 | Medical condition in easily understood language |
special type of gynecologic cancer that arises from the endometrium, or lining, of the uterus |
Tipo especial de cancer ginecológico que proviene del endometrio o de la capa interna del útero. |
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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 | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014741 |
E.1.2 | Term | Endometrial cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014740 |
E.1.2 | Term | Endometrial cancer stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Compare the overall survival (OS) of patients treated with AEZS-108 to the overall survival of patients treated with doxorubicin |
Comparar la supervivencia global (SG) de los pacientes tratados con AEZS-108 con la SG de los pacientes tratados con doxorrubicina |
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E.2.2 | Secondary objectives of the trial |
Compare efficacy based on progression-free survival (PFS), overall response rate (ORR), and clinical benefit rate (CBR). Compare safety. Determine the impact of these regimens on patient-reported quality of life. Sub-study (selected study sites only): Assess pharmacokinetics of AEZS-108. |
Comparar la eficacia basada en la supervivencia libre de progresión (SLP), tasa de respuesta global (TRG) y tasa de beneficio clínico (TBC). Comparación de seguridad. Determinar el impacto de estos regímenes en la calidad de vida del paciente. Sub-estudio (solo en los centros seleccionados): Evaluar la farmacocinética del AEZS-108. |
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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 |
Randomized controlled study comparing AEZS?108 with doxorubicin as second line therapy for locally advanced, recurrent or metastatic endometrial cancer
Pharmacokinetic sub-study in patients treated with AEZS-108, Version 0, date: 2013-05-02 |
Estudio randomizado controlado que compara AEZS?108 con doxorubicina como terapia en segunda linea para el cancer de endometrio localmente avanzado, metastásico o recurrente.
Subestudio farmacocinético en pacientes tratados con AEZS?108, version 0, fechada el 2 de mayo de 2013. |
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E.3 | Principal inclusion criteria |
1. Woman ? 18 years of age 2. Histologically confirmed endometrial adenocarcinoma of any subtype. 3. Advanced (FIGO stage III or IV), recurrent or metastatic disease. 4. Measurable or non-measurable disease that has progressed since last treatment. 5. Patients who have progressed after prior first line treatment with platinum/taxane based chemotherapy for advanced, recurrent or metastatic endometrial cancer. 6. Availability of fresh or archival FFPE tumor specimens for analysis of LHRH receptor expression. |
1. Mujeres de ? 18 años de edad 2. Adenocarcinoma de endometrio de cualquier subtipo confirmado histológicamente. 3. Enfermedad avanzada (FIGO III or IV), recurrente o con metástasis. 4. Enfermedad cuantificable o no cuantificable que haya progresado desde el último tratamiento. 5. Pacientes cuya enfermedad haya progresado tras el tratamiento de primera línea con quimioterapia basada en platino/taxano, el cáncer de endometrio sea recurrente o tenga metástasis. 6. Disponibilidad de muestras de tumor FFPE recientes o de archivo para el análisis de la expresión del receptor de LHRH. |
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E.4 | Principal exclusion criteria |
1. Eastern Cooperative Oncology Group (ECOG) performance status > 2 2. Inadequate hematologic, hepatic or renal function - thrombocyte count: < 100 x 109/L; - absolute neutrophil count (ANC): < 1.5 x 109/L; - hemoglobin: < 5.6 mmol/L (< 9 g/dL); - ASAT, ALAT, AP: > 2.5 times upper limit of normal range (ULN) (> 5x ULN if clearly related to liver metastases); - creatinine, bilirubin: > 1.5x ULN. 3. Red blood cell transfusion within 2 weeks prior to anticipated start of study treatment. 4. History of myocardial infarction, acute inflammatory heart disease, unstable angina, or uncontrolled arrhythmia within the past 6 months. 5. Impaired cardiac function defined as left ventricular ejection fraction (LVEF) < 50% (or below the study site?s lower limit of normal) as measured by MUGA or ECHO. 6. Planned concomitant use of potentially cardiotoxic medication. 7. Chemo-, immune-, hormone-, or radiotherapy (including pre- or post-operative brachytherapy) within 4 weeks prior to randomization. 8. Previous anthracycline-based chemotherapy. 9. Anticipated ongoing concomitant anticancer therapy during the study. 10. History of serious co-morbidity or uncontrolled illness that would preclude study therapy, such as active tuberculosis or any other active infection. 11. Brain metastasis, leptomeningeal disease. 12. Pregnant or lactating female or female of child-bearing potential not employing adequate contraception. Women of childbearing potential must agree to employ adequate contraception until 6 months after the last dose of study drug, defined as - complete abstinence (Note: acceptable only as ?True abstinence?, i.e. when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence, e.g., calendar, ovulation, symptothermal, post-ovulation methods, and withdrawal are not acceptable methods of contraception); - any intrauterine device (IUD) with published data showing that the lowest expected failure rate is < 1% per year; or - any other methods with published data showing that the lowest expected failure rate is less than 1% per year. 13. Subjects with known hypersensitivity to anthracyclines or peptide drugs, including LHRH agonists. 14. Receipt of 2 or more prior chemotherapy regimens for advanced, recurrent, or metastatic endometrial cancer. 15. Prior treatment with AEZS-108. 16. Use of LHRH agonist or antagonist treatment within 6 months prior to randomization. 17. Malignancy within last 5 years except non-melanoma skin cancer. 18. Any concomitant disease or condition which would interfere with the subjects? proper completion of the protocol assignment. 19. Concomitant or recent treatment with other investigational drug (within 8 weeks or 5 elimination half life times prior to anticipated start of study treatment). 20. and 21. Administrative reasons |
