Background: The majority of women with ER+ MBC develop resistance to ET. ET plus a CDK4/6 inhibitor (CDKi 4/6) demonstrate improved progression-free survival (PFS) in first/later line MBC. Preclinical evidence in PI3K mutant cell-line xenografts (PIK3CA) supported developing a triplet combination of gedatolisib (G), a dual inhibitor of PI3K/mammalian target of rapamycin (mTOR), with CDKi 4/6 palbociclib (P)+letrozole (L) or fulvestrant (F) for patients (pts) with ER⁺/HER2^- MBC. Methods: This ongoing dose escalation/expansion study in pts with ER⁺/HER2^- MBC, in first/later line MBC, evaluates dose-limiting toxicities/recommended phase 2 dose (DLTs/RP2D) for triplet regimens of G+P+L or G+P+F. A 3-arm expansion investigates objective response rate (ORR) compared to historical controls of Arm A) G+P+L in first-line, B) G+P+F in pts with no prior CDKi 4/6 in second-line and C) G+P+F in pts with prior CDKi 4/6. Pts receive G (180 mg IV/week) combined with P+L or P+F at standard of care doses. Secondary endpoints include safety, ORR, PFS, and pharmacokinetics (PK); exploratory endpoints include genomic analysis of PI3K/mTOR pathway. Results: 35 pts received G at RP2D of 180 mg with P+L (n = 15) or P+F (n = 20). Median numbers of prior therapies: G+P+L: 2 (range: 1-2); G+P+F: 1 (range 1-3). Most common (≥50%), drug-related adverse events (%): G+P+L: nausea (80), stomatitis (73), fatigue (60), neutropenia (60), dysgeusia (53); G+P+F: stomatitis (70), fatigue (70), neutropenia (60), nausea (60), dysgeusia (55). Cycle 1 DLTs: G+P+L: grade (gr) 3 neutropenia (n = 2), gr 3 stomatitis (n = 1), gr 3 febrile neutropenia (n = 1); G+P+F: gr 3 stomatitis (n = 2), gr 3 mucositis (n = 1), gr 3 abdominal pain (n = 1). Preliminary stable disease/partial response: G+P+L: 53%/33%; G+P+F: 55%/20%. No PK interactions were observed. PIK3CA and ER mutation status from circulating free deoxyribonucleic acid and duration of response will be reported. Genomic analysis of tumor tissue is underway. Conclusions: G can be combined with P+L or P+F with manageable toxicity and promising preliminary antitumor activity. Dose escalation is completed and expansion is ongoing. Clinical trial information: NCT02684032