| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Soft Tissue Sarcoma |
| Sarcoma de tejidos blandos |
|
| E.1.1.1 | Medical condition in easily understood language |
| Soft Tissue Sarcoma |
| Sarcoma de tejidos blandos |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Cohort A (Patients with diagnosis of non-operable or unresectable or not oncologically recommended metastasectomy of limited to lung metastases soft tissue sarcoma), and Cohort B (Patients with locally advanced resectable Myxoid Liposarcoma) primary objective is response to treatment of the combination of trabectedin plus radiation therapy. |
| El objetivo principal de los pacientes de Cohorte A (pacientes con sarcomas de partes blandas con metástasis limitadas a pulmones no operables, o no resecables o no recomendable una metastasectomía ) y pacientes de la Cohorte B (Paciente con Liposarcoma mixoide resecable y localmente avanzado) es la respuesta al tratamiento de combinación de trabectedina y radioterapia |
|
| E.2.2 | Secondary objectives of the trial |
For Cohort A:
- Toxicity profile
- Efficacy response
-CHOI criteria response
- Quality of Life
For Cohort B:
- Toxicity profile
-Activity
-Efficacy
-CHOI criteria response
-Quality of life measured |
Cohorte A:
- Perfil de toxicidad
- Eficacia de respuesta,
-Criterios de respuesta CHOI
-Calidad de vida
Cohorte B:
- Perfil de toxicidad
-Actividad
- Eficacia
- Criterios de respuesta CHOI
- Calidad de vida |
|
| 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 |
Title: Traslational sub-study to determine the action mechanism of trabectedin in patients with soft tissue sarcoma and evaluate the efficacy of combined treatment of trabectedin and radiotherapy
Date and version:
Objectives of sub-study are to determine:
Protein expression of FASr, CUL4A, p53, NFAT, p21, HMGA1, E2F1
RNA expression of these genes
Pharmacodinamics in cohort B
Blood detection of HMGA1 and E2F1 (pre and post treatment) |
Titulo: Sub estudio traslacional para determnar el mecanismo de acción de trabectedina en pacientes con sarcoma de partes blandas y valorar la eficacia del tratamiento combinado de trabectedina y radioterapia.
Date and version:
Los objetivos del subestudio son determinar:
Expresion de proteina en FASr, CUL4A, p53, NFAT, p21, HMGA1, E2F1
Expresion de ARN de estos genes
Farmacodinámica en la cohorte B
Detección en sangre de HMGA1 y E2F1 (pre y post tratamiento |
|
| E.3 | Principal inclusion criteria |
Inclusion Criteria Cohort A
- Aged between 18 and 70.
- Patients must have a diagnostic of Soft Tissue Sarcoma with metastasis limited to lung, and not suitable for metatasectomy or surgery resection or not oncologically recommended metastasectomy
- Patients must have documentation of disease progression within 6 months prior to study entry.
- The patient must have been considered eligible for systemic chemotherapy. A maximum of two previous lines for advanced/metastatic disease are allowed as long as trabectedin has not been included.
- The following histological subtypes can be included:
+ Undifferentiated pleomorphic sarcoma (previously, malignant fibrous histiocytoma)
+ Leiomyosarcoma
+ Angiosarcoma/ epithelial hemangioendothelioma
+ Liposarcoma and its variants (well differentiated, dedifferentiated, myxoid/round cells, pleomorphic)
+ Synovial sarcoma
+ Fibrosarcoma and its variants (epithelial fibrosarcoma/low grade fibromyxoid sarcoma)
+ Hemangiopericytoma/solitary fibroid tumor
+ Neurogenic sarcoma (Malignant peripheral nerve sheath tumor, MPNST)
+ Myxofibrosarcoma
+ Epithelioid Sarcoma
+ Unclassified sarcoma (spindle cell/epithelioid/pleomorphic/myxoid)
+ Measurable disease, according to RECIST V 1.1 criteria
+ Adequate respiratory functions: FEV1 >1L
- Adequate bone marrow function (hemoglobin > 10 g/dl, leukocytes ? 3.000/mm3, neutrophils ? 1.500/mm3, platelets ? 100.000/mm3). Patients with plasma creatinine ? 1,6 mg/dl, transaminases ? 2.5 times the UNL, total bilirubin ? UNL, CPK ? 2.5 times UNL, alkaline phosphatase ? 2.5 times the UNL are acceptable. If the increase of alkaline phosphatase is > 2.5 times the UNL, then the alkaline phosphatase liver fraction and/or 5? nucleotidase and/or GGT must be ? UNL.
