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

The purpose of this study is to determine whether the first line combination hormonal therapy of an experimental drug, atamestane, plus an FDA-approved drug, toremifene (Fareston®), is more effective than another approved drug, letrozole (Femara®), in delaying the growth of breast cancer in postmenopausal patients with locally advanced or metastatic breast cancer, and whether the side effects of the combination are different from the side effects of letrozole.

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.

Eligibility Criteria:
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