Phase III Study of Atamestane Plus Toremifene Versus Letrozole in Advanced Breast Cancer

Breast cancer cells are often very dependent on estrogens to continue to grow. Atamestane
blocks the formation of estrogens and androgenic precursors in the body. Toremifene blocks
circulating and intracellular estrogens from stimulating estrogen receptors in breast cancer
cells. The goal of therapy with atamestane, an aromatase inhibitor, in combination with the
estrogen receptor antagonist, toremifene, is to achieve maximal suppression of estrogen
stimulation of breast cancer cells. This study is designed to determine whether combination
therapy will lengthen the time to disease progression and the rate of objective response
compared to single agent aromatase inhibitor therapy with letrozole.

Inclusion Criteria:

- Women age 18 years or older

- Pathological or histological confirmation of breast cancer at initial diagnosis or at
the time of metastases

- ECOG performance status of 0, 1 or 2 or Karnofsky performance status of 60 or higher

- Predicted life expectancy of 12 weeks or more

- Postmenopausal endocrine status. LH/FSH levels in the postmenopausal range in women
whose menopause occurred less than 5 years ago

- Locally recurrent, locally advanced, locally metastatic disease not amenable to
radiation therapy or surgery and/or distant metastatic disease

- At least one tumor localization measurable in 2 dimensions (one diameter at least 2
cm for soft tissue/visceral disease assessed by CT/MRI scan or conventional X-ray
technique, one diameter at least 1 cm for bone lesions assessed by conventional X-ray
techniques)

- Estrogen receptor and/or progesterone receptor positive (by laboratory/institutional
standard) at the time of initial diagnosis or determined during subsequent
biopsy/surgery of metastases

- Written informed consent obtained

Exclusion Criteria:

- Prior hormonal therapy to treat locally recurrent, locally advanced or metastatic
disease

- Prior adjuvant therapy with aromatase inhibitors or antiestrogens/SERMs within 12
months prior to enrollment

- Progression of disease during therapy with antiestrogens (including SERMs
administered for prevention of osteoporosis)

- Life-threatening locally recurrent, locally advanced or metastatic disease or disease
requiring chemotherapeutic intervention (such as inflammatory breast cancer)

- History of known CNS metastases, significant neurological dysfunction including
active seizures, or clinical signs of other significant neurological diseases

- Other active malignancy (except basal cell carcinoma of the skin or in situ cervical
cancer). Patients with previous malignancies must be without evidence of disease for
at least five years

- Renal insufficiency (serum creatinine > 2.0 mg/dL)

- Aspartate aminotransferase, alanine aminotransferase or serum bilirubin levels more
than 2.5 times upper limit of normal

- Hemoglobin <9 g/dL

- Platelet count of less than 100,000 platelets per mm3

- Total white blood cell count of less than 2,000 cells per mm3

- Premenopausal endocrine status; pregnant or lactating females

- Usage of an investigational drug within the thirty (30) days prior to enrollment; or
the planned usage of an investigational drug other than the study medication during
the course of the current study

- Contraindication to use of toremifene, atamestane, letrozole or any of the inactive
components of their formulations

- Prior enrollment in this study