- Normal cardiac function with a LVEF ? 50% by echocardiogram or MUGA.
- Disease distribution in lungs allows meeting with normal tissue constraints of radiation therapy. Radiation therapist must confirm this point.
- Patient must have a Central Venous Catheter for treatment
Cohort B
- Aged between 18 and 70.
- Pathological diagnosis of Myxoid Liposarcoma, deep located and more than 5 cm or superficial more than 10 cm.
- Tumor must be resectable and without evidence of regional or distal spread after adequate staging procedure. Tumor must be located in limbs or superficial trunk wall.
- Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation therapist must confirm this point.
- Measurable disease, according to RECIST V 1.1 criteria
- Adequate bone marrow function (hemoglobin > 10 g/dL, leukocytes ? 3.000/mm3, neutrophils ? 1.500/mm3, platelets ? 100.000/mm3). Patients with plasma creatinine ? 1,6 mg/dL, transaminases ? 2.5 times the UNL, total bilirubin ? UNL, CPK ? 2.5 times UNL, alkaline phosphatase ? 2.5 times the UNL are acceptable. If the increase of alkaline phosphatase is > 2.5 times the UNL, then the alkaline phosphatase liver fraction and/or 5? nucleotidase and/or GGT must be ? UNL.
- Normal cardiac function with a LVEF ? 50% by echocardiogram or MUGA.
- Patient may have had one previous chemotherapy line.
- Patient must have a Central Venous Catheter for treatment. |
Cohorte A:
- Edad entre 18 y 70 años
- Pacientes con diagnóstico de sarcomas de partes blandas con metástasis limitadas a pulmones no operables, o no resecables o no recomendable una metastasectomía
-Pacientes deben haber tenido una progresión a la enfermedad en los 6 meses previos a la inclusión en el estudio.
- Pacientes deber ser elegibles para quimioterapia sistémica. Se permite un máximo de dos líneas previas para la enfermedad avanzada /metastásica siempre que no se haya incluido trabectedina.
- Los siguientes subtipos histológicos pueden ser incluidos:
+Sarcoma pleomórfico indiferenciado (previamente histiocitoma maligno fibroso)
+Leiomiosarcoma
+Angiosarcoma/hemangioendotelioma epitelial
+Liposarcoma y sus variantes (bien diferenciado, desdiferenciado, mixoide/de celulas redondas, pleomórfico)
+Sarcoma sinovial
+Fibrosarcoma y sus variantes (Fibrosarcoma epitelial/Sarcoma fibromixoide de bajo grado)
+Hemangiopericitoma/Tumor fibroide solitario
+Sarcoma neurogénico (tumor maligno de vaina nerviosa periférica, MPNST)
+Mixofibrosarcoma
+Sarcoma epiteloide
+Sarcoma inclasificado (de celulas fusiformes/epiteloide/pleomórfico/mixoide)
-Enfermedad medible, según criterios RECIST v 1.1
-Funciones respiratorias adecuadas FEV1>1L
- Parametros hematológicos y bioquímicos adecuados: (hemoglobina > 10 g/dl, leukocitos ? 3.000/mm3, neutrofilos ? 1.500/mm3, plaquetass ? 100.000/mm3).
Pacientes con creatinina plasmática ? 1,6 mg/dl, transaminasas ? 2.5 veces el límite superior, bilirubina total ? limite superior normal, CPK ? 2.5 veces el limite superior normal, fosfatasa alcalina ? 2.5 el limite superior es aceptable. Si el aumento de la fosfatasa alclaina es > 2.5 veces el límite superior normal , entonces la fracción hepática de la fosfatasa alcalina y/o nucleotidasa 5 y/o GGT deben ser ? que el limite superior de normalidad.
- Función cardiaca normal con FEVI ? 50%, por ecocardiograma o MUGA.
- Distribución de la enfermedad en pulmones permite adaptarse a las restricciones normales del tejido sano en radioterapia. El radioterapeuta debe confirmar este punto.
-Pacientes deben tener un acceso venoso central.
Cohorte B
-Edad de 18 a 70 años.
-Diagnóstico de Liposarcoma Mixoide, localizado profundamente y a más de 5cm, o superficial a más de 10cm.
-El tumor debe ser rescable y sin evidencia de extensión regional o distal despues de los procedimientos de estadiaje. El tumor debe estar en las extremidades superiores e inferiores o superficialmente en la pared torácica.
