| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| adult women with platinum partially sensitive recurring ovarian cancer. |
| pazienti con carcinoma ovarico in stadio avanzato che hanno una recidiva a 6-12 mesi dall'ultima terapia a base di platino |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced ovarian cancer |
| carcinoma ovarico in stadio avanzato |
|
| 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 | LLT |
| E.1.2 | Classification code | 10033271 |
| E.1.2 | Term | Ovarian neoplasia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| This study is aimed at assessing the efficacy and the safety of the combination of bevacizumab and trabectedin with or without carboplatin in adult women with epithelial ovarian cancer at first recurrence occurred 6-12 months after the end of the first platinum-containing regimen. According to the Bryant and Day design the primary endpoints will be the proportion of progression-free patients at 6 months (PFS-6) for the efficacy, and the proportion of patients with severe toxicity for the safety at the same time-point. Disease progression will be determined using the RECIST criteria, version 1.1. |
| valutare in termini di efficacia e sicurezza la combinazione di bevacizumab e trabectedina con o senza carboplatino in pazienti con carcinoma epiteliale dell’ovaio in progressione a 6-12 mesi dal termine della precedente chemioterapia a base di platino. L’endpoint primario per l’efficacia è la percentuale di pazienti libere da progressione a 6 mesi dall’ arruolamento (PFS-6) e per la sicurezza la proporzione di pazienti con gravi tossicità sempre a 6 mesi dall’arruolamento come specificato nel protocollo. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate: PFS, defined for each patient as the time from the date of randomization to the date of first progression, second primary malignancy or death for any cause, whichever comes first. Subjects not progressed or died at the time of the analysis will be censored at the last disease assessment date. 12 month overall survival (OS-12), defined as the percentage of patients who are alive at 12 months after the randomization. Clinical benefit, defined as the percentage of patients who are judged by the Investigators to have a complete response, or partial response or stable disease according to the RECIST criteria, version 1.1 after 4 cycles of treatment the treatment compliance. the safety profile, evaluated by the NCI-CTCAE scale, version 4.0 and by the occurrence of serious adverse reactions. |
| valutare: la sopravvivenza libera da progressione, la sopravvienza globale a 12 mesi dall'inclusione, beneficio clinici valutati dallo sperimentatore in base a risposta completa parziale o malattia stabile in accordo ai criteri RECIST, compliance al trattamento |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Age≥18years ECOG-performance status 0-2 Cytological/histological diagnosis of epithelial ovarian cancer Progression free interval between 6-12 months (calculated from the first day of the last cycle of the previous last platinum-based chemotherapy until the date of progression confirmation through radiologic imaging). Only one previous platinum-based chemotherapy line Measurable disease according to RECIST version 1.1 Life expectancy ≥ 12 weeks Patients must be able to receive dexamethasone or its equivalent, as a premedication for trabectedin Written informed consents given before the enrolment according to ICH/GCP. |
| Criteri di inclusione: •Donne con età uguale o maggiore di 18 anni •ECOG- Performance Status 0-2 •Pazienti con diagnosi istologica/citologica di carcinoma ovarico epiteliale •Pazienti con intervallo libero da malattia tra i 6 e i 12 mesi calcolato dalla data dell’ultimo ciclo dell’ultima terapia a base di platino fino alla data di progressione radiologicamente confermata. •Pazienti che hanno ricevuto solo una precedente terapia a base di platino •Aspettativa di vita ≥ di 12 settimane •Malattia misurabile in base ai criteri RECIST versione 1.1 •Pazienti che possono ricevere il desametasone o un farmaco equivalente come pre-medicazione prima della trabectedina •Consenso Informato scritto rilasciato dalla paziente prima della randomizzazione |
|
| E.4 | Principal exclusion criteria |
