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Patients receive PI3K inhibitor BYL719 PO QD and letrozole PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

PI3K inhibitor BYL719

letrozole

laboratory biomarker analysis

pharmacological studies

Ingrid Mayer

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.

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

A Phase Ib Trial of BYL719 (an α-Specific PI3K Inhibitor) in Combination With Endocrine Therapy in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer

Highest dose of BYL719 tested in which a DLT is experienced by 0 out of 3 or 1 of 6 patients, based on the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0

Highest dose of BYL719 without CTC Grade \> 2 hyperglycemia(fasting glucose \> 200 mg/dL) for \> 2 weeks, Grade \> 3 rash for \> 2 weeks , Grade \> 2 gastrointestinal toxicity for \> 2 weeks and Grade \> 2 creatinine, bilirubin, AST, ALT for \> 2 weeks.

Per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD) for more than 6 months.

Duration from on-study date to date of progressive disease.

Per RECIST version 1.1. number of patients each with CR, PR, SD, and progressive disease (PD) as their best response.

Number of patients with worst-grade toxicity at each of five grades (grade 1, least severe; to grade 5, most severe) following NCI Common Toxicity Criteria 4.0.

National Cancer Institute (NCI)

Vanderbilt-Ingram Cancer Center

Assistant Professor of Medicine

Spots Global Cancer Trial Database for pi3k inhibitor byl719