| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Cohort A:Soft Tissue Sarcoma with metastasis limited to lung, and not suitable for metastasectomy or surgery resection or not oncologically recommended metastasectomy.
Cohort B : 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. |
Coorte A: Sarcoma dei tessuti molli con metastasi limitate al polmone e non candidabili a metastesectomia o resezione chirurgica o per i quali la metastasectomia non risulti ontologicamente raccomandata.
Coorte B:
Liposarcoma mixoide profondo con dimensione superiore a 5 cm o, se superficiale, di dimensione superiore a 10 cm.
Tumore degli arti o del tronco, resecabile senza evidenza di diffusione regionale o distale dopo una accurata valutazione di stadiazione
|
|
| E.1.1.1 | Medical condition in easily understood language |
Cohort A: Soft tissue sarcoma with lung metasases
Cohort B and C: Localize Myxoid Liposarcoma of limbs or superficial trunk wall. |
Coorte A: Sarcoma dei tessuti molli con metastasi limitate al polmone
Coorte B: Liposarcoma mixoide del tronco e degli arti che può esser trattato con chirurgia localizzato |
|
| 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 | HLT |
| E.1.2 | Classification code | 10041298 |
| E.1.2 | Term | Soft tissue sarcomas histology unspecified |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
o To describe safety profile for each cohort and dose level of trabectedin in order to find the recommended dose for phase II part in a specific way for each cohort of treatment. That is, the maximum tolerable dosage according the protocol.
Toxicity will be evaluated on the basis of on adverse events (CTCAE v4.03) for both cohorts.
|
o Definire il profilo di sicurezza per ogni coorte e livello di dose di trabectedina al fine di trovare la dose raccomandata per la fase II in modo specifico per ogni coorte. Tale dose, rappresenterà la massima dose tollerata in accordo al protocollo.
La tossicità sarà valuate sulla base degli eventi avversi (CTCAE v.4.03) per entrembe le coorti |
|
| E.2.2 | Secondary objectives of the trial |
o RECIST response for the combination of trabectedin plus radiation therapy in
both cohorts.
o For cohort A: Efficacy response measured by progression free survival (PFS), overall survival (OS), ORRand potential predictive/prognostic biomarkers.
o For cohort B: Efficacy measured by recurrence free survival (RFS).
o For cohort B: Activity measured by functional imaging, pathologic response and potential predictive/prognostic biomarkers
o Choi criteria response (for both cohorts)
o Quality of Life measured by QLQ-C30 EORTC questionnaire (for both cohorts) |
oRisposta RECIS in entrambe le coorti della combinazione trabectedina più radioterapia.
oPer la coorte A: risposta di efficacia, misurata da sopravvivenza libera da progressione (PFS), da sopravvivenza globale (OS), ORR (tasso di risposta globale) e biomarcatori potenzialmente predittivi/prognostici.
oPer la coorte B: Efficacia misurata dalla sopravvivenza libera da recidiva (RFS)
oPer la coorte B: Attività misurata da imaging funzionale, risposta patologica e biomarcatori potenzialmente predittivi/prognostici.
o Risposta secondo criteri Choi per entrambe le coorti
oQualità della vita valutata in entrambe le coorti con il questionario QLQ-C-30-EORTC |
|
| 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 |
Other types of substudies
Specify title, date and version of each substudy with relative objectives: Translational study for core TRASTS study 13Nov2014 vers. 2.0
Our proposal for the translational research associated to this trial focuses on the search of factors involved in different pathways such FAS, Ca2+ and NER pathways and angiogenic and inflammatory mediators that could be good predictive biomarkers for the response to the treatment with trabectedin plus radiotherapy in Sarcomas.
In order to achieve our aim, we will carry out the following studies:
1. Study of potential biomarkers to test the efficacy of trabectedin plus radiation therapy combination in cohorts A and B (Protein and RNA expression)
2. In vitro studies
3. Blood detection of HMGA1 and VEGF
|
Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudio traslazionale opzionale per la valutazione dei biomarcatori che possano predire una risposta al trattamento combinato con trabectedin nei sarcomi. Tale studio ha come scopo quello di ricercare fattori coinvolti nei diversi pathways – come FAS, Ca2+ e NER – e i mediatori angiogenici ed infiammatori.
|
|
| E.3 | Principal inclusion criteria |
Cohort A
1. The patient must sign voluntarily the informed consent
2. Age = 18 years old
3. Patients must have a diagnostic of Soft Tissue Sarcoma with metastasis and not suitable for metastasectomy or surgery resection
4. Documentation of disease progression within 6 months prior to study entry.
5. 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.
