BYL719 and Nab-Paclitaxel in Locally Recurrent or Metastatic HER-2 Negative Breast Cancer

Breast cancer is the most common cancer and the second leading cause of cancer related death
in American women. Despite recent improvement in the treatment of breast cancer, 40,000 women
still die each year in the US as a result of breast cancer. Chemotherapy (usually consisting
of sequential single agent) remains the backbone of treatment for patients with HER-2
negative metastatic breast cancer. A majority of patients show an initial response to
treatment, but all eventually show disease progression.

The purpose of this study is to determine the highest dose of BYL719 combined with
Nab-Paclitaxel that results in no serious side effects. The safety and effectiveness of
BYL719 combined with Nab-Paclitaxel to treat patients with HER-2 negative breast cancer will
be assessed, along with the determination of how long this drug combination will keep the
disease from getting worse.

The study will be done in two parts:

Part 1 will determine the highest dose of BYL719 that is safe and tolerable to take in
combination with Nab-Paclitaxel. Part 1 will be completed before Part 2 begins.

Part 2 will investigate taking BYL719 (at the dose determined in Part 1) + Nab-Paclitaxel is
safe and effective for patients with HER-2 negative breast cancer.

Inclusion Criteria:

- HER-2 negative breast cancer that is either stage III disease not amenable to curative
therapy or stage IV

- Have measurable disease of ≥ 2 cm by conventional measurement or ≥ 1 cm on spiral CT

- Prior chemotherapy for metastatic disease is allowed. No limitations to number of
prior chemotherapies. Prior taxanes (except Nab-Paclitaxel) is allowed if it has been
≥ 6 months since prior taxane. NOTE: For subjects who are, or who have previously
received, endocrine therapy for breast cancer, the treating investigator will decide
how many days should pass between the last dose of endocrine therapy and the first
dose of study treatment.

- All patients should have received at least one line of chemotherapy in either the
advanced or adjuvant setting and hormonal therapy (where appropriate)

- ECOG Performance status ≥ 2

- Subject is able to swallow and retain oral medicines

- Laboratory values as follows:

- Absolute neutrophil count ≥ 1500/uL

- Platelets 100,000/uL (no transfusion ≤ 2 weeks)

- Hemoglobin > 9 g/dL (may be reached by transfusion)

- Total bilirubin within normal range or ≤ 1.5X IULN if liver metastases

- Total bilirubin ≤ 3.0X IULN with direct bilirubin within normal range in subjects
with Gilbert's Syndrome

- AST(SGOT)/ALT(SPGT) ≤ 2.5X IULN or ≤ 5X IULN if liver metastases

- Serum creatinine ≤ 1.5X IULN

- INR ≤ 1.5

- Fasting plasma glucose ≤ 140 mg/dL or 7.8 mmol/L

- HBA1c ≤ 8%

- Potassium, calcium (corrected for serum albumin) & magnesium within IULN

- IV bisphosphate and denosumab for bony metastatic disease will be allowed

- Radiation to bony metastases is allowed ≥ 14 days before starting study treatment

- Subjects with previously treated brain metastases who are free of CNS symptoms and > 3
months from treatment are eligible

- Subjects should be > 2 weeks from last chemotherapy for breast cancer AND be recovered
to Grade 1 from related side effects

NOTE: Subjects who have had previous treatment with Nab-Paclitaxel will NOT be excluded if
given in the adjuvant or neoadjuvant setting Only in the metastatic setting, will subjects
previously treated with Nab-Paclitaxel be excluded from this trial.

- Women of child bearing potential and their partners must use contraception prior to
study entry, continuing for 90 days after treatment

Exclusion Criteria:

- Other medical or psychiatric disorder placing the subject at undue risk for treatment
complications

- Subject is pregnant or nursing

- Subject has been treated with Nab-Paclitaxel NOTE: Subjects who have had previous
treatment with Nab-Paclitaxel will NOT be excluded if given in the adjuvant or
neoadjuvant setting.

NOTE: Only in the metastatic setting, will subjects previously treated with Nab-Paclitaxel
be excluded from this trial.

- Subject has inflammatory breast cancer

- Subject has a known hypersensitivity to Nab-Paclitaxel or BYL719

- Subject has a concurrent malignancy or malignancy within 3 years, except for
basal/squamous cell carcinoma, non-melanoma skin cancer or curatively resected
cervical cancer

- Subject has diabetes mellitus or steroid-induced diabetes mellitus

- Subject has impaired gastrointestinal function or disease altering the absorption of
study drugs

- Subject is classified into Child-Pugh class C

- Subject has a known history of HIV infection (testing not mandatory)

- Subject has an active and uncontrolled infection

- Subject has symptomatic/untreated CNS disease

- Subject has ≥ Grade 2 peripheral neuropathy

- Subject has active or history of cardiac disease including:

- Unstable angina within 6 months before study entry

- Symptomatic peritonitis

- Documented heart attack within 6 months before study entry

- History of congestive heart failure (New York Heart Association functional
classification III-IV)

- Documented cardiomyopathy

- Left Ventricular Ejection Fraction (LVEF) < 50% measured by Multiple Gated
Acquisition (MUGA) scan or echocardiogram (ECHO)

- Subject has any of the following cardiac abnormalities

- Ventricular arrhythmias except benign premature contractions

- Other arrhythmias requiring a pacemaker or not controlled with medicine

- Conduction abnormality requiring a pacemaker

- Subject has a QTcF > 480 msec on the screening ECG

- Subject must continue to take a drug that causes ECG abnormalities or induces Torsades
de Pointes

- Subject had major surgery within 14 days before starting study drug or has not
recovered from major side effects

- Subject is taking or has taken systemic corticosteroids ≤ 2 weeks prior to starting
study drug or have not fully recovered from side effects

- Subject is taking drugs known to be inhibitors or inducers of CYP3A.

- Subject is taking warfarin or other coumarin-derived anti-coagulant. Therapy with
heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed

- Patient has received previous treatment with a PI3K inhibitor. Exceptions may be made
for subjects who discontinued treatment with a previous PI3K inhibitor for reasons
other than toxicity or progression and as long as it has been > 12 months since
discontinuation of the previous PI3K inhibitor. This exception will require prior
approval from the study PI.

- Subjects having participated in a clinical trial within 30 days prior enrollment