| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-neu overexpressing metastatic breast cancer after previous trastuzumab use |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
|
| 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 the combination of everolimus, vinorelbine and trastuzumab to vinorelbine and trastuzumab alone with respect to progression-free survival in women with HER2/neu overexpressing advanced or metastatic breast cancer who are resistant to trastuzumab and have been pre-treated with a taxane |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objective of this study is to compare the two treatment arms with respect to overall survival (OS).
Other secondary objectives are to evaluate the two treatment arms with respect to
• Objective response rate (ORR)
• Time to deterioration of ECOG performance status
• Safety
• Change in QoL scores over time
• Clinical benefit rate (CBR)
• Duration of response (DoR)
• Time to response
• To evaluate the impact of co-administration of everolimus to vinorelbine pharmacokinetics in the presence of trastuzumab in a subgroup of patients
• To evaluate the impact of co-administration of everolimus to trastuzumab pharmacokinetics in the presence of vinorelbine in a subgroup of patients
• To evaluate the concentrations of everolimus at predose (Cmin) and at 2 hours post-dose (C2h) when co-administrated with vinorelbine and trastuzumab in a subgroup of patients
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Women ≥ 18 years old;
- Histologically or cytologically confirmed invasive breast carcinoma with locally recurrent or radiological evidence of metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent;
- HER2+ status defined as IHC 3+ staining or in situ hybridization positive.
Note: The pathology report confirming HER2+ status must be available at the study center prior to randomization;
- Patients with resistance to trastuzumab, defined as:
• Recurrence while on trastuzumab or within 12 months since the last infusion for patients who received trastuzumab as adjuvant treatment.
• Progression while on or within 4 weeks since the last infusion of trastuzumab for patients who received trastuzumab for metastatic disease.
- Prior taxane therapy.
Note: Patients must have recovered to grade 1 from any adverse event (except alopecia) related to prior therapy before randomization;
- Patients with an ECOG performance status of 0 - 2;
- Patients with measurable disease as per RECIST criteria;
- Documentation of negative pregnancy test for patients of child bearing potential prior to enrollment within 7 days prior to randomization. Sexually active pre-menopausal women must use adequate contraceptive measures, excluding estrogen containing contraceptives, while on study;
- Patients must meet the following laboratory criteria within 21 days prior to randomization:
• Hematology
• Absolute neutrophil count (ANC) ≥ 1500 /mm3 or 1.5 × 109/L;
• Platelets ≥ 100,000 /mm3 or 100 × 109/L;
• Hemoglobin ≥ 90 g/L or 5.6 mmol/L;
• INR ≤ 2;
• Biochemistry
• AST/SGOT and ALT/SGPT ≤ 2.5 × upper limit of normal (ULN) )or ≤ 5.0 × ULN if the transaminase elevation is due to liver metastases);
• Total serum bilirubin ≤ 1.5 × ULN (In patients with known Gilbert syndrome, total bilirubin ≤ 3 × ULN, with direct bilirubin ≤1.5 × ULN);
• Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 × ULN (with lipid-lowering drugs permitted);
• Serum creatinine ≤ 1.5 × ULN;
- Left ventricular ejection fraction assessment (echocardiogram or MUGA scan) performed within 4 weeks prior to randomization, showing a LVEF value ≥ LLN |
|
| E.4 | Principal exclusion criteria |
1. Prior mTOR inhibitors or vinca alkaloid agents for the treatment of cancer;
2. More than three prior chemotherapy lines for advanced disease.
Note: If recurrence occurred during adjuvant therapy or ≤ 6 months since the last administration of adjuvant therapy (with the exception of endocrine treatments), the adjuvant therapy will be considered as one prior regimen of systemic chemotherapy for advanced disease;
3. Patients who have received prior radiotherapy to ≥ 25% of the bone marrow within the last 4 weeks prior to randomization;
4. History of central nervous system metastasis;
5. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below:
Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed;
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. Peripheral neuropathy ≥ grade 2 at randomization;
9. Active cardiac disease including any of the following:
• 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 documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function;
• History of documented congestive heart failure (New York Heart Association functional classification III-IV);
• Documented cardiomyopathy;
11. Known human immunodeficiency virus infection;
12. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes mellitus, active untreated or uncontrolled infection including systemic fungal infections, chronic obstructive or chronic restrictive pulmonary disease including dyspnea at rest from any cause) that could cause unacceptable safety risks or compromise compliance with the protocol;
13. Any malignancy within 5 years prior to randomization, with the exception of adequately treated in-situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer;
14. Known hypersensitivity to any study medication;
15. Active bleeding diathesis or on oral anti-vitamin K medication (except low-dose warfarin and aspirin or equivalent, as long as the INR ≤ 2.0);
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. Breastfeeding or pregnant. |
|
| 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 radiologically documented tumor progression or death from any cause. If a patient has not had an event, PFS will be censored at the date of last adequate tumor assessment. Tumor progression will be determined by local assessment according to RECIST, see Post-text Supplement 1. |
|
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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.8.4.1 | 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 | 50 |
| 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 | 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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