Phase 1 of this study will evaluate the maximum tolerated dose (MTD) of XL147 when given in combination with letrozole (Femara) and of XL765 when given in combination with letrozole. After the MTD is established for each combination (Phase 2), subjects will be enrolled to evaluate the preliminary efficacy and safety of these combinations in subjects with breast cancer refractory to a non-steroidal aromatase inhibitor that is ER+/PGR+ and HER2-. Letrozole is used in the treatment of different types of breast cancer, but patients can develop resistance.

Upregulation of PI3K activity is one of the most common characteristics of human cancer cells, including breast tumor cells. Activation of PI3K results in stimulation of AKT and mTOR kinases, resulting in the promotion of tumor cell proliferation and survival. Preclinical and retrospective clinical data suggest that aberrant activation of the PI3K pathway may play a role in aromatase inhibitor resistance in patients with ER+, HER2- breast cancer. XL147 is a potent inhibitor of PI3K, and XL765 is a potent dual inhibitor of PI3K and mTOR; therefore either of these compounds in combination with letrozole warrants clinical investigation.

Inclusion Criteria:

• The subject has histologically confirmed breast cancer that is ER+ and/or PGR+.
• The subject's breast cancer is negative for HER2.
• The subject has recurrent or metastatic breast cancer that is refractory to a nonsteroidal aromatase inhibitor and has either disease progression or disease recurrence.
• Subjects previously treated with letrozole must be able to tolerate the approved dose and schedule of letrozole.
• For subjects enrolled in Phase 2, either archival tumor samples must be available, or the subject must be willing to undergo a fresh biopsy.
• In Phase 2, at least 30 subjects in each arm must have measurable disease
• The subject is a postmenopausal female.
• If a subject is currently receiving bisphosphonates, the subject must have received the bisphosphonates for at least 2 months before starting study treatment.
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
• The subject has adequate organ and marrow function.
• The subject has no other diagnosis of malignancy or evidence of other malignancy for 2 years before screening for this study (except non-melanoma skin cancer or in situ carcinoma of the cervix).
• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.

Exclusion Criteria:

• The subject has received prior treatment with a selective inhibitor of PI3K, AKT, and/or mTOR.
• Certain restrictions on prior therapies apply.
• The subject has not recovered from toxicity due to prior therapy to Grade ≤ 1 or to pre-therapy baseline.
• The subject has untreated, symptomatic, or progressive brain metastases.
• The subject has only non-measurable lesions, other than bone, skin, or chest wall metastasis
• The subject has to start cytotoxic chemotherapy due to rapid progressive disease involving major organs.
• The subject has prothrombin time/ International Normalized Ratio (PT/ INR) or partial thromboplastin time (PTT) test results at screening that are above 1.3 x the laboratory upper limit of normal.
• The subject has uncontrolled significant intercurrent illness.
• The subject has a baseline corrected QT interval (QTc) > 470 ms.
• The subject has a diagnosis of uncontrolled diabetes mellitus.
• The subject is known to be positive for the human immunodeficiency virus (HIV).
• The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation(s).
• The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.