BYL719 and Letrozole in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer

PRIMARY OBJECTIVE: To determine the safety and tolerability of BYL719 given in combination
with endocrine therapy in post-menopausal patients with hormone receptor-positive metastatic
breast cancer by determining:

I. Dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1).

II. Maximum tolerated dose (MTD) of BYL719 (PI3K inhibitor BYL719) given in combination with
letrozole.

III. Highest tolerated dose - ability to tolerate BYL719 with letrozole for a total of 8
weeks without development of:

- Hyperglycemia (fasting glucose > 200 mg/dL) for more than 2 weeks in a row despite
optimal medical treatment

- CTC Grade 3 or > rash for more than 2 weeks in a row despite optimal medical treatment

- CTC Grade 2 or > GI toxicity for more than 2 weeks in a row despite optimal medical
treatment

- CTC Grade 2 or > serum creatinine, bilirubin, AST, ALT elevation from baseline for more
than 2 weeks in a row despite optimal medical treatment

SECONDARY OBJECTIVES: To determine the anti-tumor effect of the combinations of endocrine
therapy with BYL719 in post-menopausal patients with hormone receptor-positive metastatic
breast cancer by assessing:

I. Progression free survival (PFS). II. Objective response rate (ORR). III. Clinical benefit
rate (complete response [CR]+partial response [PR]+stable disease [SD] >= 6 months).

EXPLORATORY OBJECTIVES:

I. Pharmacokinetics of BYL719 in combination with letrozole: Plasma concentration-time
profiles and derived basic pharmacokinetic (PK) parameters of BYL719 and letrozole, including
but not limited to area under the plasma concentration-time curve from time zero to the last
measurable concentration (AUC0-tlast), AUC curve to infinite time (AUC0-inf), maximum
observed concentration (Cmax), time to peak concentration (Tmax), clearance over
bioavailability (CL/F), apparent volume of distribution (Vz/F) and the terminal half-life
(t1/2) and other PK parameters if deemed appropriate.

II. Correlation of response with alterations of the PI3K pathway: Mutational analysis of
PIK3CA (exons 9 and 20), phosphatase and tensin homolog (PTEN), and AKT1 in formalin-fixed
paraffin blocks (FFPB) from previous surgeries or fresh-frozen biopsies (if available) on all
patients enrolled in the trial.

OUTLINE: This is an open-label phase Ib dose-escalation study of the PI3K inhibitor BYL719 in
combination with letrozole in post-menopausal patients with ER+ metastatic breast cancer.

Patients receive BYL719 orally (PO) once daily (QD) and letrozole PO QD. Courses repeat every
4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria

- Patients must provide informed written consent.

- Patients must be >/= 18 years of age.

- ECOG performance status 0 - 1.

- Clinical stage IV invasive mammary carcinoma, ER-positive and/or PR-positive by
immunohistochemistry (IHC) and HER2 negative (by IHC or ISH). Patients may have either
measurable or non-measurable disease, both are allowed.

- A minimum of 10 patients in the trial (~50%) will need to have a PIK3CA mutation in
their cancer

- Patients must have had at least one line of endocrine therapy in the metastatic
setting, or be diagnosed with metastatic breast cancer during or within 1 year of
adjuvant endocrine therapy. There is no limit on lines of prior treatment in the
metastatic setting.

- Patients must have available tissue (archived formalin-fixed paraffin embedded blocks
(FFPB) or fresh frozen tissue from original diagnosis or metastatic setting) for
correlative studies. Tissue needs to be located and available at the time of
registration (tissue needs to be submitted within 3 weeks of study initiation).
Patients will not be able to start study drugs without tissue availability.

- Life expectancy ≥ 6 months

- Patients must have adequate hematologic, hepatic, and renal function. All laboratory
tests must be obtained less than 1 week from study entry. This includes:

1. ANC >/= 1,500/mm3

2. platelet count >/=100,000/mm3

3. HgB ≥ 9 g/dL

4. Creatinine ≤ 1.5x ULN

5. INR ≤ 2

6. Fasting plasma glucose ≤ 140 mg/dL

7. HgBA1C ≤ 8%

8. Total Serum Bilirubin ≤ 1.5 x ULN (Patients with known Gilbert Syndrome, a total
bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)

9. SGOT, SGPT ≤ 3 X ULN if no liver metastasis present

10. SGOT, SGPT ≤ 5 X ULN if liver metastasis present

- Patients must be able to swallow and retain oral medication.

