| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Translocation-related Sarcomas |
| sarcoma associato a traslocazione cromosomica (SAT). |
|
| 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 | 14.1 |
| 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of trabectedin vs. standard doxorubicin-based chemotherapy (DXCT) as first-line treatment of patients with advanced TRS, by comparing progression-free survival (PFS) in each treatment arm. |
| Valutare l`efficacia della Trabectedina vs chemioterapia standard basata su Doxorubicina (DXCT) come trattamento di prima linea di pazienti affetti da SAT in fase avanzata, mediante confronto della sopravvivenza libera da progressione (SLP) in ciascun braccio del trattamento. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare 6-month PFS rates. To compare response rates and duration of response, by the Response Evaluation Criteria In Solid Tumors (RECIST). To compare the exploratory computed tomography (CT) evaluations conducted using the Choi response criteria. To compare PFS and response rates in the subgroups of patients stratified by histological type (myxoid - round cell liposarcoma vs. other TRS subtypes). To compare overall survival (OS). To compare the safety profile in each treatment arm. To conduct exploratory, pharmacogenomic (PGx) studies to correlate fusion-protein type and variants, and deoxyribonucleic acid (DNA)repair markers with clinical outcomes. |
| Confrontare le percentuali di SLP a 6 mesi.Confrontare le percentuali di risposta e la durata della risposta mediante i criteri RECIST (Response Evaluation Criteria In Solid Tumors).Confrontare le valutazioni della tomografia computerizzata esplorativa (CE) effettuate usando i criteri di risposta Choi.Confrontare le percentuali di SLP e di risposta nei sottogruppi di pazienti stratificati per tipo istologico (liposarcoma mixoide a cellule rotonde vs altri sottotipi di SAT).Confrontare la sopravvivenza globale (SG).Confrontare il profilo di sicurezza in ciascun braccio del trattamento.Condurre studi esplorativi,farmacogenomici (PGx) per correlare il tipo di proteina di fusione e le varianti,e i geniriparatori dell`acido deossiribonucleico (DNA) con i risultati clinici. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1) Patient`s written informed consent before any study-specific procedures. 2) Adult patients (age > 18 years). 3) Patients with pathological diagnosis of TRS (institutional assessment), of any, but restricted to the following subtypes: alveolar soft part sarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma (prior hormone therapy allowed), low grade fibromyxoid sarcoma, myxoid chondrosarcoma, myxoid - round cell liposarcomas (MRCL) and synovial sarcoma. Availability of adequate tumor material for external review is mandatory. 4)Patients must have unresectable locally advanced or metastatic progressive disease prior to enrolment. 5)Measurable disease as defined by the radiological (CT-scan and MRI) Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines. 6)ECOG PS score of 0-2. 7)Adequate cardiac function, defined as LVEF within normal limits according to institutional standards, as shown by echocardiography or scintigraphy [multiple-gated acquisition scan (MUGA)]. 8)Hematological variables: a)Hemoglobin `‰¥ 9 g/dl. b)Absolute neutrophil count (ANC) `‰¥ 1,500/µl. c)Platelet count `‰¥ 100,000/µl. 9)Biochemical variables: a)Serum creatinine `‰¤ 1.5 mg/dl b)Creatine phosphokinase (CPK) `‰¤ 2.5 x upper limit of normal range of values (ULN). 10)Hepatic function variables: a)Total bilirubin `‰¤ ULN, unless in case of Gilbert`s syndrome b)Total alkaline phosphatase (AP) `‰¤ 2.5 x ULN, or if > 2.5 x ULN consider AP liver fraction, and/or gamma-glutamyltransferase (GGT), and/or 5` nucleotidase must be `‰¤ ULN. c)Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) must be `‰¤ 2.5 x ULN. d)Albumin `‰¥ 25 g/l. |
