E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable or metastatic soft tissue sarcoma |
Sarcoma de tejidos blandos irresecable o metastásico |
|
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10041299 |
E.1.2 | Term | Soft tissue sarcomas |
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 | 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) |
|
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 |
The primary objective of the trial is to evaluate whether L19TNF in combination with doxorubicin given for advanced or metastatic soft tissue sarcoma prolongs progression free survival, as compared to doxorubicin alone.
The following efficacy endpoint will be considered: - Progression-free survival (PFS) |
El objetivo principal del ensayo es evaluar si L19TNF en combinación con doxorrubicina administrada para el sarcoma de tejidos blandos avanzado o metastásico prolonga la supervivencia libre de progresión, en comparación con la doxorrubicina sola.
Se considerará la siguiente variable de eficacia: - Supervivencia libre de progresión (SLP) |
|
E.2.2 | Secondary objectives of the trial |
To assess the efficacy, the following measurements will be considered:
- Overall survival (OS) - Median Progression Free Survival (mPFS) - Median Overall Survival (mOS). - Overall Response Rate (ORR, consisting of CR and PR) and Best Overall Response Rate (BORR)
To assess the safety profile of L19TNF combined with doxorubicin. The following safety endpoints will be considered: - Adverse Events (AEs) assessment based on CTCAE v.4.03. - Standard laboratory (haematology, biochemistry and urinalysis) parameters. - Physical examination findings including assessment of vital signs and physical measurements. |
Para evaluar la eficacia, las siguientes medidas serán consideradas: - Supervivencia global (SG) - Mediana de supervivencia libre de progresión (mSLP) - Mediana de supervivencia global (mSG) - Tasa de respuesta global (TRG, que consiste en RC y RP) y tasa de mejor respuesta global (TMRG)
Evaluar el perfil de seguridad de L19TNF combinada con doxorrubicina. Se considerarán las siguientes variables de seguridad: - Evaluación de acontecimientos adversos (AAs) basada en CTCAE v.4.03. - Parámetros estándar de laboratorio (hematología, bioquímica y análisis de orina). - Hallazgos del examen físico, incluida la evaluación de los signos vitales y las mediciones físicas. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients must have histological evidence of advanced unresectable and/or metastatic high-grade soft tissue sarcoma (grade 2 – 3 according to the FNLCC grading system) not amenable to curative treatment with surgery or radiotherapy. The following tumor types are included: – Malignant fibrous histiocytoma – Myxoid and round cell liposarcoma, pleomorphic liposarcoma or dedifferentiated – Liposarcoma – Pleomorphic rhabdomyosarcoma – Myxofibrosarcoma intermediate and high-grade – Fibrosarcoma – Leiomyosarcoma – Angiosarcoma – Alveolar rhabdomyosarcoma – Unclassified sarcoma NOS
The following tumor types will not be included: – GIST – Mixed mesodermal tumor – Chondrosarcoma – Synovial sarcoma – Malignant peripheral nerve sheath tumor – Epithelioid sarcoma – Embryonal rhabdomyosarcoma – Malignant mesothelioma – Neuroblastoma – Osteosarcoma – Ewing's sarcoma / primitive neuroectodermal tumor – Desmoplastic small round cell tumor – Alveolar soft part sarcoma • Patients aged 18-75 years. • No prior therapy (except surgery and radiation) for the advanced or metastatic stage of soft tissue sarcoma. • Patients who had received prior anthracyclines will not be eligible. • Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria 1.1. This lesion should not have been irradiated during previous treatments. • Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. • Life expectancy of at least 3 months. |
• Los pacientes deben tener evidencia histológica de sarcoma de tejidos blandos avanzado irresecable y/o metastásico de alto grado (grado 2-3 según el sistema de clasificación FNLCC) no susceptible de tratamiento curativo con cirugía o radioterapia. Se incluyen los siguientes tipos de tumores: - Histiocitoma fibroso maligno - Liposarcoma mixoide de células redondas, liposarcoma pleomórfico o desdiferenciado - Liposarcoma - Rabdomiosarcoma pleomórfico - Mixofibrosarcoma de grado intermedio y alto - Fibrosarcoma - Leiomiosarcoma - Angiosarcoma - Rabdomiosarcoma alveolar - Sarcoma no clasificado NEOM
