| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients who have experienced progression of disease after first-line antineoplasic treatment of advanced endometrial carcinoma |
| Pazienti adulte con carcinoma dell’endometrio in progressione (o recidiva) durante o dopo terapia antineoplastica di prima linea per la malattia in stadio avanzato |
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| 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 | 10014745 |
| E.1.2 | Term | Endometrial carcinoma metastatic |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To demonstrate the efficacy of BEZ235 as measured by Overall Response Rate (ORR) per RECIST (Novartis guidelines based on RECIST Version 1.1) in patients with advanced endometrial carcinoma who exhibit PI3K pathway activation defined as the presence of a PIK3CA and/or PTEN mutation and/or PTEN negative by IHC (less than 10% staining). • To demonstrate the efficacy of BEZ235 as measured by Overall Response Rate (ORR) per RECIST in all patients enrolled in the study. |
| • Dimostrare l’efficacia di BEZ235 misurata mediante valutazione della percentuale di risposta obiettiva (ORR) in base ai criteri RECIST (linee-guida Novartis basate su RECIST Versione 1.1) in pazienti con carcinoma dell’endometrio in stadio avanzato con attivazione della via PI3K, definita dalla presenza di mutazione di PIK3CA e/o PTEN e/o PTEN negativo all’immunoistochimica (colorazione inferiore al 10%). • Dimostrare l’efficacia di BEZ235 misurata mediante valutazione della percentuale di risposta obiettiva (ORR) in base ai criteri RECIST in tutte le pazienti arruolate nello studio |
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| E.2.2 | Secondary objectives of the trial |
| • To determine the efficacy of BKM120 as measured by Objective Response • To determine Progression Free Survival (PFS) • To determine the efficacy of BEZ235 as measured by Overall Response Rate (ORR) per RECIST in patients with advanced endometrial carcinoma who exhibit a non-activated PI3K pathway • To determine the Disease Control Rate (DCR) • To determine Time to Response (TTR) • To determine Duration of Response • To assess Overall Survival (OS) • To evaluate the safety of BEZ235 |
| • Determinare la sopravvivenza libera da progressione (PFS). • Determinare l’efficacia di BEZ235 misurata mediante valutazione della percentuale di risposta obiettiva (ORR) in base ai criteri RECIST in pazienti con carcinoma dell’endometrio in stadio avanzato che non presentano attivazione della via PI3K. • Determinare il tasso di controllo della malattia (DCR). • Determinare il tempo alla risposta (TTR). • Determinare la durata della risposta. • Valutare la sopravvivenza globale (OS). • Valutare la sicurezza di BEZ235. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Patient written informed consent obtained prior to any screening procedures 2. Patient is a female ≥ 18 years at the day of consenting to the study 3. Patient has a histologically confirmed diagnosis of advanced endometrial carcinoma with available tissue specimen, either archival tissue (one block or a minimum of 20 unstained slides) or fresh formalin fixed tumor biopsy, for identification of PI3K pathway activation • all of the following histological types are eligible: endometrioid, papillary serous, clear cell, papillary endometrioid, mucinous, and adeno-squamous • confirmation that the specimen has been collected by the courier service and will be sent to the Novartis-designated lab (e.g., tracking number of courier service) must be communicated to the sponsor prior to enrolling the patient into the treatment phase of the trial 4. Patient has experienced objective progression of disease on or after first-line antineoplastic treatment for advanced or metastatic endometrial carcinoma as defined by the investigator. One prior line of anti-neoplastic treatment is defined as: • First-line treatment for advanced disease including at least one cytotoxic agent. • Any adjuvant treatment is generally not considered a prior line of treatment unless the recurrence occurred while on adjuvant chemotherapy or ≤ 6 months since the last administration of adjuvant chemotherapy (with the exception of endocrine treatments), • Any prior hormonal treatment is not considered a line of treatment in any setting. 