E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | HER2 overexpressing metastatic breast cancer | |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 | E.1.2 | Level | LLT | E.1.2 | Classification code | 10021977 | E.1.2 | Term | Inflammatory carcinoma of breast recurrent | |
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 establish the feasible dose levels/regimens of RAD001 combined with weekly trastuzumab and vinorelbine HV therapy in patients with HER2-overexpressing metastatic breast cancer whose disease progressed on/after trastuzumab mono and/or combination therapy based on the evaluation of safety in terms of dose limiting toxicities. | |
E.2.2 | Secondary objectives of the trial | To assess the ability to deliver the HV therapy To determine potential PK drug-drug interactions based on the assessment of pharmacokinetic profiles of study drugs administered alone and in combination To assess the clinical efficacy of combined administration of different RAD001 dose levels / regimens with HV based on tumor response | |
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria | Female or male patients 8805;18 years WHO performance status 8804;1 Histologically confirmed diagnosis of metastatic breast cancer demonstrating HER2-overexpression IHC 3 or FISH positive Progressive disease on prior trastuzumab alone or in combination with other anticancer agents, or relapsed any time after completion of this therapy Patients may have received treatment with lapatinib or other HER2 targeted therapies after progression on trastuzumab Patients may have received adjuvant chemotherapy and one or more prior chemotherapies for advanced disease Measurable or non-measurable disease according to RECIST Patients may have received treatment for brain metastases, but must be neurologically stable and off corticosteroids Baseline LVEF 50 MUGA or echo Adequate bone marrow function as shown by Absolute Neutrophil Count ANC 8805; 1.5 x 109/L Platelets 8805; 100 x 109/L Hemoglobin Hgb 8805; 9g/dL Adequate liver function as shown by Serum aspartate aminotransferase AST and alanine aminotransferase ALT 8804; 2.5 ULN or 8804; 5 if hepatic metastases are present Total bilirubin 8804; 1.5 x ULN INR 1.3 x ULN or 3 ULN on antigoagulants Adequate renal function as shown by Serum creatinine 8804; 1.5 x ULN Women using an acceptable form of contraception or women who meet the protocol definition of post-menopausal 12 months of natural spontaneous amenorrhea or 6 months of spontaneous or induced amenorrhea with serum FSH levels 40 mIU/ml or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy Patients who give a written informed consent obtained according to local guidelines | |
E.4 | Principal exclusion criteria | Patients receiving endocrine therapy for breast cancer endocrine therapy must have either failed in patients with hormone receptor positive disease or patients must be considered unsuitable for endocrine therapy Patients currently receiving chemotherapy, immunotherapy, or radio-therapy or who have received these 8804;4 weeks prior to study treatment start Patients who have previously received vinorelbine Patients who have previously received mTOR inhibitors Patients with a known hypersensitivity to RAD001 everolimus or other rapamycins sirolimus, temsirolimus or to its excipients Patients receiving chronic treatment with steroids or another immunosuppressive agent Patients who are using other investigational agents or who had received investigational drugs 8804; 4 weeks prior to study treatment start Patients who have received radiotherapy 8804; 4 weeks prior to study treatment start or who have not recovered from such therapy Patients who have undergone major surgery 8804; 2 weeks prior to starting study treatment or who have not recovered from such therapy Patients with uncontrolled or symptomatic CNS disease Patients with a known history of HIV seropositivity HIV testing is not mandatory Patients with an active, bleeding diathesis or on oral anti-vitamin K medication except low dose coumadin Patients treated with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A Persistent 8805;Grade 2 neuropathy or history of grade 3/4 neuropathy of any etiology Patients who have any severe and/or uncontrolled medical conditions such as unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction 8804; 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia uncontrolled diabetes as defined by fasting serum glucose 1.5X ULN 8805; grade 3 hypercholesterolemia / hypertriglyceridemia or 8805; grade 2 hypercholesterolemia / hypertriglyceridemia with history of coronary artery disease despite lipid-lowering treatment if given acute and chronic, active infectious disorders and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of RAD001 e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome active skin, mucosa, ocular or GI disorders of grade 1 pulmonary insufficiency or diseases that lead to impairment of lung function Patients who have liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Unless demonstrated to be post-menopausal see inclusion criteria , pregnancy should be excluded by serum pregnancy test 8804; 48 hours prior to the administration of the first study treatment. History of noncompliance to medical regimens Patients unwilling to or unable to comply with the protocol | |
E.5 End points |
E.5.1 | Primary end point(s) | Feasibility of the study treatment combination will be evaluated using Dose Limiting Toxicities DLT occurring at any time during the study The Relative Dose Intensity RDI of chemotherapy and the discontinuation rate of trastuzumab will be evaluated in order to confirm that the feasible dose allows the delivery of the combination therapy. The pharmacokinetic PK drug-drug interaction will be evaluated from the comparison of study drug levels when administered alone and in combination. Efficacy will be evaluated on the overall tumor response according to RECIST. | |
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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | |
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |