Phase II Trial of EVEROLIMUS ± Trastuzumab in Hormone-Refractory Metastatic Breast Cancer

Breast cancer is the most common type of invasive cancer in women, with more than 1 million
cases and almost 600,000 deaths occurring worldwide annually. Breast cancer that has spread
to other parts of the body (metastasized) is usually not curable. Patients with a type of
metastatic breast cancer that has hormone receptors on the surface of the cancer cells are
usually treated with the drug tamoxifen, which interferes with the function of these hormone
receptors. However, the average survival time for these patients remains at around 36 months.

In patients who no longer respond to tamoxifen (hormone-refractory breast cancer), the cancer
drug trastuzumab (Herceptin), which acts on a protein called human epidermal growth factor
receptor 2 (HER2), may have some activity. In addition, studies suggest that the drug
everolimus, which acts on a pathway within cancer cells that is important for growth of the
tumor, may make the cancer cells more sensitive to treatment with trastuzumab. Thus, the two
drugs may act together to increase their anti-cancer potential.

Inclusion Criteria:

Patients will be included in the study based on the following criteria:

- Hormone-refractory metastatic breast cancer defined as disease progression within 6
months from starting most recent hormonal therapy

- At least one line of endocrine therapy in the metastatic setting

- Candidate for hormonal therapy (ER and/or progestin receptor [PR]-positive at primary
diagnosis and at metastatic diagnosis where tissue is available)

- HER2/neu-negative breast cancer by standard criteria (immunohistochemistry [IHC] < 3+
or fluorescence in situ hybridization [FISH]-negative if IHC 3+) at primary diagnosis

- Must have a biopsy in the metastatic setting with HER2 expression of 1+ or 2+ by IHC

- If biopsy of metastatic lesion is performed prior to study entry, HER2 expression by
IHC must be 1+ or 2+

- Histologically confirmed, measurable or evaluable disease; if disease is measurable,
Response Evaluation Criteria In Solid Tumors (RECIST) criteria should be used

- Life expectancy > 6 months

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

- Adequate bone marrow function as indicated by the following:

- Absolute neutrophil count (ANC) > 1500/µL

- Platelets ≥ 100,000/µL

- Hemoglobin > 10 g/dL

- Adequate renal function, as indicated by creatinine ≤ 1.5x upper limit of normal (ULN)

- Adequate liver function, as indicated by bilirubin ≤ 1.5x ULN

- International normalized ratio (INR) ≤ 1.3 (or ≤ 3 on anticoagulants)

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2x ULN unless
related to primary disease

- Signed informed consent

- Adequate birth control

- 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.

Exclusion Criteria:

Patients will be excluded from the study based on the following criteria:

- Prior treatment with trastuzumab or other HER2-directed therapies or with an mammalian
target of rapamycin (mTOR) inhibitor within 12 months of study entry (when cancer was
not definitely hormone refractory)

- HER2 0 or 3+ by IHC on pre-treatment biopsy of metastatic lesion (if performed)

- Active infection

- Uncontrolled central nervous system metastases

- Life-threatening, visceral metastases

- Pregnant or lactating women

- Prior chemotherapy within the last 4 weeks

- Prior radiation therapy within the last 4 weeks; prior radiation therapy to indicator
lesion (unless objective disease recurrence or progression within the radiation portal
has been documented since completion of radiation)

- Concomitant malignancies or previous malignancies within the last 5 years, with the
exception of adequately treated basal or squamous cell carcinoma of the skin or
carcinoma in situ of the cervix

- History of significant cardiac disease, cardiac risk factors or uncontrolled
arrhythmias

- Ejection fraction < 50% or below the lower limit of the institutional normal range,
whichever is lower

- Hypersensitivity to trial medications

- Emotional limitations

- Prior treatment with any investigational drug within the preceding 4 weeks

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent

- Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN

- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis

- A known history of HIV seropositivity

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection)

- Patients with an active, bleeding diathesis

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. If barrier contraceptives
are being used, these must be continued throughout the trial by both sexes. Hormonal
contraceptives are not acceptable as a sole method of contraception. (Women of
childbearing potential must have a negative urine or serum pregnancy test within 7
days prior to administration of everolimus)

- Patients who have received prior treatment with an mTOR inhibitor (sirolimus,
temsirolimus, everolimus)

- Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs,
resulting in dyspnea at rest

- Taking any of the following agents:

- Chronic treatment with systemic steroids or another immunosuppressive agent

- Live vaccines

- Drugs or substances known to be inhibitors or inducers of the isoenzyme
cytochrome P450, family 3, subfamily A (CYP3A)