| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| endometrial cancer |
| Carcinoma endometrio |
|
| E.1.1.1 | Medical condition in easily understood language |
| endometrial cancer |
| Carcinoma endometrio |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| 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 | 10014770 |
| E.1.2 | Term | Endometrioid adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
| • To compare progression-free survival (PFS) of patients with advanced or recurrent chemonaive endometrial cancer when treated with Carboplatin-Paclitaxel vs Carboplatin-Paclitaxel-Bevacizumab. |
| • Valutazione della progression-free survival (PFS) in pazienti con neoplasia endometriale avanzata o metastatica che ricevono Carboplatino-Paclitaxel vs Carboplatino-Paclitaxel-Bevacizumab. |
|
| E.2.2 | Secondary objectives of the trial |
| • To compare the overall survival (OS) of patients receiving Carboplatin-Paclitaxel vs Carboplatin-Paclitaxel Bevacizumab • To compare the best response rate of patients receiving Carboplatin-Paclitaxel vs Carboplatin-Paclitaxel-Bevacizumab • To assess the safety and tolerability of Carboplatin-Paclitaxel-Bevacizumab in this population • To assess changes in Quality of Life parameters in patients treated with Carboplatin-Paclitaxel compared to those treated with Carboplatin-Paclitaxel-Bevacizumab |
| • Valutare l’Overall Survival (OS) in pazienti che ricevono Carboplatino-Paclitaxel vs Carboplatino-Paclitaxel-Bevacizumab • Valutare il tasso di risposta delle pazienti che ricevono Carboplatino-Paclitaxel vs Carboplatino-Paclitaxel-Bevacizumab • Verificare in questa popolazione la sicurezza e la tollerabilità dell’associazione Carboplatino-Paclitaxel-Bevacizumab • Evidenziare variazioni nei parametri di qualità della vita nelle pazienti trattate con Carboplatin-Paclitaxel versus Carboplatin-Paclitaxel-Bevacizumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥18 years of age. 2. ECOG Performance Status of 0–2. 3. Life expectancy of at least 12 weeks. 4. Patients must have advanced stage III or IV, or recurrent histologically-confirmed endometrial cancer. 5. Endometrial cancer will include all carcinomas, including endometrioid carcinoma, papillary serous carcinoma, clear cell carcinoma. 6. No previous chemotherapy lines (previous radiotherapy is allowed). 7 Measurable and not measurable disease. 8 Adequate renal and hepatic function, defined as: • Total serum bilirubin ≤ institutional ULN unless patient has Gilbert’s syndrome in which case direct bilirubin must be < ULN for the institution. • AST and/or ALT ≤ 2.5 x ULN for the institution. (or ≤ 5 x ULN if liver metastases are present) • Alkaline phosphatase < 1.5 x ULN for the institution (if > 1.5 x ULN, then alkaline phosphatase liver fraction must be < 1.5 ULN). • Serum creatinine ≤ 1.5 x ULN for the institution (or calculated creatinine clearance ≥ 50 mL/min/1.73 m2) 9 Adequate bone marrow function, defined as: • Total leukocytes ³ 3.0 x 109/L. • ANC ³ 1.5 x 109/L. • Platelet count ³ 100 x 109/L. Able to understand and give written informed consent. 10 Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.
one previous chemoterapy lines is allowed if platinum free interval is more than six mounths (previous radiotherapy is allowed) |
1. Età ≥18 anni. 2. ECOG Performance Status fra 0–2. 3. Aspettativa di vita di almeno 12 settimane 4. Pazienti con malattia avanzata stadio III o IVa, o malattia metastatica (stadio IVb), o recidiva di malattia con conferma istologica di neoplasia endometriale mai chemiotrattate. 1. Possono essere inclusi tutti i carcinomi, compresi carcinoma endometrioide, sieroso papillare o a cellule chiare. 6. Malattia misurabile e non misurabile 7 Adeguata funzione renale ed epatica: • Bilirubina totale ≤ ULN istituzionale salvo che la paziente non sia affetta da sindrome di Gilbert in questo caso la bilirubina diretta deve essere < ULN istituzionale. • AST e/o ALT ≤ 2.5 x ULN istituzionale. (o ≤ 5 x ULN se sono presenti metastasi epatiche) • Fosfatasi alcalina < 1.5 x ULN istituzionale (se > 1.5 x ULN, in tal caso la frazione epatica deve essere < 1.5 ULN). • Creatinina sierica ≤ 1.5 x ULN istituzionale (o creatinina clearance calcolata ≥ 50 mL/min/1.73 m2) 8 Adeguata funzione midollare, definite come: • Leucociti totali ³ 3.0 x 109/L. • ANC ³ 1.5 x 109/L. • Conta piastrinica ³ 100 x 109/L. 9 Firma del consenso informato 10 Le donne in età fertile devono avere un test sierico di gravidanza negativo entro 7 giorni prima dell’arruolamento.