6. The following histological subtypes can be included:
- Undifferentiated pleomorphic sarcoma (previously, malignant fibrous histiocytoma)
- Leiomyosarcoma
- Angiosarcoma/ epithelial hemangioendothelioma
- Liposarcoma and its variants
- Synovial sarcoma
- Fibrosarcoma and its variants
- Hemangiopericytoma/solitary fibroid tumor
- Neurogenic sarcoma (Malignant peripheral nerve sheath tumor, MPNST)
- Myxofibrosarcoma
- Epithelioid Sarcoma
- Unclassified sarcoma (spindle cell/epithelioid/pleomorphic/myxoid)
7. Measurable disease, according to RECIST V 1.1 criteria
8. Performance status =1
9. Adequate respiratory functions: FEV1 >1L, DLCO>40% (patients with pulmonary target lesions)
10. Adequate bone marrow, hepatic and renal function.
11. Men or women of childbearing potential should be using an effective method of contraception before entry into the study and throughout the same and for 6 months after ending the study.
12. Normal cardiac function with a LVEF = 50%
Cohort B
1. The patient must sign voluntarily the informed consent
2. Age = 18 years old
3. Pathological diagnosis of Myxoid Liposarcoma, deep located and more than 5 cm or superficial more than 10 cm.
4. 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.
5. Measurable disease, according to RECIST 1.1
6. Performance status 0-1 (ECOG).
7. Adequate bone marrow, renal and hepatic function
8. Men or women of child bearing potential should be using an effective method of contraception before entry into the study and throughout the same and for 6 months after ending the study.
9. Normal cardiac function with a LVEF = 50%
Cohort C
1. The patient must sign voluntarily the informed consent
2. Age = 18 years old
3. The following histological subtypes may be included: High grade leiomyosarcoma (G2-3), liposarcoma, if at least 30% of the tumour is dedifferentiated, pleomorphic liposarcoma.
4. The tumour must be located in the retroperitoneum and it must be resectable
5. Measurable disease, according to RECIST 1.1
6. ECOG performance status 0–1.
7. Adequate bone marrow, renal and hepatic function
8. Fertile men or women must use an effective contraceptive method before starting the study, during the study and for 6 months following the conclusion thereof.
9. Normal cardiac function with LVEF =50% by echocardiogram or MUGA. |
Coorte A
1. Firma volontaria Consenso informato facente parte della normale pratica clinica di routine della cura del paziente
2. Età =18 anni
3. Diagnosi di STS metastatico non candidabile a metastesectomia o resezione chirurgica o
4. Presenza di localizzazione di malattia polmonare che permetta il trattamento con RT
5. Diffusione metastatica presente al massimo in due organi (es polmoni e fossa pelvica)
6. Progressione documentata di malattia nei 6 mesi precedenti l’ingresso in studio.
7. Paziente eleggibile per il trattamento di chemioterapia sistemica. Un massimo di 2 linee precedenti per la malattia avanzata/metastatica è ammesso, purché non sia inclusa la trabectina
8. I seguenti sottotipi istologici possono essere inclusi:
- Sarcoma pleomorfo indifferenziato (precedentemente definito come istiocitoma fibroso maligno)
- Leiomiosarcoma
- Angiosarcoma/ emangioendotelioma epiteliale
- Liposarcoma nelle sue varianti
- Sarcoma sinoviale
- Fibrosarcoma e le sue varianti
- Emangiopericitoma / tumore fibroso solitario
- Sarcoma neurogenico (tumore maligno della guaina dei nervi periferici, MPNST )
- Myxofibrosarcoma
- Sarcoma epiteliode
- Sarcoma non classificati (a cellule fusate/ epitelioide/ pleomorfo/ mixoide)
9. Malattia misurabile secondo i criteri RECIST V 1.1
10. Performance status =1 (ECOG).
11. Adeguata funzionalità respiratoria FEV1 >1L DLco >40% (in pazienti con malattia polmonare)
12. Adeguata funzionalità midollare , epatica e renale
13. Uomini o donne in età fertile debbono usare un metodo contraccettivo efficace prima dell’ingresso, durante e fino a 6 mesi dopo la fine dello studio..
