| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-overexpressing locally advanced or metastatic breast cancer. |
| Carcinoma mammario localmente avanzato o metastatico con sovra-espressione di HER2. |
|
| 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 | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
| 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 |
| To compare progression free survival (PFS) between combination treatment of everolimus/ trastuzumab/ paclitaxel and the combination treatment with trastuzumab/paclitaxel. |
| Confrontare la sopravvivenza libera da progressione (PFS) fra il trattamento di associazione everolimus/ trastuzumab/ paclitaxel e il trattamento trastuzumab/ paclitaxel in pazienti con carcinoma mammario, non operabile, localmente avanzato o metastatico e sovra-espressione di HER2. |
|
| E.2.2 | Secondary objectives of the trial |
| Key Secondary - To compare the two treatment arms with respect to Overall Survival (OS) Other Secondary - To evaluate the two treatment arms with respect to `Overall response rate (ORR) `Time to deterioration of ECOG Performance Status `Safety `Clinical benefit rate (CBR) `Time to response `Duration of response Pharmacokinetics `To evaluate the impact of co-administration of everolimus on paclitaxel pharmacokinetics in presence of trastuzumab `To evaluate the impact of co-administration of paclitaxel on everolimus pharmacokinetics in the presence of trastuzumab. |
| Confrontare la sopravvivenza (OS) fra i due gruppi di trattamento.Altri obiettivi secondari sono: Valutare i due gruppi di trattamento per: ï‚Ÿ frequenza della migliore risposta globale (ORR) ï‚Ÿ tempo al deterioramento dell`ECOG Performance Status ï‚Ÿ tollerabilita` ï‚Ÿ frequenza di beneficio clinico (CBR) ï‚Ÿ tempo alla risposta ï‚Ÿ durata della risposta Obiettivi di farmacocinetica ï‚Ÿ valutare l`impatto della somministrazione congiunta di everolimus sulla farmacocinetica di paclitaxel in presenza di trastuzumab ï‚Ÿ valutare l`impatto della somministrazione congiunta di paclitaxel sulla farmacocinetica di everolimus in presenza di trastuzumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Written informed consent must be obtained prior to any study-related procedures. 2. Women `‰¥ 18 years old. 3. Patients with an ECOG performance status of 0-1. 4. Histologically or cytologically confirmed invasive breast carcinoma with local recurrence or radiological evidence of metastatic disease. Local disease must not be amenable to resection with curative intent. 5. Patients fulfilling one of the following criteria are eligible to participate in this study: • Patients with measurable disease as per RECIST criteria. • Patients with bone lesions, lytic or mixed (lytic + sclerotic), in the absence of measurable disease as defined by RECIST criteria. 6. HER2 positive patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive). 7. Patients fulfilling one of the following criteria are eligible to participate in this study: • Patient never treated with trastuzumab • Prior trastuzumab and/or chemotherapy (taxanes included) as neo-adjuvant or adjuvant treatment is discontinued > 12 months prior to randomization 8. Prior treatment for breast cancer with endocrine therapy (adjuvant or metastatic settings) is allowed but, in the metastatic setting, it must be discontinued because of disease progression before randomization. Patients treated with bisphosphonates at entry or who start bisphosphonates during study may continue this therapy during protocol treatment. 9. Documentation of negative pregnancy test for patients of child bearing potential prior to enrollment within 7 days prior to randomization. Sexually active pre-menopausal patients must use adequate contraceptive measures while on study. 10. Patients must meet the following laboratory criteria within 21 days prior to randomization: • Hematology: • Neutrophil count of `‰¥ 1.5 109/L • Platelet count of `‰¥ 100 x109/L • Hemoglobin `‰¥ 90g/L • Biochemistry: • AST/SGOT and ALT/SGPT `‰¤ 2.5 x upper limit of normal (ULN) (or `‰¤ 5.0 x ULN if the transaminase elevation is due to hepatic metastasis). • Total serum bilirubin `‰¤ 1.5 x ULN [Patients with Gilbert Syndrome must have total bilirubin < 3ULN]. • INR `‰¤ 2 • Fasting serum cholesterol `‰¤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides `‰¤ 2.5 x ULN (with lipid-lowering drugs permitted) • Serum creatinine < 1.5 x ULN 11. Left ventricular ejection fraction assessment (echocardiogram or MUGA scan) performed within 4 weeks prior to randomization, showing a LVEF value `‰¥ LLN. |
