Dose Escalation Followed by Study of RAD001 in Combination With Trastuzumab in HER2-Positive Metastatic Breast Cancer

- 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