1.Rendimiento de estado de ECOG > 2 2.Función hematológica, hepática o renal inadecuadas: - Recuento de trombocitos: <75x109100x109/L; - Recuento absoluto de neutrófilos (RAN): <1.5x109/L; - Hemoglobina: <5.6 mmol/L(< 9 g/dL); - GOT, GPT, FA: > 2.5 veces sobre el límite superior del rango normal ULN) (> 5x ULN si está claramente relacionado con metástasis del hígado); - Creatinina, Bilirubina: >1.5xULN. 3.Transfusión de glóbulos rojos en las dos semanas previas al inicio previsto del tratamiento del estudio. 4.Historia de infartos de miocardio, enfermedad cardíaca inflamatoria aguda, angina no estable o arritmia no controlada en los últimos 6 meses. 5.Función cardiaca disminuida definida como Fracción de expulsión del ventrículo izquierdo (FEVI) <50 % (o por debajo del límite normal inferior definido en el centro) según MUGA o Ecocardiograma. 6.Uso previsto de medicación potencialmente cardio-tóxica (tal y como se especifica en el Apéndice 4) 7.Quimioterapia, inmunoterapia, hormonoterapia o radioterapia (incluyendo braquiterapia pre o post-operatoria) recibida dentro de las 4 semanas previas a la aleatorización. 8.Tratamiento previo con quimioterapia basada en antraciclina (ver Apéndice 4 para los nombres de la medicación). 9.Terapia anticancerígena concomitante prevista para su uso durante la duración del estudio. 10.Historia de comorbilidad seria o enfermedad no controlada que pueda excluir la terapia del estudio, como por ejemplo tuberculosis actica o cualquier otra infección activa. 11.Metástasis cerebral, enfermedad leptomeníngea. 12.Mujeres embarazadas, en periodo de lactancia o aquellas en edad fértil que no empleen métodos anticonceptivos adecuados. Las mujeres en edad fértil deben comprometerse a emplear métodos anticonceptivos adecuados hasta 6 meses después de la última dosis del fármaco del estudio, definidos como: - abstinencia completa (Nota: aceptable solo como ?abstinencia real?, es decir, cuando esto se ajuste con el estilo de vida preferente y habitual del sujeto. La abstinencia periódica, (por ejemplo, el calendario, la ovulación, los métodos sintotérmicos y post-ovulación) y la marcha atrás no son métodos anticonceptivos aceptables) - cualquier dispositivo intrauterino (DIU) con datos publicados que demuestren que la tasa más baja de fracaso es <1 % al año - cualquier otro método con datos publicados que demuestren que la tasa más baja de fracaso es <1 % al año. 13.Sujetos con hipersensibilidad conocida a antraciclinas o fármacos peptídicos, incluyendo agonisitas LHRH. 14.Haber recibido 2 o más regímenes previos de quimioterapia para el tratamiento del cáncer de endometrio avanzado, recurrente o con metástasis. 15.Tratamiento previo con AEZS-108. 16.Uso de tratamientos agonistas o antagonistas del LHRH en los 6 meses previos a la aleatorización. (VerApéndice5 para ejemplos de medicaciones). 17.Malignidad en los últimos 5 años, exceptuando cáncer de piel no-melanoma. 18.Cualquier enfermedad concomitante o condición que pueda interferir con la finalización adecuada del protocolo asignado. 19.Tratamiento concomitante o reciente con otro medicamento en investigación (dentro de las 8 semanas previas o 5 veces la vida media de eliminación antes del comienzo anticipado del tratamiento del estudio). 20.Carencia de la capacidad o del deseo de otorgar consentimiento informado. 21.No disponibilidad prevista par a las visitas/procedimientos del estudio |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival |
supervivencia global |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of the primary efficacy variable will be based on the ITT population. The final overall survival analysis, which is event-based, will be conducted after approximately 384 randomized patients have died. |
Los análisis primarios para evaluar la variable primaria de eficacia se basarán en la población por intención de tratar. Los análisis finales de supervivencia global, los cuales se basan en los eventos ocurridos, se llevarán a cabo después de que unas 384 pacientes hayan fallecido. |
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E.5.2 | Secondary end point(s) |
Efficacy based on progression-free survival (PFS), overall response rate (ORR), and clinical benefit rate (CBR). Safety: adverse events, clinical laboratory and LVEF. Quality of Life: EORTC QLQ30 + QLQ-EN24 questionnaires. |
Eficacia basada en la supervivencia libre de progresión, tasa de respuesta total y tasa de beneficio clínico. Seguridad: Efectos adversos, laboratorio clínico y FEVI Calidad de vida:cuestionarios EORTC QLQ30 + QLQ-EN24 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of the primary efficacy variable will be based on the ITT population. The final overall survival analysis, which is event-based, will be conducted after approximately 384 randomized patients have died. |
Los análisis primarios para evaluar la variable primaria de eficacia se basarán en la población por intención de tratar. Los análisis finales de supervivencia global, los cuales se basan en los eventos ocurridos, se llevarán a cabo después de que unas 384 pacientes hayan fallecido. |
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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 | 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 | 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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Belarus |
Bosnia and Herzegovina |
Canada |
Israel |
Russian Federation |
Spain |
Ukraine |
United States |
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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
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LVLS |
Ultima visita del ultimo paciente |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
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 | 3 |
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 |