Background: PLX2853 is a potent, orally active small molecule BET inhibitor. Its unique pharmacokinetic (PK) profile is associated with less thrombocytopenia and improved tolerability by allowing transient target engagement with a prolonged pharmacodynamic (PD) response and time for recovery after dosing. Methods: We conducted a first-in-human 3+3 Ph1b/2a study of PLX2853 in adults with relapsed or refractory solid tumors and lymphoma to determine the safety, PK and recommended phase II dose (RP2D) (NCT03297424). Secondary endpoints included efficacy and PD. Results: As of 2 February 2021, 44 subjects (median age 65, range 39 - 84) received PLX2853 in escalating doses from 5mg to 120mg QD and 40mg to 60mg BID. Ovarian cancer (n = 11), uveal melanoma, colorectal, and prostate (n = 5 each) were the most represented tumor types. Adverse events (AE) occurring in ≥15% of subjects included nausea (41%), decrease appetite (39%), fatigue (27%), vomiting (25%), diarrhea (25%), dysgeusia (25%), dehydration (23%), anemia (20%), dry mouth (18%), dizziness (16%), abdominal pain (16%), and pyrexia (16%). Thrombocytopenia occurred in 11% of subjects. Most AEs ( > 85%) were grades (G) 1-2. Of all AEs, 40% were related. There were 5 treatment-related serious AEs in 2 subjects (n = 1 G4 thrombocytopenia, G4 ischemic stroke, G3 subarachnoid hemorrhage [SAH], and G3 thromboembolic event; n = 1 G3 vomiting). Dose-limiting toxicities were observed at 120mg QD (G4 thrombocytopenia, G4 ischemic stroke, G3 thromboembolic event, and G3 SAH; asymptomatic G4 thrombocytopenia), 60mg BID (G3 thrombocytopenia with recovery > 7 days), and 40mg BID (dose reduction for transient G3 fatigue). PLX2853 systemic exposure was dose-proportional up to 120mg with a short terminal half-life ( < 3.5 hr). Plasma concentrations were above the IC₉₀ in the MYC-responsive reporter assay for 9 hr at 80mg or higher doses. RNA-seq analyses of peripheral blood mononuclear cells showed a dose-dependent modulation of BET target gene expression. One complete response (ongoing 9+ months) was seen in a patient with DLBCL, two patients had partial responses (1 uveal melanoma, 1 primary peritoneal cancer), and 14 patients had stable disease. The median PFS was 82.5 days (range: 51 – 209 days). Conclusions: PLX2853 shows encouraging signs of clinical activity and is well tolerated at the anticipated RP2D of 80 mg/day. PLX2853 is being evaluated as monotherapy and in combination. Clinical trial information: NCT03297424