PURPOSE. To investigate tolerability, efficacy, and pharmacokinetics/-dynamics (PK/PD) of Debio 1347, a selective fibroblast growth factor receptor (FGFR) inhibitor. PATIENTS AND METHODS. This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1–3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose limiting toxicities (DLTs) were evaluated during the first 4 weeks on treatment, PK/PD post-first dose and after 4 weeks. RESULTS. Seventy-one patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had 6 DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, stomatitis). The maximum tolerated dose was not reached, but dermatological toxicity became sometimes dose-limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, three with FGFR fusions, demonstrated partial responses, 10 additional patients tumor size regressions of ≤30%. Plasma half-life was 11.5 h. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day. CONCLUSION. Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.