- Patients must be post-menopausal. Post-menopausal female subjects should be defined
prior to protocol enrollment by any of the following:

1. Subjects at least 55 years of age; OR

2. Subjects under 55 years of age and naturally (spontaneous) amenorrhea for at
least 12 months or follicle-stimulating hormone (FSH) values ≥ 40 IU/L and
estradiol levels
3. Prior bilateral oophorectomy; OR

4. Prior radiation castration with amenorrhea for at least 6 months

NOTE: Treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist
(such as goserelin acetate or leuprolide acetate) is not permitted for induction
of ovarian suppression.

- Patients must complete all screening assessments as outlined in the protocol.

Exclusion Criteria

- Locally recurrent resectable breast cancer.

- Any kind of malabsorption syndrome significantly affecting gastrointestinal function.

- Patients with clinically manifest diabetes mellitus (treated and/or clinical signs or
with fasting glucose >/= 140 mg/dL / 7.8 mmol/L), history of gestational diabetes
mellitus or documented steroid-induced diabetes mellitus.

- Patients who have received radiation therapy Patients who have received prior radiotherapy must have recovered from toxicity (≤
grade 1) induced by this treatment.

- Patients who have received systemic anti-cancer therapy such as chemotherapy,
immunotherapy and/or biologic therapy anti-cancer therapy (chemotherapy, immunotherapy, biologic therapy) other than the
ones specified in the protocol is not permitted during study participation. Patients
must have discontinued the above cancer therapies for 4 weeks prior to the first dose
of study medication, as well as recovered from toxicity (to ≤ than grade 1, except for
alopecia) induced by previous treatments. Any investigational drugs should be
discontinued 4 weeks prior to the first dose of study medication.

- Prior hormonal / endocrine therapy have recovered from toxicity > grade 1, except for alopecia.

- Prior therapy with a PI3K inhibitor. Prior use of Akt or mTOR inhibitors are allowed.

- Patients who have received herbal medications medications include, but are not limited to: St. John's wort, Kava, ephedra (ma
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and
ginseng.

- Use of drugs that are CYP3A4 modifiers

- Patients who are currently receiving medication with a known risk of prolonging the QT
interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be
discontinued or switched to a different medication prior to starting study drug
treatment.

- Patients with a family history of congenital long QT syndrome

- Patients with abnormal calcium, potassium, or magnesium levels that cannot be
adequately corrected to within normal range prior to initiation of study drugs

- Uncontrolled intercurrent illness including, but not limited to:

1. ongoing or active infection requiring parenteral antibiotics

2. impairment of lung function (COPD > grade 2, lung conditions requiring oxygen
therapy)

3. symptomatic congestive heart failure (class III or IV of the New York Heart
Association classification for heart disease)

4. Left Ventricular Ejection Fraction (LVEF) < 50%

5. unstable angina pectoris, angioplasty, stenting, or myocardial infarction within
6 months

6. uncontrolled hypertension within 2 weeks of study initiation (systolic blood
pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg, found on two
consecutive measurements separated by a 1 or 2-week period despite adequate
medical support)

7. clinically significant cardiac arrhythmia (multifocal premature ventricular
contractions, bigeminy,trigeminy, ventricular tachycardia that is symptomatic or
requires treatment [National Cancer Institute -Common Terminology Criteria for
Adverse Events, Version 4.0, grade 3]

8. QTcF ≥ 480 msec on screening EKG

9. known history of QT/QTc prolongation or Torsades de Pointes (TdP)

10. ST depression or elevation of ≥ 1.5 mm in 2 or more leads

11. Diarrhea of any cause ≥ CTCAE grade 2

12. psychiatric illness/social situations that would compromise patient safety or
limit compliance with study requirements including maintenance of a
compliance/pill diary

13. patients with symptomatic brain metastases (patients with a history of brain
metastases must be clinically stable for more than 4 weeks from completion of
radiation treatment)

14. patients with known history of chronic liver or renal failure

15. patients with known history of chronic or acute pancreatitis

Individuals of all races and ethnic groups are eligible for this trial. There is no bias
towards age or race in the clinical trial outlined. This trial is open to the accrual of
women.