Combination of Letrozole, Everolimus and TRC105 in Postmenopausal Women With Hormone-Receptor Positive and Her2 Negative Breast Cancer

A Phase I/II Study of Preoperative (Neoadjuvant) Combination of Letrozole (Femara), Everolimus (Afinitor), and TRC105 in Postmenopausal Women With Newly Diagnosed Local or Locally Advanced Potentially Resectable Hormone-Receptor Positive and Her2 Negative Breast Cancer

This study will test how well a new combination of three drugs (Letrozole, Everolimus, and TRC105) is tolerated and how well it works in Stage 2 and 3 breast cancer when given prior to definitive surgery. Letrozole blocks the estrogen receptor expressed by many breast cancers while everolimus blocks signals that drive cancer cells to grow. TRC105 is an investigational drug that blocks the formation and growth of blood vessels that feed the cancer and promote its growth. The goal of this study is to investigate the safety and efficacy of this multitargeted approach in breast cancer.

In postmenopausal women with hormone receptor-positive and Her2 negative non-metastatic breast cancer, downstaging or the achievement of a complete pathologic remission before definitive surgery has been associated with the lowest risk of recurrence of breast cancer. In order to achieve a better response in these patients in the preoperative setting, this study combines 3 potentially synergistic agents. Letrozole blocks the synthesis of estrogens and, in doing so, deprives the tumor from hormones which drive its growth. Everolimus is a drug that blocks growth factor signaling which is essential for tumor cells to maintain their growth and proliferation. Everolimus has already been shown to work very well in this subtype of breast cancer in the recurrent and metastatic setting. TRC105 is an investigational agent that prevents the formation and growth of new blood vessels that support tumors by providing oxygen and nutrients.

The study has 2 components. First the investigators will determine the ideal in terms of tolerance combination of doses of the 3 agents. Once the ideal regimen is determined, more patients will be treated with the investigational combination. During this second stage, the investigators will get a preliminary idea of how effective the investigational therapy is. Further studies will need to be done to confirm the efficacy of the investigational combination.

Inclusion Criteria:

• Recent diagnosis of hormone receptor positive and HER2 negative breast cancer.
• Stage 2 and 3 hormone receptor positive and HER2 negative breast cancer (stage T2-4 but not inflammatory, N0-2, M0).
• Histological grade I, II or III according to the modified Bloom Richardson scale.
• No prior treatment specific for breast cancer.
• Postmenopausal status as defined by the National Comprehensive Cancer Network.
• ECOG performance status < 2 (Karnofsky > 60%).
• Must have signed study-specific informed consent.
• Liver Function Tests < 2.5 times the upper normal limit (UNL).
• ANC ≥ 1,500/mm3, platelets ≥ 100,000/mm3, Hemoglobin ≥ 10g%.
• Renal function: serum creatinine < 1.5 institutional UNL or creatinine clearance > 40 cc/min.

Exclusion Criteria:

• Inflammatory breast cancer.
• Pre- and peri-menopausal state.
• Pregnancy.
• Metastatic disease.
• HER2 positive breast cancer by immunohistochemistry or FISH.
• Triple negative breast cancer (hormone receptor and Her2 negative).
• Disease that cannot be followed by imaging studies.