Background: Eftilagimod alpha (efti), a soluble LAG-3 protein, acts as an MHC class II agonist that enhances immunity by mediating antigen presenting cell and CD8 T-cell activation. Data from a randomized, phase 2b trial of efti plus paclitaxel compared to placebo plus paclitaxel in patients (pts) with HR+ HER2– metastatic breast cancer (MBC) (AIPAC; NCT02614833) showed sustained pharmacodynamic activity that was linked to improved overall survival (OS) in the efti arm. AIPAC-003 is a randomized, double-blind, placebo-controlled phase 3 trial testing efti plus paclitaxel in HER2-neg/low MBC pts, including an initial open-label dose optimization lead-in (DOL) component to determine the optimal biological dose (OBD) of efti in this combination. Methods: Enrolment for the DOL will begin in March 2023 in max. 66 pts. Primary endpoints (EP) in the DOL include safety and tolerability of 90 mg vs 30 mg efti and defining the OBD of efti in combination with weekly paclitaxel. Determination of the OBD will be based on the totality of safety and tolerability data together with overall response rate (ORR) and pharmacodynamic marker (CD8+ T cells, absolute lymphocyte count) data. In the Phase 3 component approx. 771 pts are randomized to receive either paclitaxel + efti or paclitaxel + placebo in a double-blinded fashion. The primary EP for the proposed Phase 3 is OS. Key secondary EPs include progression free survival and ORR by RECIST 1.1, quality of life and safety. Pts will receive paclitaxel (80 mg/m² I.V. on D1, 8 and 15 in a 4-week cycle), followed by efti or placebo (DOL: 30 or 90 mg efti; Phase 3: OBD of efti or placebo) S.C. on D1 and 15 in a 4-week cycle for up to 12 months. Key inclusion criteria: Pts with either a) HR+ and HER2-neg/low and endocrine therapy-resistant MBC or b) TNBC not eligible for anti-PD-1-based therapy. Pts must have measurable disease, ECOG PS 0-1 and no prior chemo for metastatic disease.