5. Patient has recovered (to grade ≤ 1) from all clinically significant toxicities related to prior antineoplastic therapies with the exception of alopecia and bone marrow and organ functions (described separately) 6. Patient has at least one measurable lesion as per RECIST criteria. Lesions in previously irradiated areas should not be considered measurable, unless they have clearly progressed since the radiotherapy. 7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 which is not declining during the last 2 weeks before the signature of the main study Informed Consent Form (S-ICF). 8. Patient has adequate bone marrow and organ function as defined by the following laboratory values: • Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L • Platelets ≥ 100 x 109/L • Hemoglobin ≥ 9.0 g/dL • INR ≤ 2 • Serum Creatinine ≤ 1.5 x ULN • Serum Bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, total bilirubin ≤ 3 x ULN, with direct bilirubin ≤ 1.5 x ULN) • AST and ALT ≤ 3 x ULN or ≤ 5.0 x ULN if liver metastases are present • Fasting plasma glucose (FPG) ≤ 140 mg/dL (≤ 7.8 mmol/L) • HbA1c ≤ 8 % |
| 1. Consenso informato scritto ottenuto prima di qualsiasi procedura di screening. 2. La paziente e' una donna di eta' >= 18 anni al momento della firma del consenso. 3. La paziente e' affetta da carcinoma dell’endometrio in stadio avanzato con conferma istologica della diagnosi ed e' disponibile un campione di tessuto, o tessuto tumorale archiviato (un blocchetto o un minimo di 20 vetrini non colorati) oppure una biopsia fresca fissata in formalina, per l’identificazione dell’attivazione della via PI3K: • sono eleggibili tutti i seguenti tipi istologici: endometrioide, papillare sieroso, a cellule chiare, papillare endometrioide, mucinoso e adenosquamoso • la conferma che il campione sia stato raccolto dal corriere e sia stato inviato al laboratorio centralizzato (ad es: numero di riferimento della spedizione) deve essere comunicata allo sponsor prima di arruolare la paziente nella fase di trattamento dello studio 4. La paziente deve aver presentato progressione obiettiva della malattia dopo trattamento antineoplastico di prima linea per il carcinoma dell’endometrio in stadio avanzato o metastatico, come stabilito dallo sperimentatore. Il precedente trattamento antineoplastico di prima linea viene definito come segue: • trattamento di prima linea per la malattia in stadio avanzato che comprende almeno un agente citotossico • Qualsiasi trattamento adiuvante non e' generalmente considerato un trattamento di prima linea a meno che la recidiva non si sia manifestata durante terapia adiuvante o <= 6 mesi dall’ultima somministrazione di chemioterapia adiuvante (ad eccezione dei trattamenti endocrini). • Qualsiasi trattamento ormonale precedente non e' considerato una linea di trattamento in nessuna categoria 5. La paziente e' guarita (al Grado <= 1) da tutte le tossicita' clinicamente rilevanti correlate alla precedente terapie antineoplastica a eccezione di alopecia e della funzionalita' midollare e organica (descritte separatamente). 6. La paziente ha almeno una lesione misurabile in base ai criteri RECIST. Le lesioni in aree irradiate in precedenza non dovrebbero essere considerate come lesioni misurabili, a meno di una franca progressione dopo la radioterapia. 7. Eastern Cooperative Oncology Group (ECOG) performance status <= 2 che non e' diminuito nelle ultime 2 settimane precedenti la firma del modulo di consenso informato principale. 8. Presenza di adeguata funzionalita' midollare e organica definita dai seguenti valori degli esami di laboratorio: • Conta neutrofilica assoluta (ANC) >= 1,0 x 109/L • Piastrine >= 100 x 109/L • Emoglobina >= 9,0 g/dl • INR <= 2 • Creatininemia <= 1,5 x ULN • Bilirubinemia <= 1,5 x ULN (in pazienti con sindrome di Gilbert nota, bilirubinemia totale <= 3 x ULN, bilirubina diretta <= 1,5 x ULN) • AST/SGOT e ALT/SGPT <= 3 x ULN o <= 5,0 x ULN se sono presenti metastasi epatiche • Glicemia a digiuno < 140 mg/dL (7,8 mmol/L) • HbA1c <= 8%. |