pazienti che hanno fatto precedente linea di chemioterapia, purchè l'intervallo libero da platino sia di almeno 6 mesi ( è consentita precedente radioterapia) |
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| E.4 | Principal exclusion criteria |
| 1. Previous cytotoxic chemotherapy. 2. Women who are pregnant or lactating. 3. Presence of brain or other central nervous system metastases. 4. Anticancer treatment (Hormonal therapy, radiotherapy) within 4 weeks prior to randomization. 5. Ongoing toxicity associated with prior anticancer therapy. 6. Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 4 weeks prior to randomization. Patients who have recovered from placement of a central venous access port within 2 weeks of Cycle 1 Day 1 will be considered eligible. 7. Another primary malignancy within the past five years (except for non-melanoma skin cancer and cervical carcinoma in situ). 8. Current or recent (within 10 days prior to the first study drug dose) chronic daily treatment with aspirin (>325 mg/day). 9. 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. 10. Inadequate coagulation parameters:activated partial thromboplastin time (APTT) >1.5 xULN or INR >1.5. 11. Known HIV infection. 12. Known hepatitis B or C infection. 13. Concurrent treatment with immunosuppressive or investigational agents. 14. History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or subarachnoid haemorrhage within _6 months prior to the first study treatment). 15. Uncontrolled hypertension (sustained systolic >150 mm Hg and/or diastolic >100 mm Hg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including. 16. Myocardial infarction or unstable angina within _6 months prior to the first study treatment. 17. New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF). 18. Serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia). 19. Peripheral vascular disease _grade 3 (i.e.symptomatic and interfering with activities of daily living requiring repair or revision). 20. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to the first study treatment. 21. Non-healing wound, ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require three weekly wound examinations. 22. Serious active infection requiring i.v. antibiotics at enrolment. 23. Significant traumatic injury during the 4 weeks preceding the first dose of bevacizumab. 24. Known hypersensitivity to any of the study drugs or excipients (including cremophor and hamster Ovary cell products). 25. Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer, etc.), physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment related complications. |
| 1. Le donne in gravidanza o allattamento. 2. Presenza di metastasi cerebrali. 3. Recupero inadeguate da qualsiasi precedente procedura chirurgica o procedure di chirurgia maggiore entro 4 settimane della randomizzazione. Devono intercorrere almeno due settimane dal posizionamento di un catetere venoso centrale e il primo ciclo di chemioterapia per considerare le pazienti eleggibili. 4. Diagnosi di una seconda neoplasia negli ultimi cinque anni (ad eccezione di tumore cutaneo non-melanoma e carcinoma cervicale in situ). 5. Contemporaneo o recente (entro i 10 giorni precedenti la prima dose del farmaco in studio) trattamento giornaliero con l'aspirina (> 325 mg/die). 6. Contemporaneo o recente (entro i 10 giorni precedenti la prima dose del farmaco in studio) uso di anticoagulanti orali o parenterali o agenti trombolitici per scopi terapeutici (ad eccezione dell’uso profilattico, nel qual caso International Normalized Ratio [INR] deve essere mantenuto al di sotto 1,5. 7. Parametri di coagulazione inadeguata: tempo di tromboplastina parziale attivata (APTT) > 1,5 x ULN o INR> 1,5 8. HIV. 9. Epatite B o C. 10. Trattamento concomitante con farmaci immunosoppressivi o in fase di sperimentazione. 11. Storia o evidenza di alterazioni trombotiche o emorragiche, compresi accidenti cerebrovascolari (CVA), Ictus o attacco ischemico transitorio (TIA) o di emorragia subaracnoidea entro 6 mesi prima del trattamento in studio prima). 12. Ipertensione non controllata (sistolica > 150 mmHg e/o diastolica > 100 mm Hg, nonostante la terapia antipertensiva) o malattie cardiovascolari, tra cui: 13. Infarto miocardico o angina instabile entro i 6 mesi precedenti il trattamento in studio; 14. Insufficienza cardiaca congestizia (CHF) New York Heart Association (NYHA) di grado II o maggiore. 15. Grave aritmia cardiaca che richiede l’uso di farmaci (ad eccezione della fibrillazione atriale o tachicardia parossistica sopraventricolare). 16. Malattia vascolare periferica di grado 3 (sintomatica e/o che interferisce con le attività della vita quotidiana). 17. Storia di fistola addominale, perforazione gastrointestinale o ascesso intra-addominale entro i 6 mesi precedenti al trattamento in studio. 18. Alterata cicatrizzazione delle ferite, ulcere o fratture ossee. I pazienti con tessuto di granulazione nella guarigione per seconda intenzione, senza evidenza di deiscenza o d’infezione sono ammissibili, ma richiedono controlli a giorni alterni della ferita. 19. Gravi infezioni attive che richiedono antibiotici con somministrazione endovena al momento dell'arruolamento. 20. Lesioni traumatiche di rilievo durante le 4 settimane precedenti la prima dose di bevacizumab. 21. Ipersensibilità nota ad uno qualsiasi degli eccipienti o dei farmaci in studio (compresi Cremophor e prodotti derivati da cellule ovariche di criceto). 22. Presenza di patologie concomitanti (la malattia psichiatrica, ulcera peptica, ecc), esame fisico o dati di laboratorio che possono interferire con il trattamento previsto, che influenzano la compliance del paziente, o possono mettere il paziente ad alto rischio di complicanze legate al trattamento in studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Progression-free survival, defined as the time from the date of randomization to the date of documented progressive disease, recurrence or death (whichever occurs first) |
| • Progression-free survival, definite come il tempo dalla data di randomizzazione alla data di progressione di malattia, alla recidiva o morte (quale avvenga per prima). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| • Overall survival defined as the time from the date of randomization to the date of death • Best target lesion response, defined as best change in sum of the target lesions from baseline to disease progression. • Duration of response • Safety and tolerability Changes Quality of Life parameters as measured using EORTC QLQ-30 & EORTC-QLQ-EN-24 |
| • Overall survival definito come il tempo dalla data di randomizzazione fino alla data di morte. • Best target lesion response, definito come la migliore variazione nella somma delle lesioni target dal baseline fino alla progressione di malattia • Durata della risposta • Sicurezza e tollerabilità • Variazioni nei parametri di qualità di vita attraverso il questionario EQ-5D. |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| 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 | 16 |
| 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 | 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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