No se incluirán los siguientes tipos de tumores: - GIST - Tumor mesodérmico mixto - Condrosarcoma - Sarcoma sinovial - Tumor maligno de la vaina del nervio periférico - Sarcoma epitelioide - Rabdomiosarcoma embrionario - Mesotelioma maligno - Neuroblastoma - Osteosarcoma - Sarcoma de Ewing / tumor neuroectodérmico primitivo - Tumor desmoplásico de células pequeñas y redondas - Sarcoma alveolar de partes blandas
• Pacientes con edad de 18 a 75 años. • Sin terapia previa (excepto cirugía y radiación) para el estadio avanzado o metastásico del sarcoma de tejidos blandos. • Los pacientes que hayan recibido antraciclinas previas no serán elegibles. • Los pacientes deben tener al menos una lesión medible unidimensionalmente mediante tomografía computarizada según lo definido por los criterios RECIST 1.1. Esta lesión no debería haber sido irradiada durante tratamientos previos. • Estado funcional del Eastern Cooperative Oncology Group (ECOG) de ≤ 2. • Esperanza de vida de al menos 3 meses. |
|
E.4 | Principal exclusion criteria |
1. Prior therapy (except surgery and radiation) for unresectable or metastatic malignant soft tissue sarcoma. 2. Previous treatment with anthracycline-containing chemotherapy. 3. Radiotherapy within 4 weeks prior therapy. 4. Known history of allergy to TNFα, anthracyclines or other intravenously administered human proteins/peptides/antibodies. 5. Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and haemoglobin (Hb) < 9.0 g/dl. 6. Chronically impaired renal function as expressed by creatinine ≥ 2.0 x ULN. 7. Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 2.5 x ULN, except for patients with liver metastasis, in which case values up to 3.0 x ULN are allowed). 8. Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol. 9. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris. 10. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria). 11. Clinically significant cardiac arrhythmias or requiring permanent medication. 12. Uncontrolled hypertension, despite optimal therapy. 13. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification). 14. Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative retinopathy. 15. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 4 weeks of administration of study treatment. 16. Pregnancy or breast-feeding. 17. Requirement of chronic administration of corticosteroids or other immunosuppressant drugs. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion. 18. Presence of active and uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study. 19. Known active or latent tuberculosis (TB). 20. Concurrent malignancies other than Soft Tissue Sarcoma, unless the patient has been disease-free for at least 2 years. 21. Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment. 22. Serious, non-healing wound, ulcer or bone fracture. 23. Allergy to study medication or excipients in study medication. 24. Concurrent therapy with oral anticoagulants . 25. Concurrent use of other anti-cancer treatments or agents other than study medication |
1. Terapia previa (excepto cirugía y radiación) para el sarcoma de tejido blando maligno no resecable o metastásico. 2. Tratamiento previo con quimioterapia que contenga antraciclinas. 3. Radioterapia dentro de las 4 semanas previas a la terapia. 4. Historia conocida de alergia al TNFα, antraciclinas u otras proteínas/péptidos/anticuerpos humanos administrados por vía intravenosa. 5. Recuento absoluto de neutrófilos (RAN) <1,5 x 10^9/L, plaquetas <100 x 10^9 / L y hemoglobina (Hb) <9,0 g / dl. 6. Función renal con insuficiencia crónica expresada por creatinina ≥ 2,0 x LSN. 7. Función hepática inadecuada (ALT, AST, ALP o bilirrubina total ≥ 2,5 x LSN, excepto en pacientes con metástasis hepática, en cuyo caso se permiten valores de hasta 3,0 x LSN). 8. Cualquier condición concomitante grave que haga desaconsejable que el paciente participe en el estudio o que pueda poner en peligro el cumplimiento del protocolo. 9. Historia dentro del último año de síndromes coronarios agudos o subagudos, incluyendo infarto de miocardio, angina de pecho estable inestable o severa. 10. Insuficiencia cardíaca (> Grado II, criterios de la New York Heart Association (NYHA)). 11. Arritmias cardíacas clínicamente significativas o que requieran medicación permanente. 12. Hipertensión incontrolada, a pesar de una terapia óptima. 13. Enfermedad vascular periférica isquémica (Grado IIb-IV según la clasificación de Leriche-Fontaine). 