E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic soft tissue sarcoma |
sarcoma de tejidos blandos metastásico |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic soft tissue sarcoma |
sarcoma de tejidos blandos metastásico |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10075333 |
E.1.2 | Term | Soft tissue sarcoma |
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 |
The main objective of the trial is to evaluate whether maintenance trabectedin given after 6 cycles of doxorubicin first-line therapy for advanced or metastatic STS prolongs progression-free survival (PFS) as compared to an observational approach. |
El principal objetivo del ensayo es evaluar si trabectedina de mantenimiento administrada después de 6 ciclos de tratamiento de primera línea con doxorrubicina para el STB avanzado o metastásico prolonga la supervivencia libre progresión (SLP) en comparación con un enfoque observacional. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are: • To assess the treatment safety and tolerability • To assess the efficacy of the treatment in terms of overall survival (determined from randomization) • To assess the time to second progression • To compare the quality of life in patients randomized to the two study arms |
Los objetivos secundarios son: Evaluar la seguridad y la tolerabilidad del tratamiento Evaluar la eficacia del tratamiento en términos de supervivencia global (determinada desde la aleatorización) Evaluar el tiempo hasta la segunda progresión Comparar la calidad de vida en pacientes aleatorizados a los dos grupos de tratamiento |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Histologically proven locally advanced or metastatic high grade STS (excluding histologies insensitive to chemotherapy such as ASPS and PECOMA subtypes). • Non-progressive disease (CR, PR or SD according to RECIST 1.1) after 6 cycles of first-line chemotherapy with doxorubicin for advanced and/or metastatic malignant STS. • Interval from last dose of doxorubicin to randomization is maximum 6 weeks. • Prior neoadjuvant or adjuvant non-anthracycline-chemotherapy is allowed, provided that the disease did not progress during neoadjuvant and/or adjuvant therapy or within 12 weeks after completion of the perioperative treatment. • Representative formalin fixed, paraffin embedded tumor blocks or 10 unstained tissue slides, either from the primary tumor or a metastatic lesion, must be available for histological central review. Histological central review is not required before treatment start but it is mandatory to send unstained tumor slides (blocks optional) at time of study entry. Local histopathological diagnosis will be accepted for entry into this trial. • Age 18 years or older • WHO performance status (PS) ≤ 1 • Adequate bone marrow, liver and renal function and coagulation parameters • Normal cardiac function (LVEF assessed by MUGA or ECHO within normal range of the institution), normal 12 lead ECG (without clinically significant abnormalities). • Recovery from toxicity (no more than Grade 1, except for alopecia) • Evidence of post-menopausal status or for female pre-menopausal patients negative urinary or serum pregnancy test within 72 hours prior to first dose of study treatment. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). • Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). • Women of childbearing potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months after the last study treatment. Men in fertile age must use effective contraception during treatment and 5 months after treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include: • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) • Intrauterine device (IUD) • Intrauterine hormone-releasing system (IUS) • Bilateral tubal occlusion • Vasectomised partner • Sexual abstinence • Note: Trabectedin can have genotoxic effects. Advice on the possibility of ovules or sperm conservation should be given to the patient prior to start of treatment because of the possibility of irreversible infertility. • Female patients who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 3 months after the last study treatment. • Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. |
• STB de alto grado localmente avanzado o metastásico demostrado histológicamente (excluyendo histologías no sensibles a quimioterapia, como los subtipos ASPS y PECOMA). • Enfermedad no progresiva (RC, RP o EE según RECIST 1.1) después de 6 ciclos de quimioterapia de primera línea con doxorrubicina para STB maligno avanzado y/o metastásico. • El intervalo desde la última dosis de doxorrubicina hasta la aleatorización es, como máximo, de 6 semanas. • La quimioterapia neoadyuvante o adyuvante distinta de la antraciclina está permitida, siempre que la enfermedad no progresara durante el tratamiento neoadyuvante o adyuvante o en el plazo de 12 semanas después de completar el tratamiento perioperatorio. • Los 10 cortes de tejido sin tinción o los bloques tumorales representativos fijados en formalina y embebidos en parafina, ya sea del tumor primario o de una lesión metastásica, deben estar disponibles para la revisión histológica central. La revisión histológica central no es necesaria antes del inicio del tratamiento, pero es obligatorio enviar cortes de tumor sin tinción (bloques opcionales) en el momento de entrada en el estudio. Se aceptará el diagnóstico histopatológico local para la inclusión de pacientes en este ensayo. • Edad de 18 años o más. • Estado funcional (EF) ≤1 según la OMS. • Función renal, hepática y de la médula ósea, y parámetros de coagulación adecuados • Función cardíaca normal (FEVI evaluada mediante ventriculografía isotópica (MUGA) o ecocardiografía (ECHO) dentro del rango normal del centro), ECG de 12 derivaciones normal (sin anomalías clínicamente significativas). • Evidencia de estatus postmenopáusico o para mujeres premenopáusicas, un test de embarazo en suero o en orina debe ser negativo en las 72 horas previas al a la administración de la primera dosis del tratamiento en el estudio. Las mujeres < 50 años de edad serían consideradas postmenopausicas si han estado con amenorrea por 12 meses o más tras la suspensión de tratamientos hormonales exógenos y si presentan los niveles de hormona luteinizante y de la hormona folículo-estimulante en un rango de postmenopausia para la institución o fueron sometidas a una cirugía de esterilización (oforectomia bilateral o