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| E.4 | Principal exclusion criteria |
| 1. Patient has received previous treatment with PI3K and/or mTOR inhibitors. 2. Patient has received more than one line of antineoplastic treatment for advanced or metastatic disease (for definition of prior lines of therapy please refer to inclusion criterion 4). 3. Patient has active uncontrolled or symptomatic CNS metastases. 4. Note: Patients with controlled and asymptomatic CNS metastases may participate in this trial. As such, the patient must have completed any prior treatment for CNS metastases > 28 days (including radiotherapy and/or surgery) prior to enrollment in this study and should not be receiving chronic corticosteroid therapy for the CNS metastases. 5. Patient has a concurrent malignancy or has had a malignancy in the last 3 years prior to start of study treatment (with the exception of adequately treated basal or squamous cell carcinoma or cervical carcinoma in situ)6. Patient has received pelvic and/or para-aortic radiotherapy ≤ 28 days or limited filed palliative radiotherapy ≤ 14 days prior to enrollment in this study or has not recovered from side effects of such therapy at the time of initiation of screening procedures. 7. Patient has had major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery 8. Patient has active cardiac disease including any of the following: • Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) • QTc > 480 msec on screening ECG (using the QTcF formula) • Unstable angina pectoris • Ventricular arrhythmias except for benign premature ventricular contractions • Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication • Conduction abnormality requiring a pacemaker • Valvular disease with documented compromise in cardiac function • Symptomatic pericarditis9. Patient has a history of cardiac dysfunction 10. Family history of congenital long or short QT, or known history of QT/QTc prolongation or Torsade de Point(TdP) 11. Inadequately controlled hypertension(i.e, SBP >180 mmHg or DBP >100mmHg) 12. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BEZ235 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea grade ≥ 2, malabsorption syndrome, or small bowel resection). 13. Patient is concurrently using other approved antineoplastic or any investigational agents (hormonal agent included) in the last 30 days prior to start of treatment 14. Patient receiving chronic treatment with systemic steroids or another immunosuppressive agent at start of study treatment. 15. Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular) are allowed. 16. Patient is currently being treated with any of the following drugs: • Moderate and strong inhibitors or inducers of CYP3A4/5 (see Appendix 1) • Drugs with known risk to induce Torsades de Pointes (see Appendix 3) • Warfarin or coumarin analogues • LHRH agonists17. Patient is consuming Seville oranges, grapefruit, grapefruit hybrids, pummelos and exotic citrus fruits (as well as their juices) during the last 7 days prior to start of treatment. Regular orange juice is permitted. 18. Immunocompromised patients, including known seropositivity for HIV (testing is not mandatory). 19. Patient has other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment contraindicate her participation in the clinical study (e.g. uncontrolled diabetes, chronic pancreatitis, active chronic hepatitis etc.). See protocol for last 3 criteria (20, 21 and 22). |
