Background: Second mitochondria-derived activator of caspase (SMAC) mimetics regulate apoptosis and modulate NFκB signaling which drives the expression of genes involved in immune and inflammatory responses. In patient (pt) tumors, Debio 1143 increased PD-1/PD-L1 expression and tumor infiltrating lymphocytes. In pre-clinical models, it synergizes in vitro and in vivo with PD1/PD-L1 checkpoint inhibitors (CPIs). Methods: In a phase I study, using a mCRM model, avelumab (10 mg/kg i.v. on D1&15 q4w) was combined with escalating doses of Debio 1143 (100 mg/d to 250 mg/d orally, D1-10 & D15-24 q4w) to define the RP2D. Consenting adult pts with advanced solid tumors, normal organ function, and PS-ECOG = 0-1 were eligible provided none received prior CPI. Dose-limiting toxicities (DLTs), efficacy, safety, PK, PD and biomarkers were assessed. Results: As of DEC’18, 16 pts were treated; M/F: 8/8; ECOG = 0 in 6 (38%); median age = 58 (28-79); 5 pts had NSCLC, 2 MPM, 2 ovarian and 7 had other tumors (n = 1 each). Common AEs were: nausea (69%); fatigue (62%); vomiting (50%); cough, dyspnea, myalgia (44% each); diarrhea, anorexia (38% each); pruritus and constipation (31% each). These were generally grade 1-2, occasionally grade 3. One pt had a DLT at 250 mg/d dose: a grade 3 AST/ALT increase. No treatment-related AEs grade 4 or higher occurred. No dose-relationships for laboratory abnormalities were observed, except for ALT/AST increases, which at 200 mg/d were all grade 1 and asymptomatic. Maximal tolerated dose was not reached and there were no dose reductions. In 15 evaluable pts, 1 PR (NSCLC) and 5 SD (RECIST v1.1) were observed. Tumor shrinkage > 15% was seen in 2 other NSCLC pts. PK showed high interpatient variability and dose-proportional increase. TNFα and IFNγ peaked in plasma following Debio 1143 dose on D1 after 8 hrs, and on D17/22, in a dose-proportional manner. Four pts developed anti-avelumab antibodies. Conclusions: Debio 1143 at 200 mg/d can be safely combined with avelumab. Toxicity was predictable and mild. Clinical activity was observed in NSCLC pts. PK was linear; no drug interaction was suspected. PD and biomarker analysis is ongoing. Expansion at this RP2D is ongoing in NSCLC. Clinical trial information: NCT03270176.