histerectomía) . Las mujeres ≥ 50 años de edad serían consideradas postmenopausicas si han estado amenorreicas durante 12 meses o mas tras la cesación de todos los tratamientos hormonales exógenos, tuvieron una menopausia inducida por radiación presentando las últimas menstruaciones > 1 año, tuvieron una menopausia inducida por quimioterapia presentando las últimas quirúrgica (oforectomia bilateral, salpinguectomia bilateral o histerectomía) • Las mujeres en edad fértil deben utilizar métodos anticonceptivos adecuados, de acuerdo con lo definido por el investigador, durante el periodo de tratamiento del estudio y durante al menos 3 meses tras la última dosis del tratamiento del estudio. Los hombres en edad fértil deben utilizar métodos anticonceptivos eficaces durante el tratamiento y 5 meses después del tratamiento. Un método anticonceptivo altamente eficaz se define como aquel que tiene una baja tasa de fallo (es decir, inferior al 1 % anual) cuando se usa de manera sistemática y correcta. Tales métodos incluyen: • Contracepción hormonal combinada (con estrógenos y progesterona) asociada con inhibición de la ovulación (oral, intravaginal o transdérmica) • Contracepción basada sólo en progesterona asociada con inhibición de la ovulación (oral, inyectable, implantable) • Dispositivo intrauterino (DIU) • Dispositivo intrauterino de liberación hormonal (DIULH) • Oclusión tubárica bilateral • Pareja sometida a vasectomía • Abstinencia sexual • Las pacientes de sexo femenino que estén en periodo de lactancia, deben interrumpirlo antes de la primera dosis del tratamiento del estudio y hasta 3 meses después del último tratamiento del estudio. • Antes de la aleatorización del paciente, se debe dar el consentimiento informado por escrito conforme a las ICH/BPC y a los reglamentos nacionales/locales. |
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E.4 | Principal exclusion criteria |
• prior exposure to trabectedin • active or uncontrolled infections or serious illnesses or medical conditions, including a • history of chronic alcohol abuse, hepatitis, HIV and/or cirrhosis. • active brain metastases • history, within the past five years, of malignancies other than soft tissue sarcoma (except: basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, resected incidental prostate cancer staged pT2 with Gleason Score ≤ 6 and postoperative PSA < 0.5 ng/ml). Patients with any history of malignancies who are disease-free for more than 5 years are eligible. • any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial. • Recuperación de toxicidad (no superior a grado 1, excepto para la alopecia). |
• exposición previa a la trabectedina. • infecciones activas o no controladas, o bien enfermedades graves o afecciones médicas, incluidos antecedentes de alcoholismo crónico, hepatitis, VIH y/o cirrosis. • metástasis cerebral active • antecedentes, en los últimos cinco años, de neoplasias malignas distintas de sarcoma de tejidos blandos • cualquier afección psicológica o situación familiar, sociológica o geográfica que pudiera potencialmente afectar al cumplimiento del protocolo del estudio y el calendario de seguimiento; estos aspectos deben comentarse con el paciente antes de la aleatorización en el ensayo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end-point is progression-free survival defined from randomization until progression according to RECIST 1.1. |
El criterio de valoración principal es la supervivencia libre de progresión, definida desde la aleatorización hasta la progresión, según los criterios RECIST 1.1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumor evaluations for the assessment of PFS will be done every 6 weeks during the first 6 months and every 12 weeks thereafter until PD or start of new treatment |
desde la aleatorización hasta la progresión, según los criterios RECIST 1.1. |
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E.5.2 | Secondary end point(s) |
Secondary end-points include: • Safety and tolerability (Common Terminology Criteria for Adverse Events CTCAE 4.0) • Overall survival • Time to second progression (PFS2) • Health related quality of life (QLQ-C30) |
Los criterios de valoración secundarios incluyen: Seguridad y tolerabilidad (criterios comunes de terminología para efectos adversos CTCAE 4.0) Supervivencia general. Tiempo hasta la segunda progresión (SLP2) Calidad de vida relacionada con la salud (QLQ-C30) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Safety and tolerability • Overall survival: every 6 weeks during the first 6 months; every 12 weeks thereafter until PD on first and on second line treatment; every 6 months thereafter until death. • Time to second progression (PFS2): every 6 weeks during the first 6 months; every 12 weeks thereafter until PD on first and on second line treatment; • Health related quality of life (QLQ-C30): within 7 days before randomization, every 6 weeks during the first 6 months and every 12 weeks thereafter until PD or start of new treatment |
• Seguridad y tolerabilidad • Supervivencia general: cada 6 semanas durante los primeros 6 meses; cada 12 semanas hasta progression; cada 6 meses hasta la muerte • Tiempo hasta la segunda progresión (SLP2) cada 6 semanas durante los primeros 6 meses; cada 12 semanas hasta progression • Calidad de vida relacionada con la salud (QLQ-C30): en los 7 dias antes de la aleatorizacion, cada 6 semanas durante los primeros 6 meses y cada 12 semanas hasta progression o comienzo de in Nuevo tratamiento |
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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 | No |
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 | 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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
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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 | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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End of study occurs when all of the following criteria have been satisfied: 1. Thirty days after all patients have stopped protocol treatment 2. The trial is mature for the analysis of the primary endpoint as defined in the protocol 3. The database has been fully cleaned and frozen for this analysis |
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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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |