Background: Although adding a CDK4/6i to endocrine therapy (ET) has proved to prolong progression-free survival in patients (pts) with HR+/HER2- MBC, it is unclear if continuing a CDK4/6i, together with subsequent lines of ET, is beneficial. Preclinical data showed that the combination of PI3K inhibitors and CDK4/6i are synergistic, and could restore sensitivity to both CDK4/6i and ET. We present phase Ib data of PALBO + EVE + EXE in pts with HR+/HER2- MBC. Methods: In this phase Ib/II study (NCT02871791), pts received escalating doses of PALBO (once daily, days 1–21 of 28-day cycle) + EVE (5 mg/d) + EXE (25 mg/d). Eligible pts had HR+/HER2- MBC, with measurable disease, and prior progression on any CDK4/6i and a non-steroidal aromatase inhibitor. Pts may have received any number of prior lines of ET, and 0-1 prior line of chemotherapy. Exclusion criteria included prior intolerance to 125mg of PALBO and prior use of mTORi or EXE. The primary objective of the phase Ib was to evaluate the safety, tolerability, and to define the maximal tolerated dose (MTD)/recommended Phase II dose (RP2D) of the triplet. Secondary objectives included PK analyses and characterization of genomic alterations by circulating tumor DNA (ctDNA). Results: 9 pts were treated on the phase 1 portion of the trial. In the first dose level of PALBO (100mg), 1 out of 3 pts experienced a DLT (G3 neutropenia and G2 mucositis). None of the 3 pts subsequently enrolled had a DLT. PALBO dose was escalated 125mg, and all the 3pts had a DLT (all had G3 neutropenia). PALBO 100mg/d (21 of 28 days) was declared the MTD. Most common G3/4 treatment-related adverse events were neutropenia (77%), and thrombocytopenia (22%). Five pts developed G2 oral mucositis; prophylactic oral dexamethasone rinse was not mandatory. The RP2D was PALBO 100mg/d (21 of 28 days), EVE 5mg/d, and EXE 25mg/d. PK analysis and genomic alterations seen in ctDNA will be presented. Conclusions: The triplet combination of PALBO 100mg/d (21 of 28 days) + EVE 5mg/d + EXE 25mg/d is safe in pts with HR+/HER2- MBC. The phase II portion of this trial is ongoing. Clinical trial information: 02871791.