A Phase 1/2 Study of XL147 (SAR245408) Administered in Combination With Trastuzumab or Paclitaxel and Trastuzumab in Subjects With Metastatic Breast Cancer Who Have Progressed on a Previous Trastuzumab-Based Regimen

Inclusion Criteria:

- The subject has pathologically and radiologically confirmed metastatic HER2 positive
breast cancer (Stage IV disease). Subjects must have received and progressed on at
least one prior trastuzumab-containing regimen for metastatic disease. For subjects
in Arm 2, they must also have received at least one prior taxane-containing regimen.

- The subject has at least one lesion that is not within a previously radiated field
and measurable on computerized tomography (CT) or magnetic resonance imaging scan
(MRI)

- The subjects enrolled in Phase 2 must be willing to undergo a biopsy of the primary
tumor or a tumor metastasis at baseline, if tumor tissue is amenable to biopsy

- The subject's primary tumor and/or metastatic lesion must overexpress HER2

- For subjects enrolled in Phase 2: samples from archival or fresh tissue, or a tissue
block of the subject's tumor.

- The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤
2

- The subject has adequate organ and marrow function

- The subject is capable of understanding the informed consent and complying with the
protocol and has signed the informed consent document prior to any study-specific
screening procedures or evaluations being performed.

- Sexually active subjects must agree to use a medically-accepted barrier method of
contraception during the course of the study and for 3 months following
discontinuation of study treatments. For subjects using oral contraceptives, a
barrier method must be used in addition to the oral contraceptive

- Subjects of childbearing potential must have a negative pregnancy test at screening
and enrollment

Exclusion Criteria:

- The subject has previously been treated with a selective inhibitor of PI3K and / or
AKT

- 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. Any
corticosteroid use for brain metastases must have been discontinued without the
subsequent appearance of symptoms for ≥4 weeks prior to first study treatment

- The subject has prothrombin time/International Normalized Ratio (PT/INR) or partial
thromboplastin time (PTT) test results at screening that are ≥ 1.3 times above the
laboratory upper limit of normal

- The subject has a diagnosis of uncontrolled diabetes mellitus

- The subject has uncontrolled significant intercurrent illness

- The subject has uncontrolled hypertension or other clinically significant
cardiovascular disease

- The subject has left ventricular ejection fraction (LVEF) ≤ 50%

- The subject has a baseline corrected QT interval ≥ 460 ms

- The subject is currently receiving anticoagulation with therapeutic doses of warfarin
(low-dose warfarin ≤ 1mg/day is permitted)

- The subject is pregnant or breastfeeding

- The subject is known to be positive for the human immunodeficiency virus (HIV) (a
test for HIV at screening is not required)

- The subject has any other diagnosis of malignancy or evidence of malignancy (except
non-melanoma skin cancer, in situ carcinoma of the cervix) within 2 years prior to
screening for this study

- The subject has a previously identified allergy or hypersensitivity or is intolerant
to components of any of the study treatment formulations

- The subject is unable or unwilling to abide by the study protocol or cooperate fully
with the investigator or designee