Background: Immune checkpoint inhibitor monotherapy has limited efficacy in patients (pts) with previously treated advanced gastric cancer (GC). LAG-3 is upregulated in GC pts and therefore treatment targeting LAG-3 may be effective. Tebotelimab is a first-in-class, Fc-bearing bispecific tetravalent DART molecule that can bind both PD-1 and LAG-3. Meanwhile, synergistic antitumor activities of tebotelimab and niraparib, a poly (ADP-ribose) polymerase inhibitor, were demonstrated in preclinical studies. Methods: This open-label, single-arm, dose escalation and dose expansion, phase 1 trial explored dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, and preliminary antitumor activity of tebotelimab plus niraparib in pts with locally advanced or metastatic GC who failed ≥2 prior systemic treatments. The dose escalation followed a 3+3 design. Niraparib was administered orally once daily (QD) at fixed, individualized starting doses (ISD; 300 mg if baseline body weight ≥77 kg and platelet count ≥150,000/µL; 200 mg otherwise). Tebotelimab (120 mg [dose level 1], 300 mg [dose level 2], 600 mg [dose level 3]) was administered intravenously once every two weeks (Q2W) on days 1 and 15 of each 28-day cycle. The expansion cohort received RP2D. Results: At data cut-off as of 26 Feb 2022, 27 pts with metastatic GC were treated (escalation phase 12, expansion phase 15), of whom, 7.4% were PD-L1 positive (combined positive score ≥1) and 63.0% were LAG-3 positive (moderate/high expression). In the escalation phase, no DLT was observed and RP2D was determined as tebotelimab 600 mg Q2W plus niraparib ISD QD. Across both phases (n=27), the most common treatment emergent adverse events (TEAEs) included nausea (63.0%), anemia (59.3%), decreased appetite (51.9%), platelet count decreased (37.0%), hypoalbuminemia (33.3%), vomiting (33.3%), aspartate aminotransferase increased (29.6%), constipation (29.6%), and weight decreased (29.6%). Grade ≥3 TEAEs occurred in 18 pts (66.7%) and serious adverse events in 12 (44.4%), with no treatment-related death. Immune-related TEAEs occurred in 15 pts (55.6%), with hypothyroidism in five (18.5%), and arthralgia, hyperthyroidism, immune-related thyroiditis, and rash each in two (7.4%). In pts with target lesions on RP2D (n=19), one confirmed partial response per RECIST v1.1 was observed and nine pts had stable disease, with a 5.3% overall response rate and a 52.6% disease control rate. In pts on RP2D (n=21), medians for progression-free survival and overall survival were 2.7 and 6.5 months, respectively, after a median follow-up of 7.7 months. Conclusions: Tebotelimab plus niraparib preliminarily demonstrated an acceptable safety profile in pts with metastatic GC, however with limited antitumor activity. No further clinical trials are planned. Clinical trial information: NCT04178460.