Background: Activation of the PI3K/AKT/mTOR and cyclin D–CDK4/6–INK4–Rb pathways has been implicated in endocrine therapy resistance in pts with advanced HR+ breast cancer (BC). BYL719 (BYL), an α-isoform selective PI3K inhibitor and LEE011 (LEE), a CDK4/6 inhibitor have demonstrated clinical activity in pts with advanced HR+ BC and advanced solid tumors, respectively. In preclinical HR+ BC models, the combination of LEE, BYL, and letrozole (LET) had enhanced antitumor activity vs either agent alone. Here we report results from Arm (A)1 (LEE + LET) and A2 (BYL + LET) of the Ph Ib part of a Ph Ib/II, 3-arm study of LEE, BYL, and LET in pts with advanced ER+ BC (CLEE011X2107/NCT01872260). Methods: Postmenopausal women with advanced ER+, HER2− BC receive daily oral doses of LEE (3-wks on/1-wk off; A1) or BYL (continuous; A2), plus fixed, daily LET (2.5 mg, continuous), as part of a 28-day cycle. Primary objective: determine the MTD and/or RP2D of A1 and A2. Dose escalation is guided by a Bayesian Logistic Regression Model using the escalation with overdose control principle and real-time PK. Safety and preliminary efficacy are also assessed. Results: As of March 28, 2014, 10 pts have been treated with 600 mg LEE + LET (A1), and 7 pts with 300 mg BYL + LET (A2). One DLT was observed (A1: Grade [G]4 neutropenia; data cut-off: May 15). Common (all grade >30%) study drug-related AEs (all grade/G3–4) were: A1: neutropenia (90%/50%) and nausea (40%/0%); A2: hyperglycemia (57%/14%), decreased appetite, diarrhea, and nausea (43%/0% each). PK for LEE and BYL on Days 1 and 21, and LET on Day 1, are comparable to historic single-agent data. PK of LET at steady state is being evaluated. In A1, 6 pts had known responses: 1 PR, 2 SD, 1 NCRNPD, and 2 PD. In A2 5 pts had known responses: 2 SD, and 3 NCRNPD. Conclusions: LET plus LEE or BYL had an acceptable safety profile and preliminary signs of clinical activity have been observed. Upon determination of the MTD/RP2D in A1 and A2, enrollment into A3 (LEE + BYL + LET) will commence. The randomized Ph II part of the trial will compare LET + LEE or BYL with LET + LEE + BYL. MONALEESA-2 (CLEE011A2301/NCT01958021), a Ph III, randomized, double-blind, placebo-controlled study of LEE + LET in untreated advanced HR+ BC is currently recruiting pts. Clinical trial information: NCT01872260.