BYL719 and Letrozole in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer
BYL719 and Letrozole in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer
This phase I trial studies the side effects and best dose of the PI3K inhibitor BYL719 when
 given together with letrozole in treating patients with hormone receptor-positive metastatic
 breast cancer. The PI3K inhibitor BYL719 may stop the growth of tumor cells by blocking some
 of the proteins needed for cell growth. Hormone therapy using letrozole may fight breast
 cancer by blocking the use of estrogen by the tumor cells. Giving the PI3K inhibitor BYL719
 together with letrozole may kill more tumor cells
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 </= 20 IU/L; OR

 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 </= 2 weeks prior to study entry.
 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 </= 4 weeks prior to study entry. Concurrent
 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 </= 2 weeks prior to study entry. Patients must
 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 </= 2 weeks prior to study entry. Herbal
 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.