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

Summary

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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...

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.

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