14. Funzionalità cardiaca nella norma (LVEF = 50%)
Coorte B
1. Firma volontaria del consenso informato
2. Età =18 anni
3. Diagnosi istopatologica di Liposarcoma mixoide profondo con dimensione superiore a 5 cm o, se superficiale, di dimensione superiore a 10 cm.
4. Tumore degli arti o del tronco, resecabile senza evidenza di diffusione regionale o distale dopo una accurata stadiazione
5. Malattia misurabile secondo i criteri RECIST 1.1
6. Performance status 0-1 (ECOG).
7. Adeguata funzionalità midollare, renale, epatica
8. Uomini o donne in età fertile debbono usare un metodo contraccettivo efficace prima dell’ingresso, durante e fino a 6 mesi dopo la studio.
9. Funzionalità cardiaca nella norma (LVEF = 50%)
10. Il paziente può avere ricevuto una precedente linea di chemioterapia
Coorte C
1. Firma volontaria del consenso informato Età =18 anni
2. I seguenti sottotipi istologici possono essere inclusi:
Leiosarcoma di alto grado (G2-G3),
liposarcoma, se almeno il 30% del tumore è dedifferenziato e
liposarcoma pleomorfo.
3. La malattia dovrà essere localizzata nel retroperitoneo e dovrà essere resecabile
4. Malattia misurabile secondo i criteri RECIST 1.1
5. ECOG performance status 0–1.
6. Adeguata funzionalità midollare, renale ed epatica
7. Uomini o donne in età fertile debbono usare un metodo contraccettivo efficace prima dell’ingresso, durante e fino a 6 mesi dopo la fine dello studio.
8. Funzionalità cardiaca nella norma (LVEF = 50%) |
|
| E.4 | Principal exclusion criteria |
COHORT A
1. Previous treatment with trabectedin or RT
2. Performance status = 2
3. Plasma bilirubin > UNL.
4. Creatinine > 1.6 mg/dL.
5. History of other neoplastic disease with less than 5 years free of disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated.
6. Severe COPD or other severe pulmonary diseases.
7. Significant cardiovascular disease
8. Significant systemic diseases grade 3 or higher -CTCAE v4.03 scale.
9. Uncontrolled infections.
10. Known positive test for infection by human immunodeficiency virus (HIV).
11. Women who are pregnant or breast-feeding.
Cohort B
1. Unresectable tumors (with limb sparing surgery)
2. More than 1 previous chemotherapy treatment for local disease including trabectedin.
3. RT involving the tumoral bed.
4. Performance status = 2
5. Presence of metastases or lymph node involvement by the tumor.
6. Location other than limb or superficial trunk wall.
7. Plasma bilirubin > UNL.
8. Creatinine > 1.6 mg/dL.
9. History of other neoplastic disease with less than 5 years free of disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated.
10. Significant cardiovascular disease
11. 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.
12. Uncontrolled bacterial, mycotic or viral infections.
13. Known positive test for infection by human immunodeficiency virus (HIV).
14. Women who are pregnant or breast-feeding.
Cohort C
1. Unresectable tumours.
2. Location other than the retroperitoneum.
3. Patients who have previously received systemic treatment (chemotherapy or trabectedin).
4. Patients who underwent prior local treatment for retroperitoneal sarcoma: surgery or radiotherapy in the tumour bed.
5. ECOG performance status =2.
6. Presence of metastasis or lymph node involvement of the tumour.
7. Previous history of another neoplastic disease with less than 5 years free of disease, except for basal cell carcinoma or properly treated in situ cervical cancer.
