A Study Of Everolimus, Trastuzumab And Vinorelbine In HER2-Positive Breast Cancer Brain Metastases

Inclusion Criteria

• Histologically-confirmed HER2-positive (IHC 3+ or fluorescence in situ hybridization (FISH) amplified; by clinical assay on either primary or metastatic tumor) adenocarcinoma of the breast with at least one progressive and/or new metastatic brain lesion (>/=5 mm on radiographic imaging) after receipt of intracranial radiation therapy (whole brain radiation therapy, stereotactic radiosurgery, gamma knife, or equivalent). Patients in whom brain metastases (BM) are asymptomatic and detected during routine brain MRI screening per institutional protocols are eligible.
• Prior intracranial radiation therapy (whole brain radiation therapy, stereotactic radiosurgery, gamma knife or equivalent) is allowed but not required.
• Patients with no prior treatment with intracranial Response (ICR) may be included unless ICR is emergently indicated (in consultation with a local therapist, ie neurosurgeon or radiation oncologist)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Life expectancy >12 weeks.
• At least 21 years of age.
• No prior mTOR inhibitors
• Prior navelbine allowed provided navelbine therapy discontinued >/= 12 months from Day 1 of treatment under this protocol.
• Last anti-cancer treatment (including any investigational drug) >/= 2 weeks from initiation of protocol based therapy, provided all adverse events (AEs) (other than alopecia) have resolved to ≤grade 1 at baseline.
• No active serious infection or other comorbid illness which would impair ability to participate in the trial.
• Left ventricular ejection fraction assessment (echocardiogram or multigated acquisition scan (MUGA) scan) performed within 4 weeks prior to study initiation, showing a Left ventricular ejection fraction (LVEF) value ≥ lower limit of normal (LLN).
• If patient is on dexamethasone, must be on stable or decreasing dose of dexamethasone for ≥7 days. If patient is on different glucocorticoid e.g., prednisone, must be converted to dexamethasone prior to enrollment. Refer to dose modification of everolimus for patients taking dexamethasone.
• Interval ≥4 weeks between open brain biopsy and initiation of protocol-based therapy.
• international normalized ratio (INR) ≤2.0. Anticoagulation is allowed if target INR ≤2.0 on a stable dose of warfarin or if patient on a stable dose of Low-molecular-weight (LMW) heparin for >1 weeks at time of enrollment.
• Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5 x ULN. Note: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
• Patients must have adequate organ function as evidenced by:
• Absolute neutrophil count ≥1.5/µL
• Platelet count ≥100,000/µL
• Hg ≥9 g/dL
• Bilirubin ≤1.5 x upper limit of normal (ULN)
• aspartate aminotransferase (AST) or Alanine transaminase (ALT) ≤2.5 x ULN (≤5 x ULN if liver metastases are present)
• Serum creatinine ≤1.5 x ULN
• Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies is required.
• Signed, institutional review board (IRB)-approved written informed consent.

Exclusion Criteria

• Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus); patients who have received prior treatment with navelbine within prior 12 months.
• patients with a known hypersensitivity to everolimus or other rapamycins (e.g. sirolimus, temsirolimus) or to its excipients.
• Patients requiring treatment with any other systemic glucocorticoid. Note: This restriction regarding choice of glucocorticoid does not apply should patient need 1.5 x ULN (Note: Optimal glycemic control should be achieved before starting trial therapy)
• active (acute or chronic) or uncontrolled severe infections
• liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).

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