| 1) Consenso informato scritto del paziente prima di qualsiasi procedura specifica dello studio. 2) Pazienti adulti (di eta` > 18 anni). 3)Pazienti con diagnosi istologica di SAT (valutazione istituzionale), di qualsiasi ma limitate ai seguenti sottotipi: sarcoma dei tessuti molli alveolare, istiocitoma fibroso angiomatoide, sarcoma a cellule chiare, tumore desmoplastico a cellule rotonde, sarcoma di stroma endometriale di basso grado (consentita precedente terapia ormonale), sarcoma fibromixoide di basso grado, condrosarcoma mixoide, liposarcoma mixoide a cellule rotonde (LMCR) e sarcoma sinoviale. E` obbligatoria la disponibilita` di materiale tumorale adeguato per esame esterno. 4)I pazienti devono essere affetti da malattia progressiva avanzata a livello locale non resecabile o metastatico. 5)Malattia valutabile con tecniche radiologiche (CT Scan e MRI) in accordo con le definizioni delle Linee Guida RECIST 6)Punteggio ECOG PS di 0-2. 7)Funzione cardiaca adeguata, definita come FEVS entro limiti normali secondo gli standard istituzionali, cosi` come mostrato da ecocardiografia o scintigrafia (scansione MUGA). 8)Variabili ematologiche: a)Emoglobina `‰¥ 9 g/dl. b)Conteggio neutrofili in numero assoluto (ANC) `‰¥ 1.500/µl. c)Conteggio piastrine `‰¥ 100.000/µl. 9)Variabili biochimiche: a)Creatinina nel siero `‰¤ 1,5 mg/dl b)Creatina fosfochinasi (CPK) `‰¤ 2,5 x limite superiore del valore normale (ULN). 10)Variabili della funzione epatica: a)Bilirubina totale `‰¤ ULN tranne nel caso di sindrome di Gilbert. b)Fosfatasi alcalina totale (AP) `‰¤ 2,5 x ULN, o se > 2,5 x ULN prendere in considerazione la frazione epatica AP, e/o gamma-glutamiltransferasi (GGT), e/o la 5` nucleotidasi deve essere `‰¤ ULN. c)Aspartate aminotransferasi (AST/SGOT) e alaninoaminotransferasi (ALT/SGPT) devono essere `‰¤ 2,5 x ULN. d)Albumina `‰¥ 25 g/l. |
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| E.4 | Principal exclusion criteria |
| 1) Known hypersensitivity to any components of the intravenous (i.v.) formulation of trabectedin or the comparators. 2) Prior chemotherapy treatment. 3) Prior irradiation of the lesion, if only one target lesion (i.e., measurable) is available. 4) Pregnant or lactating women or men and women of reproductive potential who are not using effective contraceptive methods (one or more of the following): a) Complete abstinence from intercourse from two weeks prior to administration of the study treatment, throughout the study, and for at least six months after completion or premature discontinuation from the study to account for elimination of the investigational drug(s); or, b) Physical sterilization of the patient or the patient`s partner; or, c) One of the following, for female patients or female partners of male patients: Implants of levonorgestrel; or, Injectable progestogen; or, Oral contraceptive (combined or progestogen only; patients taking oral contraceptives should have been on a stable regimen for at least two months prior to screening), or, Any intrauterine device (IUD) with published data showing that the lowest expected failure rate is less than 1% per year (not all IUDs meet this criterion); or, Double barrier method (two physical barriers or one physical barrier plus spermicide); or, Any other methods with published data showing that the lowest expected failure rate for that method is less than 1% per year. 5) History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for five years or more. 6) Brain metastases and/or leptomeningeal metastases, even if treated. 7) Other serious illnesses, such as: a) Congestive heart failure or angina pectoris; myocardial infarction within one year before enrolment; uncontrolled arterial hypertension [according to World Health Organization(WHO) criteria), arrhythmias or abnormal LVEF. 8) Psychiatric disorder or any other personal circumstances that prevent compliance with the study protocol. 9) Active viral hepatitis or chronic liver disease. 10) Active infection. 11) Any other unstable medical condition. 12) Inability or unwillingness to comply with the study protocol. 13) Prior treatment with any investigational drugs/treatments within 30 days before inclusion into the current study. |
