Background: Postmenopausal women with advanced ER+ BC are usually treated with aromatase inhibitors (AIs) as first-line therapy but resistance eventually develops. Dysregulation of the PI3K pathway and cyclin D kinases 4 and 6 (CDK4/6) has been implicated in resistance to endocrine therapy. LEE011 (a selective CDK4/6 inhibitor) and BYL719 (an α-selective PI3K inhibitor) demonstrate clinical activity in ER+ BC as single agents. In ER+ BC xenograft models, LEE011 has demonstrated enhanced antitumor activity when combined with BYL719 and letrozole versus each agent alone, suggesting this combination may optimize treatment in ER+ BC. In the ongoing Phase Ib part of this study (NCT01872260), two doublet combinations, LEE011 + letrozole (Arm 1) and BYL719 + letrozole (Arm 2), and the triplet combination of LEE011 + BYL719 + letrozole (Arm 3), are explored in patients with ER+ BC. Methods: Postmenopausal women with locally advanced/metastatic ER+, HER2− BC not amenable to curative treatment by surgery/radiotherapy receive escalating doses of oral LEE011 QD (3-wks on/1-wk off) or BYL719 QD (continuous) and a fixed dose of letrozole QD (2.5 mg, continuous) in 28-day cycles. The primary objective is to estimate the MTD and/or RP2D of each combination by assessing DLTs in Cycle 1 using an adaptive Bayesian Logistic Regression Model (BLRM) guided by the escalation with overdose control (EWOC) principle. Secondary objectives include safety, PK and preliminary efficacy assessments. Results: As of Jan 31, 2014, 6 patients have been treated in Arm 1 (LEE011 600 mg + letrozole), and 1 DLT (G4 neutropenia) has been reported. Five patients have started treatment in Arm 2 (BYL719 300 mg + letrozole). Preliminary PK data are consistent with that for the respective single agents, with no evidence of drug–drug interactions. Conclusions: AIs are recommended as first-line endocrine therapy in postmenopausal patients with advanced ER+, HER2− BC, but most patients develop resistance. This is the first trial evaluating an AI in combination with a PI3K and CDK4/6 inhibitor in ER+, HER2− BC. Phase II will compare the preliminary antitumor activity of the doublets vs. triplet combinations. Clinical trial information: NCT01872260.