The purpose of this research study is to determine the safety of RAD001 and the highest dose of this drug that can be given to people with HER2-positive metastatic breast cancer safely in combination with trastuzumab. RAD001 has been used in patients with severe rheumatoid arthritis, in recipients of solid-organ transplants, healthy volunteers and experiments with animals, and information from those other research studies suggest that this RAD001 may help to stop cancer cells from growing abnormally.

• Since we are looking for the dose of RAD001 that can be given safely in combination with trastuzumab, not everyone will receive the same amount of RAD001. Small groups of participants will be enrolled at a certain dose of RAD001 and if they tolerate the medications well, the next small group will receive a higher dose. This will continue until the optimal dose of RAD001 that can be given in combination with trastuzumab is found.
• Blood will be drawn on days 1, 2, 8, and 15 of the first cycle of treatment and then once at every 4 cycles for everolimus pharmacokinetics analysis.
• There is an optional tissue biopsy component to this study asking for 2 biopsies performed pre-treatment and after the cycle one.
• We will keep track of the participants medical condition for the next three years by calling them on the telephone twice a year to see how they are doing.

OBJECTIVES:

Primary

- To assess the safety and tolerability of RAD001 in combination with trastuzumab in HER2-positive metastatic breast cancer

Secondary

• To evaluate the activity of RAD001 plus trastuzumab, as defined by objective response rate, in patients with progression on a trastuzumab-containing regimen
• To evaluate changes in signaling molecules in response to trastuzumab and RAD001 in circulating tumor cells and tumor tissue
• To evaluate the pharmacokinetics of RAD001 in combination with trastuzumab.

STATISTICAL DESIGN:

This Phase I study followed a standard 3+3 dose escalation design with two dose levels of everolimus in combination with trastuzumab to be evaluated. The DLT observation period was cycle one (first 21 days of treatment). There is a 20 patient expansion cohort treated at the MTD. The regimen would be considered promising if at least 2 objective responses are observed out of 20 treated patients. If the true but unknown response rate is 15% then the probability of observing at least 2 responses is 82% but if the true rate is 5% this probability reduces to 26%.

Inclusion Criteria:

• Histologically or cytologically confirmed invasive breast cancer, with stage IV disease
• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as greater than or equal to 20mm with conventional techniques or as greater than or equal to 10mm with spiral CT scan.
• Primary tumor or metastasis must overexpress HER2
• Patient must have received 1-2 prior chemotherapeutic regiments for metastatic breast cancer and must have been off treatment for at least three weeks.
• Patient must have received and progressed on at least 1 prior trastuzumab-containing regimen, but not more than 2, in the metastatic setting.
• Patients may have received prior radiation therapy
• Patients may have received hormonal therapy in the adjuvant or metastatic setting
• 18 years of age or older
• Life expectancy of greater than 6 months
• Normal organ and marrow function as defined in the protocol
• Left ventricular ejection fraction (LVEF) greater than or equal to the institutional lower limit of normal

Exclusion Criteria:

• Treatment with any investigational drug within 4 weeks
• Long-term treatment, over 3 months, with a systemic steroid or another immunosuppressive agent
• Other malignancies within the past 3 years, except for adequately treated carcinoma of teh cervix or basal-or squamous-cell carcinoma of the skin
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001
• An active, bleeding diathesis or an oral anti-vitamin K medication
• Prior treatment with an mTOR inhibitor
• History of non-compliance with medical regimens
• Unwillingness or inability to comply with the protocol
• Major surgery within 2 weeks before study entry
• Patients with active brain metastases or leptomeningeal carcinomatosis
• Patients who have experienced grade 1 or grade 2 hypersensitivity reactions to prior trastuzumab therapy are eligible ONLY IF these reactions did not prevent further administration
• Severe and/or uncontrolled intercurrent medical condition, psychiatric illness or a social situation that could limit their ability to comply with the study requirements.
• Pregnant or breast-feeding women
• HIV positive patients
• Known hypersensitivity to RAD001 (everolimus) or other rapamycins

Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months.

Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.