| Prior treatment with trabectedin Prior progression while on therapy containing bevacizumab or other VEGF pathway–target therapy Pre-existing grade > 1 sensitive/motor neurologic disorder Current or recent (within 30 days of first study dosing) treatment with another investigational drug Surgery (including open biopsy) within 4 weeks prior to the first planned dose of bevacizumab Current or recent (within 10 days prior to the first study drug dose) use of full-dose oral or parenteral anticoagulant or thrombolytic agent for therapeutic purposes (except for line patency, in which case international normalized ratio [INR] must be maintained below 1.5). Post operative prophylaxis with low molecular weight heparin sc is allowed Inadequate bone marrow function: absolute neutrophil count (ANC): <1.5 x 109/l, or platelet count <100 x 109/l or haemoglobin <9 g/dl. Patients may be transfused to maintain haemoglobin values ≥9 g/dl Inadequate coagulation parameters: activated partial thromboplastin time (APTT) >1.5 x upper limit of normal (ULN) or INR >1.5 Inadequate liver function, defined as: serum (total) bilirubin > ULN for the institution AST/SGOT or ALT/SGPT >2.5 x ULN Inadequate renal function: serum creatinine >1.5 mg/dL or >132 mol/L and urine dipstick for proteinuria 2+ and >1g of protein in their 24-hour urine collection History or evidence of brain metastases or spinal cord compression Pregnant, breastfeeding women and women of child bearing potential, who do not agree to use a medically acceptable method of contraception through the treatment period and for 6 months after discontinuation of treatment History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident, stroke or transient ischemic attack or sub-arachnoid haemorrhage within 6 months prior to the first study treatment Uncontrolled hypertension (sustained systolic >150 mmHg and/or diastolic >100 mmHg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including: myocardial infarction or unstable angina within 6 months prior to the first study treatment, New York Heart Association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication History of bowel obstruction, including subocclusive disease, related to the underlying disease and history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess. Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction Non-healing wound, ulcer or bone fracture HCV positivity Other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer |
| Criteri di esclusione: •Pazienti precedentemente esposte a trabectedina •Pazienti che hanno dimostrato progressione durante una terapia con bevacizumab o altre terapie target (VEGF pahtway – target therapy) •Pre-esistente patologia neurologica sensitivo/motoria NCI-CTCAE grado > 1 •Recente (30 giorni antecedenti la prima somministrazione) o concomitante trattamento con altri farmaci sperimentali •Chirurgia (biopsia inclusa) nelle 4 settimane antecedenti alla prima somministrazione di bevacizumab •Recente (nei 10 giorni antecedenti la prima somministrazione dei farmaci sperimentali) o concomitante utilizzo di anticoagulanti orali o parenterali o agenti trombolitici a scopo terapeutico (fanno eccezione le procedure per mantenere la pervietà degli accessi venosi in questi casi l’indice di normalizzazione deve essere sotto l’1.5); è ammessa la somministrazione di eparina a basso peso molecolare come profilassi post-operatoria •Inadeguata funzionalità del midollo osseo definita con i seguenti valori: i. Neutrofili < 1.5 x 109/l ii. Piastrine <100 x 109/l iii. Emoglobina <9 g/dl E’ ammessa la possibilità di trasfusione per mantenere il valore dell’Emoglobina >9 g/dl •Parametri non adeguati relativi alla coagulazione: APTT > 1.5 x ULN o INR > 1.5 •Funzionalità epatica inadeguata definita come: bilirubina sierica (totale)>ULN, AST/SGOT e ALT/SGPT >2,5 x ULN •Funzionalità renale inadeguata definita come creatinina sierica > 1.5 mg/dL o 132 µmol/L. Proteinuria confermato da stick diagnostico per le urine con un valore ≥ 2 e > 1g di proteine nelle 24 ore di raccolta •Diagnosi precedente o attuale di metastasi cerebrali o compressione del midollo spinale •Pazienti in gravidanza, pazienti in allattamento o in età fertile che non accettino di utilizzare metodi contraccettivi durante il trattamento e nei 6 mesi successivi dal termine dello stesso •Precedente o attuale evidenza di malattie trombotiche o emorragiche, inclusi ictus, attacco ischemico transitorio, angina instabile, emorragia sub aracnoidea nei 6 mesi che precedono la prima somministrazione dei farmaci sperimentali. •Ipertensione arteriosa non controllata (pressione arteriosa sistolica attuale > 150 mm Hg e/o pressione arteriosa diastolica > 100 mm Hg nonostante terapia anti-ipertensiva) o malattie cardiovascolari clinicamente rilevanti, includendo: infarto del miocardio o angina instabile a meno