| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2+ locally advanced or 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 | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
|
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
To compare overall survival (OS) between the 2 treatment arms
Other Secondary Objectives:
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 Objectives
→ To evaluate the impact of co-administration of everolimus to paclitaxel
pharmacokinetics in the presence of trastuzumab
→ To evaluate the impact of co-administration of paclitaxel on everolimus
pharmacokinetics in the presence of trastuzumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
→ Written informed consent must be obtained prior to any study-related procedures.
→ Women ≥18 years old.
→ Patients with an ECOG performance status of 0-1.
→ 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.
→ 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.
→ HER2+ patients by local laboratory testing (IHC 3+ staining or in situ
hybridization positive).
→ 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
→ Prior treatment for breast cancer with endocrine therapy (adjuvant or metastatic settings) is allowed but should be discontinued at randomization. Patients treated with bisphosphonates at entry or who start bisphosphonates during study may continue this therapy during protocol treatment.
→ 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.
→ Patients must meet the following laboratory criteria within 21 days prior to
randomization:
• Hematology:
• Neutrophil count of ≥ 1.5 10 9/L
• Platelet count of ≥100 x10 9/L
• Hemoglobin ≥ 90 g/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 x ULN
• 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
→ 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 |
→ Prior mTOR inhibitors for the treatment of cancer.
→ Anticancer therapy for locally advanced or metastatic breast cancer except for prior hormonal therapy. Patients who had a recurrence within 12 months weeks after end of trastuzumab and/or chemotherapy (taxanes included) as neo-adjuvant or adjuvant treatment prior to randomization are not eligible.
→ Patients with only non-measurable lesions other than bone metastasis (e.g.
pleural effusion, ascites, etc.).
→ Patients who have received radiotherapy to ≥ 25% of the bone marrow within
the last 4 weeks prior to randomization; local radiotherapy is allowed.
→ History of central nervous system metastasis.
→ Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral everolimus.
→ Active ulceration of the upper gastrointestinal tract.
→ NCI Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 peripheral
neuropathy ≥ grade 2 at randomization.
→ 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.
→ 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.
→ Uncontrolled hypertension or history of poor compliance with an antihypertensive
regimen.
→ Known human immunodeficiency virus infection (HIV).
→ 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.
→ Known hypersensitivity to any protocol treatment.
→ Requirement for therapeutic doses of warfarin or equivalent.
→ Clinically significant third space fluid accumulation.
→ Pregnant (i.e., positive beta-human chorionic gonadotropin test) or breast feeding.
→ Patients with other significant disease or disorders that, in the investigator’s
opinion, would exclude the patient from the study.
→ Patients with inability to grant a reliable informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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. |
|
| 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) | No |
| 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 | 11 |
| 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 | 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| 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 | 11 |
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