-La distribucion de la enfermedad permite encontrarse con limitaciones en el tejido normal, el radioterapeuta debe confirmar este criterio.
-Enfermedad medible, siguiendo la criteria RECIST 1.1
-Parametros hematológicos y bioquímicos adecuados: (hemoglobina > 10 g/dl, leukocitos ? 3.000/mm3, neutrofilos ? 1.500/mm3, plaquetass ? 100.000/mm3).
Pacientes con creatinina plasmática ? 1,6 mg/dl, transaminasas ? 2.5 veces el límite superior, bilirubina total ? limite superior normal, CPK ? 2.5 veces el limite superior normal, fosfatasa alcalina ? 2.5 el limite superior es aceptable. Si el aumento de la fosfatasa alclaina es > 2.5 veces el límite superior normal , entonces la fracción hepática de la fosfatasa alcalina y/o nucleotidasa 5 y/o GGT deben ser ? que el limite superior de normalidad.
-Función cardiaca normal con una FEVI de ? 50% por ecocardiograma o MUGA.
-Paciente debe haber recibido una línea previa de tratamiento.
-Pacientes deben tener un acceso venoso central. |
|
| E.4 | Principal exclusion criteria |
Cohort A
- Previous treatment with trabectedin or radiotherapy involving any lung field.
- Performance status ? 2 (ECOG).
- Metastases out of those located in lungs.
- Plasma bilirubin > UNL.
- Creatinine > 1.6 mg/dL.
- History of other neoplastic disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated.
- Severe COPD or other severe pulmonary diseases.
- Significant cardiovascular disease (for example, dyspnea > 2 NYHA)
- Significant systemic diseases grade 3 or higher on the NCI-CTCAE v4.03 scale, that limit patient availability, or according to investigator judgment may contribute significantly to treatment toxicity.
- Uncontrolled bacterial, mycotic or viral infections.
- Known positive test for infection by human immunodeficiency virus (HIV).
- Women who are pregnant or breast-feeding.
Cohort B
1. More than one previous chemotherapy treatment for local disease including trabectedin.
2. Radiotherapy involving the tumoral bed.
3. Performance status ? 2 (ECOG).
4. Presence of metastases or lymph node involvement by the tumor.
5. Location other than limb or superficial trunk wall.
6. Plasma bilirubin > UNL.
7. Creatinine > 1.6 mg/dL.
8. History of other neoplastic disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated.
9. Significant cardiovascular disease (for example, dyspnea > 2 NYHA)
10. Significant systemic diseases grade 3 or higher on the NCI-CTCAE v4.03 scale, that limit patient availability, or according to investigator judgment may contribute significantly to treatment toxicity.
11. Uncontrolled bacterial, mycotic or viral infections.
12. Known positive test for infection by human immunodeficiency virus (HIV).
13. Women who are pregnant or breast-feeding.
14. Psychological, familial, social or geographic circumstances that limit the patient?s ability to comply with the protocol or informed consent.
15. Patients participating in another clinical trial or receiving any other investigational product.
16. Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion. |
Cohorte A:
- Tratamiento previo con trabectedina, o radioterapia en cualquier area de pulmón.
- Estado Funcional (ECOG) ? 2
- Metastasis localizadas fuera del pulmón.
- Bilirrubina plasmática ? limite superior normalidad (LSN)
-Creatinina ? 1.6 mg/dl
- Otra enfermedad neoplásica a excepción de carcinoma basocelular o cancer de cervix in situ tratado adecuadamente.
- EPOC severo u otras enfermedades pulmonares graves.
- Enfermedad cardiovascular significativa (por ejemplo, disnea ? 2 NYHA)
- Enfermedad sistémica significativa grado 3 o mayor medida por CTCAE v4.03, que limite la disponibilidad del paciente, o a juicio del investigador que pueda contribuir de manera significativa a la toxicidad del tratamiento.
- Infecciones bacterianas, micóticas o virales no controladas.
- Test positivo para el virus de inmunodeficiencia humano (VIH).
- Mujeres embarazadas o en periodo de lactancia.
Cohorte B
- Más de una línea previa de quimioterapia para la enfermedad local, incluyendo trabectedina.
- Radioterapia en el lecho tumoral
- Estado funcional ?2 (ECOG)
-Presencia de metástasis o afectación ganglionar del tumor primario
-Localización que no sea en extremidades o en la superficie de la pared torácica.