| 1.Trattamento precedente con inibitore di PI3K e/o inibitore di mTOR. 2.Pazienti che hanno ricevuto piu' di una linea di trattamento antineoplastico per malattia in stadio avanzato o metastatico (per definizione di prima linea di terapia antineoplastica vedi il criterio di inclusione n. 4) 3.Pazienti con metastasi al sistema nervoso centrale in fase attiva, non controllate o sintomatiche. 4.Nota: le pazienti con metastasi del sistema nervoso centrale controllate e asintomatiche possono partecipare allo studio se hanno completato la terapia per le metastasi cerebrali (comprese radiazioni e/o chirurgia) da oltre 28 giorni al momento dell’ingresso nello studio e se non stanno assumendo trattamento corticosteroideo per le metastasi cerebrali. 5.Presenza di altra neoplasia concomitante o neoplasia nei 3 anni precedenti l’arruolamento nello studio, a eccezione di basalioma o carcinoma a cellule squamose adeguatamente trattatati o carcinoma in situ della cervice uterina. 6.Pazienti sottoposte a radioterapia pelvica e/o para-aortica <= 28 giorni o radioterapia palliativa a campo limitato <= 14 giorni prima dell’arruolamento nel presente studio o non hanno presentato guarigione dagli effetti collaterali di questa terapia al momento dell’inizio delle procedure di screening. 7.Pazienti sottoposte a intervento chirurgico maggiore nei 28 giorni precedenti l’inizio della somministrazione del trattamento in studio o che non hanno presentato guarigione dagli effetti collaterali di tale intervento. 8.Pazienti con cardiopatia in fase attiva compresa qualsiasi condizione seguente: •Frazione di eiezione del ventricolo sinistro (LVEF) < 50 % valutata mediante scansione MUGA o ecocardiografia. •QTc > 480 msec all’ECG di screening (utilizzando la formula QTcF). •Angina instabile. •Aritmia ventricolare a eccezione di contrazioni ventricolari premature benigne. •Aritmie sopraventricolari e nodali che necessitano di pacemaker o non sono controllate dalla terapia. •Alterazioni della conduzione che necessitano di pacemaker. •Patologie valvolari con compromissione documentata della funzionalita' cardiaca. •Pericardite sintomatica. 9.Pazienti con un’anamnesi positiva per disfunzione cardiaca comprendente una qualsiasi delle condizioni seguenti: •Infarto miocardico nei 6 mesi precedenti, documentato da aumento persistente degli enzimi cardiaci o alterazioni di parete persistenti alla valutazione della LVEF. •Anamnesi positiva per scompenso cardiaco congestizio (classe NYHA III- IV). •Cardiomiopatia documentata. 10.Anamnesi familiare positiva per QT lungo o QT breve congenito, o anamnesi positiva nota di prolungamento del QT/QTc o torsione di punta. 11.Ipertensione arteriosa non adeguatamente controllata (PAS > 180 mmHg o PAD > 100 mmHg). 12.Compromissione della funzionalita' gastrointestinale o patologia gastrointestinale che puo' alterare significativamente l’assorbimento di BEZ235 (ad es. patologia ulcerosa, nausea non controllata, vomito, diarrea di Grado >= 2, sindrome da malassorbimento o resezione dell’intestino tenue). 13.Pazienti che utilizzano attualmente altri agenti antineoplastici approvati o farmaci sperimentali (incluso gli agenti ormonali) negli ultimi 30 giorni prima dell’inizio del trattamento. 14.Pazienti in trattamento con corticosteroidi o altri farmaci immunosoppressori all’ingresso nello studio. 15.Nota: Le applicazioni topiche (ad es: per rash cutaneo), gli spray inalatori (ad es: per pneumopatia ostruttiva), i colliri o le iniezioni locali (ad es: intrarticolari) sono consentite. 16.Pazienti in trattamento attuale con uno qualsiasi dei farmaci elencati di seguito: •Inibitori o induttori forti o moderati del CYP3A4/5 (vedi Appendice 1). •Farmaci con rischio noto di indurre torsione di punta (vedi Appendice 3) •Warfarin o analoghi coumarinici. •Agonisti LHRH. (Vedere il protocollo per i criteri 17-22) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| - ORR per RECIST in patients with PIK3CA mutation and/or PTEN gene mutation and/or PTEN negative by IHC (less than 10% staining) - ORR per RECIST in all patients |
| • ORR in base ai criteri RECIST nelle pazienti con attivazione della via PI3K. L’attivazione della via PI3K viene definita dalla mutazione di PIK3CA e/o PTEN e da PTEN negativo all’immunoistochimica (colorazione inferiore al 10%). • ORR in base ai criteri RECIST in tutte le pazienti. |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 6 |
| 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 | 30 |
| 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 | 30 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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