8. Significant cardiovascular disease
9. A significant grade 3 or greater systemic disease on the NCI-CTCAE v4.03 scale,
10. Uncontrolled viral, mycotic or bacterial infections.
11. Known HIV-positive patients.
12. Pregnant or breast-feeding women. |
Coorte A
1. Precedente trattamento con trabectedina o precedente trattamento con RT
2. Performance status = 2
3. Bilirubina plasmatica > LSM
4. Creatinina > 1,6 mg/dL
5. Storia di altra malattia neoplastica con meno di 5 anni di libertà da malattia, con l'eccezione del carcinoma basocellulare o carcinoma della cervicale in situ adeguatamente trattato
6. BPCO grave o altre gravi malattie polmonari
7. Malattie cardiovascolari significative
8. Malattie sistemiche significative di grado 3 o superiore secondo V4.03 CTCAE,
9. Infezioni non controllate
10. Test positivo (già noto) per infezione da HIV
11. Donne in gravidanza o in allattamento
Coorte B:
1. Più di una precedente linea di chemioterapia per la malattia localizzata compresa trabectedina
2. RT che coinvolge il letto tumorale
3. Performance status = 2 (ECOG).
4. Presenza di metastasi o coinvolgimento linfonodale
5. Localizzazione in sedi diverse dagli arti o dal tronco (superficiale)
6. Bilirubina plasmatica > LSN.
7. Creatinina > 1.6 mg/dL.
8. Storia di altra malattia neoplastica con meno di 5 anni di libertà da malattia, con l'eccezione del carcinoma basocellulare o carcinoma della cervicale in situ adeguatamente trattato
9. Malattie cardiovascolari significative
10. Malattie sistemiche significative di grado 3 o superiore secondo V4.03 CTCAE,
11. Infezioni non controllate
12. Test positivo (già noto) per infezione da HIV
13. Donne in gravidanza o in allattamento
Coorte C
1. Malattia non resecabile.
2. Localizzazione non retroperitoneale
3. Pazienti che hanno ricevuto un trattamento sistemico per la malattia
4. Pazienti che hanno effettuato precedente trattamento per il sarcoma retroperitoneale localizzato
5. ECOG performance status =2.
6. Presenza di metastasi o di coinvolgimento linfonodale del tumore
7. Storia di altra malattia neoplastica con meno di 5 anni di libertà da malattia, con l'eccezione del carcinoma basocellulare o carcinoma della cervicale in situ adeguatamente trattato.
8. Malattie cardiovascolari significative
9. Malattie sistemiche significative di grado 3 o superiore secondo V4.03 CTCAE,
10. Infezioni non controllate
11. Test positivo (già noto) per infezione da HIV
12. Donne in gravidanza o in allattamento |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| All cohorts: response according RECIST 1.1 |
Tutte le coorti :
Risposta secondo i criteri RECIST al trattamento con trabectedina in combinazione con radioterapia |
|
| 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, 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 |
Coorte A: basale e ogni 6 settimane fino a progressione
Coorte B: basale, e al follow.up
Coort C: basale, e al follow.up |
|
| 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 |
oRisposta RECIST della combinazione trabectedina più radioterapia.
oPer la coorte A: risposta di efficacia, misurata da sopravvivenza libera da progressione (PFS), da sopravvivenza globale (OS) e biomarcatori potenzialmente predittivi/prognostici.
oPer la coorte B: Efficacia misurata dalla sopravvivenza libera da recidiva (RFS)
oPer la coorte B: Attività misurata da imaging funzionale, risposta patologica e biomarcatori potenzialmente predittivi/prognostici.
o Risposta secondo criteri Choi per entrambe le coorti
oQualità della vita valutata in entrambe le coorti con il questionario QLQ-C-30-EORTC
oPer la coorte C: Risposta di efficacia, misurata da sopravvivenza libera da progressione (PFS) a 3 anni e a 5, da sopravvivenza globale (OS) e biomarcatori potenzialmente predittivi/prognostici. |
|
| 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 |
AE sarrano valutati all'inzio di ogni ciclo e durante tutto il trattamento
Coorte A: rivaluatione radiologica ogni 6 settimane fino a PD
Coorte B: basale, e follow-up
Coorte C: basale, e follow-up |
|
| 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 | 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) | 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 |
| To describe safety profile for each cohort and dose level of trabectedin in order to find the recomm |
| Definire il profilo di sicurezza per ogni coorte e livello di dose di trabectedina al fine di trovar |
|
| 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 | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 5 |
| 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 | 5 |
| 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 |
Print
