A Phase I, Multicenter, Dose-Escalation Study of the Oral Selective FGFR inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations

Purpose: To investigate tolerability, efficacy, and pharmacokinetics/-dynamics (PK/PD) of Debio 1347, a selective fibroblast growth factor receptor (FGFR) Inhibitor. Experimental Design: 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. Conclusions: Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.

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