dei 6 mesi precedenti la prima somministrazione del farmaco sperimentale, di grado > II della New York Medical Association, insufficienza cardiaca congestizia, o grave aritmia cardiaca che richieda un trattamento •Anamnesi positiva per occlusione intestinale, inclusa sindrome sub-occlusiva, correlata a una patologia sottostante, fistula addominale, perforazione gastrointestinale o ascesso intra-addominale. Evidenza di coinvolgimento retto-sigma all’esame pelvico o coinvolgimento intestinale alla TAC o sintomi clinici di occlusione intestinale •Ferite non guarite, ulcere o frattura ossea •Positività per HCV •Altre patologie maligne negli ultimi 5 anni ad esclusione del carcinoma in situ della cervice o carcinoma squamoso basocellulare della pelle adeguatamente trattati. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| the proportion of progression-free patients at 6 months (PFS-6) for the efficacy, and the proportion of patients with severe toxicity for the safety at the same time-point. Disease progression will be determined using the RECIST criteria, version 1.1. The following conditions will be considered as severe toxicity: 1. absolute neutrophil count (ANC) < 0.5x109/L lasting > 7 days and/or with fever 2. platelets < 25x109/L 3. any other grade 3-4 (evaluated by the NCI-CTCAE scale, version 4.0) non-hematological toxicities except for reversible nausea/vomiting, diarrhea, hypersensitivity reactions, and ALT or AST elevation reversible to grade 1 by day 28 4. any toxicity causing a delay of >14 days in the following cycle |
| percentuale di pazienti con sopravvivenza libera da progressione a 6 mesi e sicurezza come percentuale di pazienti con tossicità gravi definite come segue: 1. absolute neutrophil count (ANC) < 0.5x109/L lasting > 7 days and/or with fever 2. platelets < 25x109/L 3. any other grade 3-4 (evaluated by the NCI-CTCAE scale, version 4.0) non-hematological toxicities except for reversible nausea/vomiting, diarrhea, hypersensitivity reactions, and ALT or AST elevation reversible to grade 1 by day 28 4. any toxicity causing a delay of >14 days in the following cycle |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS-6 and safety will be evalueted at 6 months from randomization |
| per l'efficacia:6 mesi per la sopravvivenza libera da progressione e per la sicurezza: 6 mesi per le tossicità gravi |
|
| E.5.2 | Secondary end point(s) |
| Efficacy endpoints: The PFS, defined for each patient as the time from the date of randomization to the date of first progression, second primary malignancy or death for any cause, whichever comes first. Subjects not progressed or died at the time of the analysis will be censored at the last disease assessment date. Disease progression will be determined using the RECIST criteria, version 1.1. The 12 month overall survival (OS-12), defined as the percentage of patients who are alive at 12 months after the randomization. the clinical benefit (CB), defined as the percentage of patients who are judged by the Investigators to have a complete response (CR), or partial response (PR) or stable disease (SD) according to the RECIST criteria, version 1.1 after 12 weeks from the date of randomization. Compliance endpoints Percentage of patients with dose and/or time modifications Percentage of premature withdrawals. Safety endpoints Incidence, nature, severity and seriousness of AEs, according to NCI-CTCAE, version 4.0 Maximum toxicity grade experienced by each patient for each specific toxicity Percentage of patients experiencing grade 3-4 toxicity for each specific toxicity Patients with at least a SAE Patients with at least a serious adverse drug reaction (SADR) Patients with at least a suspect unexpected serious adverse reaction (SUSAR). |
| sopravvivenza libera da progressione, percentuale di pazienti vivi a 12 mesi dalla randomizzazione, percentuale di pazienti che si sono ritirati dallo studio, percentuale di pazienti che hanno avuto una modifica di dosi e/o tempi, beneficio clinico, pazienti che hanno avuto almeno un SAE,incidenza natura e gravità di un AE,pazienti che hanno avuto almeno un SAE, pazienti che hanno avuto alemeno un SADR, pazienti che hanno avuto almeno un SUSAR,percentuale di pazienti ai quai compare una tossicità di grado 3-4, massimo grado di tossicità avuta da ciascun paziente per ciascuna tossicità |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | 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) | 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | 0 |
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