| 1. Consenso informato scritto prima di qualsiasi procedura da studio 2. Donne adulte `‰¥ 18 anni 3. ECOG performance status 0-1 4. Carcinoma mammario invasivo confermato mediante istologia o citologia con recidiva locale non operabile o evidenza radiologica di metastasi. 5. Pazienti che rispondano a uno dei seguenti criteri: - Malattia misurabile mediante criteri RECIST - Lesioni ossee, litiche o miste, in assenza di malattia misurabile secondo criteri RECIST 6. Pazienti HER2 positive (ICH3 + staining o ibridazione positiva in situ) 7. Pazienti che rispondono a uno dei seguenti criteri: - Mai trattati con trastuzumab - Un precedente trattamento con trastuzumab e/o chemioterapia (compresi i taxani) come trattamento neoadiuvante o adiuvante sospeso oltre 12 mesi prima della randomizzazione 8. Un precedente trattamento del tumore con terapia endocrina e` ammesso ma, nel gruppo di pazienti con malattia metastatica deve essere sospeso a causa della progressione della malattia prima della randomizzazione. I bisfosfonati sono ammessi. 9. Test di gravidanza negativo per le donne fertili 7 giorni prima della randomizzazione. Le pazienti non in menopausa sessualmente attive devono usare un contraccettivo adeguato 10. Pazienti che rispondono a uno dei seguenti criteri nei 21 giorni precedenti la randomizzazione: - Ematologia: neutrofili `‰¥ 1.5 x 109/l; piastrine `‰¥ 100 x 109/l; emoglobina `‰¥ 90g/l. - Biochimica: AST/SGOT e ALT/SGPT `‰¤ 2.5 x limiti superiori della norma (ULN) (o `‰¤ 5.0 x ULN se l`aumento delle transaminasi e` dovuto a metastasi epatiche); bilirubina totale `‰¤ 1.5 x ULN (< 3ULN per i pazienti con sindrome di Gilbert); INR `‰¤ 2; colesterolo a digiuno `‰¤ 300 mg/dl o 7.75 mmol/l e trigliceridi a digiuno `‰¤ 2.5 x ULN (ipolipemizzanti permessi); creatinina < 1.5 x ULN 11. Frazione di eiezione del ventricolo sinistro (ecocardiografia o MUGA) nelle 4 settimane precedenti la randomizzazione, con LVEF `‰¥ LLN. |
|
| E.4 | Principal exclusion criteria |
| 1. Prior mTOR inhibitors for the treatment of cancer. 2. Anticancer therapy for locally advanced or metastatic breast cancer except for prior hormonal therapy. Patients who had a recurrence within 12 months after end of trastuzumab and/or chemotherapy (taxanes included) as neo-adjuvant or adjuvant treatment prior to randomization are not eligible. 3. Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites, etc.). 4. Patients who have received radiotherapy to `‰¥ 25% of the bone marrow within the last 4 weeks prior to randomization; local radiotherapy is allowed. 5. History of central nervous system metastasis. 6. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus. 7. Active ulceration of the upper gastrointestinal tract. 8. NCI Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 peripheral neuropathy `‰¥ grade 2 at randomization. 9. Active cardiac disease: • Angina pectoris that requires the use of anti-anginal medication, • 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 pericarditis. 10. History of cardiac dysfunction including any one of the following: • Myocardial infarction, • History of documented congestive heart failure (New York Heart Association functional classification III-IV), • Documented cardiomyopathy. 11. Uncontrolled hypertension or history of poor compliance with an antihypertensive regimen. 12. Known human immunodeficiency virus infection (HIV). 13. