Background: Novel combination therapies are needed to extend survival in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Magrolimab is a monoclonal antibody that blocks CD47, a "don't eat me" signal often overexpressed on HNSCC cells. CD47 blockade by magrolimab induces macrophage-mediated phagocytosis of tumor cells and has shown preclinical activity and promising clinical efficacy in hematologic malignancies. Certain chemotherapies, including taxanes, enhance prophagocytic signals on tumor cells, leading to potential synergistic antitumor activity when combined with magrolimab. This study is evaluating the safety, tolerability, and efficacy of magrolimab combination therapy in pts with RM-HNSCC. Methods: This open-label study includes 2 safety run-ins and 2 phase (ph) 2 cohorts. Safety run-in 1 includes pts with RM-HNSCC untreated in the RM setting to receive magrolimab + pembrolizumab (pembro) + platinum (cisplatin or carboplatin) + 5-fluorouracil (FU); safety run-in 2 enrolls pts with locally advanced or RM-HNSCC treated with 1-2 lines of prior systemic therapy in the locally advanced or RM setting who received magrolimab + docetaxel. Magrolimab is given intravenously as a 1-mg/kg priming dose on cycle 1 day 1 (C1 D1) to mitigate on-target anemia and 30 mg/kg on D8 and D15. Magrolimab 30 mg/kg is given on C2 D1, D8, and D15 and 60 mg/kg on D1 of C3+. Once the recommended ph 2 dose is determined, the ph 2 cohorts will follow the same dose schedules. In ph 2 cohort 1, pts receive magrolimab + pembro + platinum + 5-FU (arm A), pembro + platinum + 5-FU (arm B), or magrolimab + zimberelimab (anti-PD-1) + platinum + 5-FU (arm C). Pts enrolled in ph 2 cohort 3 receive magrolimab + docetaxel. An optional safety run-in and ph 2 cohort (cohort 2) of magrolimab + pembro in PD-L1+ RM-HNSCC may be opened at sponsor’s discretion. Pembro, platinum, 5-FU, and docetaxel are given per standard of care. Reasons for treatment discontinuation may include unacceptable toxicity or disease progression. Safety is monitored throughout the study. Primary endpoints of the safety run-ins cohorts were incidence of adverse events and dose-limiting toxicities per CTCAE v5.0. Primary endpoints for the Ph 2 cohorts are progression-free survival (PFS) by independent central review (cohort 1 arm A vs B) and investigator-assessed objective response rate (ORR) by RECIST 1.1 (cohorts 2, 3). Secondary endpoints include magrolimab pharmacokinetics and antidrug antibodies (safety run-in, ph2 all cohorts), ORR assessed by independent central review, investigator-assessed PFS by RECIST 1.1 (all cohorts) and overall survival (all cohorts), duration of response, and pt-reported outcomes. Planned enrollment is ≈230 pts. Clinical trial information: NCT04854499.