Phase II Study of Everolimus Beyond Progression

PRIMARY OBJECTIVE:

Progression free survival in patients with advanced or metastatic breast cancer receiving
everolimus plus hormonal therapy beyond first progression.

SECONDARY OBJECTIVES:

1. Clinical benefit rate (sum of stable disease, partial response, complete response).

2. Response rate (partial response and complete response).

3. Overall survival.

4. Safety, side effects and tolerability profile of everolimus.

OUTLINE:

Patients receive everolimus orally (PO) daily and a hormone therapy regimen chosen at the
discretion of the investigator (anastrozole PO daily; letrozole PO daily; tamoxifen citrate
PO daily; fulvestrant intramuscularly [IM] or PO on days 1, 15, and 29, and then monthly;
megestrol acetate PO 4 times daily [QID]; or other regimen). Treatment continues in the
absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- Estrogen (ER) and/or progesterone (PR)-positive at primary diagnosis and at metastatic
diagnosis where tissue is available (defined as > or = 1% of staining nuclei)

- Progressive or recurrent breast cancer defined as disease progression or recurrence
while on a combination of exemestane with everolimus

- Human epidermal growth factor receptor 2 (HER2)/neu-negative breast cancer by standard
criteria (immunohistochemistry [IHC] < 3+ or fluorescence in situ hybridization [FISH]
negative if IHC 2+) at primary diagnosis

- Histologically confirmed, measurable or evaluable disease; patients should have at
least one measurable lesion; if applicable, Response Evaluation Criteria in Solid
Tumors (RECIST) criteria should be used

- Life expectancy > 6 months

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

- Absolute neutrophil count (ANC) > 1,500/µL

- Platelets ≥ 100,000/µL

- Hemoglobin > 10 g/dL

- Creatinine ≤ 1.5 x upper limit of normal (ULN)

- Bilirubin ≤ 1.5 x ULN

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

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2 x UNL 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:

- Prior treatment with everolimus other than in combination with hormonal therapy for
treatment of breast cancer or prior treatment with another mammalian target of
rapamycin (mTOR) inhibitor (sirolimus, temsirolimus) for any indication

- HER2 positive disease as defined by 3+ IHC or positive FISH (both in primary and
metastatic sites)

- Active infection: temperature > 100 Fahrenheit (F), fever of unknown origin, active
symptoms or signs of infection as defined by the investigator

- 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

- Hypersensitivity to trial medications (everolimus)

- Emotional limitations, which the investigator judges could limit the patient's ability
to follow up and comply with study procedures

- 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 human immunodeficiency virus (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)

- 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 (use
of steroids as part of management of everolimus toxicities will be allowed)

- Live vaccines

- Patients who have received live attenuated vaccines within 1 week of start of
everolimus and during the study; patient should also avoid close contact with
others who have received live attenuated vaccines; examples of live attenuated
vaccines include intranasal influenza, measles, mumps, rubella, oral polio,
bacillus Calmette-Guérin (BCG), yellow fever, varicella and TY21a typhoid
vaccines

- Drugs or substances known to be inhibitors or inducers of the isoenzyme
cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A)