| 1) Ipersensibilita` nota a qualcuno dei componenti della formulazione intravenosa (i.v.) dei Trabectedina o dei comparatori. 2) Trattamento chemioterapico precedente. 3) Irradiazione precedente della lesione, in caso sia disponibile solo la lesione target (cioe`, misurabile). 4) Donne incinte o in fase di allattamento o uomini e donne potenzialmente fertili che non usano metodi contraccettivi efficaci (uno o piu` dei seguenti): a) Astinenza totale da rapporti sessuali a partire da due settimane precedenti la somministrazione del trattamento dello studio, per la durata dello studio e per almeno sei mesi dopo il termine o l`interruzione precoce dello studio in modo da garantire l`eliminazione del/i farmaci dello studio; oppure, b) Sterilizzazione fisica del paziente o del partner del paziente; oppure, c) Uno dei seguenti metodi, per le pazienti di sesso femminile o partner femminili di pazienti di sesso maschile: Applicazioni di levonorgestrelo; oppure, Progestogene iniettabile; oppure, Contraccettivo orale (combinato o solo progestogene; le pazienti che assumono contraccettivi orali devono essere state a regime stabile per almeno due mesi prima dello screening); oppure, Qualsiasi dispositivo intrauterino (IUD) con dati pubblicati che dimostrano che il tasso di fallimento inferiore previsto e` meno dell`1% all`anno (non tutti gli IUD rispettano questo criterio); oppure, Metodo a barriera doppia (due barriere fisiche o una barriera fisica piu` spermicida); oppure, Qualsiasi altro metodo con dati pubblicati che dimostrano che il tasso di fallimento inferiore previsto per tale metodo e` meno dell`1% all`anno. 5) Anamnesi di un`altra malattia neoplastica (tranne il carcinoma cellulare basale o il carcinoma cervicale in situ adeguatamente trattato) a meno che non sia in remissione per cinque anni o piu`. 6) Metastasi cerebrali e/o metastasi leptomeningee, anche se trattate. 7) Altre patologie gravi, tipo: a) Insufficienza cardiaca congestizia o angina pectoris; infarto miocardico entro un anno prima dell`arruolamento; ipertensione arteriosa incontrollata [secondo i criteri del World Health Organization (WHO)), aritmia o FEVS anomala. 8) Disturbi psichiatrici o qualsiasi altra circostanza personale che impedisca il rispetto del protocollo dello studio. 9) Epatite virale attiva o malattia epatica cronica. 10) Infezione attiva. 11) Qualsiasi altra condizione medica instabile. 12) Incapacita` o mancata volonta` di rispettare il protocollo dello studio. 13) Precedente trattamento con qualsiasi farmaco/trattamento dello studio entro i 30 giorni precedenti l`inclusione dello studio attuale. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS: will be calculated as the time from the date of randomization to the date of documented PD or death (regardless of the cause of death). If the patient receives further antitumor therapy before PD and within the timeframe expected for first follow-up, PFS will be censored on the date of administration of this antitumor therapy. If the patient is lost to follow-up for the assessment of progression, or has more than one missing follow-up between the date of last tumor assessment and the date of death or further antitumor therapy, the PFS will be censored at the date of last tumor assessment. |
| PFS: will be calculated as the time from the date of randomization to the date of documented PD or death (regardless of the cause of death). If the patient receives further antitumor therapy before PD and within the timeframe expected for first follow-up, PFS will be censored on the date of administration of this antitumor therapy. If the patient is lost to follow-up for the assessment of progression, or has more than one missing follow-up between the date of last tumor assessment and the date of death or further antitumor therapy, the PFS will be censored at the date of last tumor assessment. |
|
| 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 | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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