Background: GB1275 is a first-in-class, oral CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs), repolarized M2 immunosuppressive TAMs to an M1 phenotype, resulting in increased tumor infiltration of activated CD8+ T cells and antitumor efficacy in preclinical models. Here, we report preliminary results from an ongoing, first-in-human dose-escalation study in specific advanced tumors using GB1275 alone or with pembrolizumab. (NCT04060342) Methods: Phase 1 comprises dose escalation and expansion. During dose escalation, cohorts of 3 to 6 subjects were sequentially assigned to ascending dose levels of GB1275 from 100 mg to 1200 mg BID in one of two dosing regimens: Regimen A [GB1275 monotherapy orally (PO) twice a day (BID)] and Regimen B [GB1275 PO BID plus pembrolizumab 200 mg IV every 3 weeks (q3wks)]. Dose escalation was based on safety including dose-limiting toxicities (DLTs). Following dose escalation, up to 40 subjects with specific tumor types are to be treated in expansion with the selected GB1275 dose plus pembrolizumab to assess safety, pharmacokinetics, and preliminary clinical and biomarker activity. Results: As of January 8, 2021, 45 subjects were treated [44 in dose escalation: 23, Regimen A; 21, Regimen B. 1 in expansion, Regimen B], with median (range) GB1275 exposure of 42.0 days (4-263). No DLTs were reported. GB1275-related adverse events occurred in 24/45 (53.3%) subjects; photosensitivity reaction (20.0%), dysesthesia (13.3%) and pruritus (13.3%) were most frequent (≥10%). Stable disease was reported in 6/19 (31.6%) response-evaluable subjects in Regimen A and 9/16 (56.3%) in Regimen B. In Regimen B (800 mg), one partial response was reported in a subject with MSS-CRC treated for 263 days, and one prolonged stable disease (227 days) was reported in a gastric cancer (GC) subject previously treated with pembrolizumab plus bavituximab for less than 3 months due to progression; both subjects are continuing study treatment. A dose-dependent increase in GB1275 systemic exposure was observed up to 800 mg BID. Down-regulation of peripheral MDSCs was seen with both regimens. Regimen-dependent gene clusters in whole blood were noted. An increase in tumor infiltrating lymphocyte (TIL) counts was noted in both Regimens A and B. Conclusions: Dose escalation of GB1275, up to 1200 mg in Regimens A and B, demonstrated tolerability as monotherapy and combined with pembrolizumab in subjects with advanced cancers. Encouraging antitumor activity in Regimen B (800 mg) was observed in subjects with MSS-CRC and GC. Biological activity reflected by MDSC modulations in blood and TIL Increases in tumor biopsies with GB1275 alone and with pembrolizumab supports the mechanism of GB1275. GB1275 800 mg BID plus pembrolizumab 200 mg IV q3wks was selected for evaluation in the expansion phase. Clinical trial information: NCT04060342