14. Retinopatía diabética grave, como retinopatía no proliferativa grave y retinopatía proliferativa. 15. Traumatismo mayor, incluida cirugía mayor (como cirugía abdominal/cardíaca/torácica) en las 4 semanas anteriores a la administración del tratamiento del estudio. 16. Embarazo o lactancia. 17. Requisito de administración crónica de corticosteroides u otros fármacos inmunosupresores. El uso limitado de corticosteroides para tratar o prevenir reacciones de hipersensibilidad aguda no se considera un criterio de exclusión. 18. Presencia de infecciones activas y no controladas u otra enfermedad concurrente grave que, en opinión del investigador, colocaría al paciente en un riesgo indebido o interferiría con el estudio. 19. Tuberculosis (TB) activa o latente conocida. 20. Neoplasias malignas concurrentes distintas del sarcoma de tejidos blandos, a menos que el paciente haya estado libre de enfermedad durante al menos 2 años. 21. Factores de crecimiento o agentes inmunomoduladores en los 7 días anteriores a la administración del tratamiento del estudio. 22. Herida, úlcera o fractura ósea grave que no cicatriza. 23. Alergia a la medicación del estudio o excipientes en la medicación del estudio. 24. Terapia concurrente con anticoagulantes orales. 25. Uso concurrente de otros tratamientos o agentes contra el cáncer distintos de la medicación del estudio |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of the trial is to evaluate whether L19TNF in combination with doxorubicin given for advanced or metastatic soft tissue sarcoma prolongs progression free survival, as compared to doxorubicin alone.
The following efficacy endpoint will be considered: - Progression-free survival (PFS) |
El objetivo principal del ensayo es evaluar si L19TNF en combinación con doxorrubicina administrada para el sarcoma de tejidos blandos avanzado o metastásico prolonga la supervivencia libre de progresión, en comparación con la doxorrubicina sola.
Se considerará la siguiente variable de eficacia: - Supervivencia libre de progresión (SLP) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of study |
Final del estudio |
|
E.5.2 | Secondary end point(s) |
To assess the efficacy, the following measurements will be considered: - Overall survival (OS) - Median Progression Free Survival (mPFS) - Median Overall Survival (mOS). - Overall Response Rate (ORR, consisting of CR and PR) and Best Overall Response Rate (BORR)
To assess the safety profile of L19TNF combined with doxorubicin. The following safety endpoints will be considered: - Adverse Events (AEs) assessment based on CTCAE v.4.03. - Standard laboratory (haematology, biochemistry and urinalysis) parameters. - Physical examination findings including assessment of vital signs and physical measurements. |
Para evaluar la eficacia, las siguientes medidas serán consideradas: - Supervivencia global (SG) - Mediana de supervivencia libre de progresión (mSLP) - Mediana de supervivencia global (mSG) - Tasa de respuesta global (TRG, que consiste en RC y RP) y tasa de mejor respuesta global (TMRG)
Evaluar el perfil de seguridad de L19TNF combinada con doxorrubicina. Se considerarán las siguientes variables de seguridad: - Evaluación de acontecimientos adversos (AAs) basada en CTCAE v.4.03. - Parámetros estándar de laboratorio (hematología, bioquímica y análisis de orina). - Hallazgos del examen físico, incluida la evaluación de los signos vitales y las mediciones físicas. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Median Overall survival (mOS). - Overall response rate (ORR, consisting of CR and PR). - Progression-free survival (PFS) rate at 3, 6, 9, 12 and 18 months. - Overall survival (OS) rate at 12 and 18 months.
Safety profile of L19TNF combined with doxorubicin: throughout the study |
- Mediana de supervivencia global (mSG) - Tasa de respuesta global (TRG, que consiste en RC y RP) - Tasa de supervivencia libre de progresión (SLP) a los 3, 6, 9, 12 y 18 meses - Tasa de supervivencia global (SG) a los 12 y 18 meses |
|
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 | Yes |
E.8.2.3.1 | Comparator description |
Doxorrubicina |
Doxorubicin |
|
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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
|
Last Patient Last Visit |
Última visita de último paciente |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 8 |
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 |