-Bilirrubina plasmática > Límite superior de normalidad (LSN)
-Creatinina > 1.6mg/dl
- History of other neoplastic disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated.
- Significant cardiovascular disease (for example, dyspnea > 2 NYHA)
- Significant systemic diseases grade 3 or higher on the NCI-CTCAE v4.03 scale, that limit patient availability, or according to investigator judgment may contribute significantly to treatment toxicity.
- Uncontrolled bacterial, mycotic or viral infections.
- Known positive test for infection by human immunodeficiency virus (HIV).
- Women who are pregnant or breast-feeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Evaluation of RECIST criteria |
| Evaluación por criterios RECIST |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For phase I and II of cohort A, the imaging evaluation will be performed at baseline and every 6 weeks until disease progression.
For phase I and II of cohort B, the imaging evaluation to assess response following RECIST criteria, will be performed at baseline, week 10 from starting treatment and at follow up: MRI every 4 months in 1st year, every 6 months during 2nd and 3rd year; Thorax/Abdo CT scan will be performed every 4 months during 3 years. |
Para la fase I y II de la cohorte A, se realizarán pruebas de imagen en el periodo basal y cada 6 semanas hasta progresión de la enfermedad.
Para la fase I y II de la cohorte B, se realizarán pruebas de imagen para valorar respuesta por RECIST en el periodo basal, en la semana 10 desde el inicio del tratamiento y en las visitas de seguimiento: Resonancia magnética cada 4 meses durante el primer año, cada 6 meses durante el segundo y el tercer año. Un TAC se realizará cada 4 meses durante tres años. |
|
| E.5.2 | Secondary end point(s) |
Cohort A:
- Assessment of adverse events following CTCAE v4.03
- Progression Free survival, Overall Survival, potential predictive/prognostic biomarkers.
- CHOI criteria response
- QLQ-C30 EORTC questionnaire
Cohort B:
-Assessment of adverse events following CTCAE v4.03
- Activity assessed by Functional imaging, pathologic response and potential predictive/prognostic biomarkers.
-Recurrence free survival
-CHOI criteria Response
-QLQ-C30 EORTC questionnaire |
Cohorte A:
- Evaluación de acontecimientos adversos por CTCAE v4.03
-Supervivencia libre de progresión, supervivencia global, biomarcadores potenciales predictivos/de pronóstico
-Respuesta según criterios CHOI
-Cuestionarios QLQ-C30
Cohorte B:
-Evaluación de acontecimientos adversos por CTCAE v4.03
- Actividad evaluada a través de Imagen Funcional, respuesta patológica y biomarcadores potenciales predictivos/de pronóstico.
- Supervivencia libre de recaída.
- respuesta segun Criterios CHOI |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Adverse events will be evaluated at the beginning of each cycle prior to treatment, and end of treatment
-For phase I and II of cohort A, the imaging evaluation will be performed at baseline and every 6 weeks until disease progression.
For phase I and II of cohort B, the imaging evaluation to assess response following RECIST criteria, will be performed at baseline, week 10 from starting treatment and at follow up: MRI every 4 months in 1st year, every 6 months during 2nd and 3rd year; Thorax/Abdo CT scan will be performed every 4 months during 3 years.
- tumor collection and blood extractions.
-Questionnaires in cohort A will be done at baseline, and every 3 cycles until end of treatment; cohort B at baseline, week 10 from beginning of treatment and at end of treatment. |
-Acontecimientos adversos serán evaluados al comienzo de cada ciclo antes de cada tratamiento y en la visita basal, asi como la visita final de tratamiento
-Fase I,II cohorte A: pruebas de imagen: periodo basal y cada 6 semanas hasta progresión de la enfermedad.
Fase I,II cohorte B: pruebas de imagen en el periodo basal, en la semana 10 desde el inicio del tratamiento y en las visitas de seguimiento: Resonancia magnética cada 4 meses durante el primer año, cada 6 meses durante el segundo y el tercer año. Un TAC se realizará cada 4 meses durante tres años.
- Se extraerán muestras de sangre, y se recogeran muestras de tumor.
-Los cuestionarios en cohorte A: basal, y cada tres semanas hasta fin de tratamiento. Cohorte B: basal, semana 10 y fin de tratamiento |
|
| 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 | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| trial to evaluate the potentially synergist effect for combination of trabectedin and radiotherapy |
| Ensayo que evalua el efecto sinérgico de la combinacion de trabectedina con radioterapia |
|
| 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 | No |
| 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 | 1 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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
|
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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