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes mellitus, active untreated or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease including dyspnoea at rest from any cause) that could cause unacceptable safety risks or compromise compliance with the protocol. 14. Known hypersensitivity to any protocol treatment. 15. Requirement for therapeutic doses of warfarin or equivalent. 16. Clinically significant third space fluid accumulation (i.e., ascites requiring tap or pleural effusion that is either requiring tap or associated with shortness of breath). 17. Pregnant (i.e., positive beta-human chorionic gonadotropin test) or breast feeding. 18. Patients with other significant disease or disorders that, in the investigator`s opinion, would exclude the patient from the study. 19. Patients with inability to grant a reliable informed consent. |
| 1. Precedente trattamento con inibitori mTOR per il trattamento del carcinoma mammario 2. Terapia antitumorale per il carcinoma mammario localmente avanzato o metastatico ad eccezione di precedente terapia ormonale. Non sono eleggibili i pazienti che hanno una recidiva entro 12 mesi dalla fine di trastuzumab e/o chemioterapia (inclusi taxane) come terapia neoadiuvante o adiuvante prima della randomizzazione. 3. Solo lesioni non misurabili diverse dalle metastasi ossee 4. Radioterapia a `‰¥ 25% del midollo osseo nelle 4 settimane precedenti la randomizzazione. (radioterapia locale ammessa) 5. Anamnesi di metastasi al SNC 6. Disfunzione o malattia gastrointestinale che puo` significativamente alterare l`assorbimento di everolimus orale 7. Ulcere attive del tratto gastrointestinale superiore 8. Neuropatia periferica `‰¥ grado 2 alla randomizzazione secondo i NCI Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 9. Cardiopatia attiva: - Angina pectoris che richiede uso di antianginosi - Aritmie ventricolari eccetto le sistoli ventricolari premature benigne - Aritmie sopraventricolari e nodali che richiedono uso di pacemaker o non controllate dalla terapia - Anomalie della conduzione che richiedono uso di pacemaker - Valvulopatia con documentata compromissione della funzione cardiaca - Pericardite sintomatica 10. Anamnesi di cardiopatia comprensiva di almeno uno dei seguenti: - Infarto del miocardio - Anamnesi di scompenso cardiaco congestizio (NYHA classe III-IV) - Cardiomiopatia documentata 11. Ipertensione scompensata o anamnesi di scarsa aderenza a trattamento antiipertensivo 12. Infezione da HIV 13. Altre condizioni mediche gravi/non controllate (diabete scompensato, infezione non trattata o non controllata, broncopneumopatia cronica ostruttiva o restrittiva, compresa dispnea a riposo per qualsiasi causa) che possono causare rischi di sicurezza inaccettabili, o compromettere l`aderenza al protocollo 14. Ipersensibilita` a qualsiasi farmaco dello studio 15. Necessita` di warfarin o equivalenti 16. Accumulo clinicamente significativo di liquidi interstiziali (ad esempio, ascite che richiede paracentesi o versamento pleurico che richiede drenaggio o si accompagna a dispnea). 17. Gravidanza o allattamento 18. Altre malattie significative che facciano escludere la paziente a giudizio dello sperimentatore 19. Incapacita` di fornire il consenso. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint in this study is progression-free survival (PFS), defined as the time from the date of randomization to the date of first documented tumor progression or death due to any cause, whichever occurs first. If a patient has not had an event, PFS will be censored at the date of last adequate tumor assessment. |
| La variabile primaria dello studio e` la sopravvivenza libera da progressione (PFS), definita come il tempo dalla data di randomizzazione alla data della prima progressione documentata del tumore, o al decesso per qualsiasi ragione. Se non si verifica l`evento, la variabile sara` considerata alla data dell`ultimo contatto. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 | 38 |
| 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 | 38 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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