Background: Standard therapy for HR+/HER2- MBC includes a CDK 4/6i with endocrine therapy (ET). Eventual resistance results in progression of disease (PD). A potential mechanism of CDK4/6 resistance is through Src activation. Targeting Src and ET suppresses proliferation of ER+ hormone independent breast cancer cells. Therefore, adding bos, a Src inhibitor, to palbo + fulv may overcome this resistance and restore sensitivity to CDK4/6i. Methods: This is a single arm, 3+3 dose escalation phase I trial (NCT 03854903) of bos + palbo + fulv for pts with HR+/HER2- MBC who have PD after ≥ 1 AI, ≥ 1 CDK4/6i, and < 3 lines of chemo for MBC. Pts were enrolled in two cohorts, A and B, with two dose levels in cohort B. Fulv was given at standard dose. Cohort A: bos 300mg (D1-5/wk), palbo 75mg D1-21 q28 days, fulv; cohort B1: bos 300mg (D1-5/wk), palbo 100 mg D1-21 q28 days, fulv; cohort B2: bos 500mg (D1-5/wk), palbo 100 mg D1-21 q28 days, fulv. Primary objective was safety and tolerability, including MTD and recommended phase 2 dose (RP2D). Secondary objectives included ORR, and CBR 24 wks. Serum, plasma, and peripheral blood mononuclear cells were collected for Src activation, cell cycle profile arrays, and cytokine array screens. Results: 18 evaluable pts were enrolled between 4/2019 – 11/2022. To date, 16pts have completed and 2 pts remain on treatment. All pts had received prior palbo and 15/18 (83%) had received prior fulv. Median number of prior therapies in the metastatic setting was 3.2. The combination in cohort A and B1 was well tolerated. The combination in cohort B2 (bos 500mg D1-D5/wk) was toxic which resulted in bos dose reduction in all pts in the B2 cohort. There were no DLTs. The RP2D was bos 300 mg D1–5/wk, palbo 100 mg D1-21 q28 days, and standard dose fulv. No pts came off treatment due to adverse events (AEs). Most common AEs were G1/2 (9 pts) and G3/4 (7 pts) neutropenia (no neutropenic fever); G1 nausea (8 pts); G1/2 (12pts) and G3 (1pt) diarrhea; G1/2 rash (4 pts), and no G5 events. Median PFS was 5.9 months with 95% CI (3, 10.1). CBR at 6 months was 50% (9/18) (95% CI (0.26, 0.74)). The ORR was 6% (0 CR, 1 PR cohort B2), but best response was SD in 11 pts. Correlative studies underway include assessment pre and post treatment of 1) Src levels and activity to confirm that bos is acting on target and 2) RNA sequencing of Src activation and cell cycle profiles and 3) cytokine array screens to test if Bos affects inflammatory markers. Conclusions: Bos + palbo + fulv was well tolerated at the RP2D. A robust CBR of 50% was seen despite all patients having prior PD on palbo and 83% on fulv. This is an effective combination for HR+/HER2- MBC which warrants further investigation and may represent a mechanism to overcome resistance to CDK4/6i and provide another oral treatment option. Clinical trial information: NCT03854903.