A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations
| Autor: | Claudio Zanna, Cinta Hierro, A. John Iafrate, Josep Tabernero, Rebecca S. Heist, Nobuya Ishii, Funda Meric-Bernstam, Valerie Nicolas-Metral, James M. Cleary, Anna Pokorska-Bocci, Keith T. Flaherty, Martin H. Voss, Yulia Kirpicheva, Anne Vaslin Chessex, Leena Gandhi, José Baselga, Youyou Hu, Filip Janku, Darrell R. Borger |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_specialty business.industry medicine.disease Gastroenterology 03 medical and health sciences Hyperphosphatemia 030104 developmental biology 0302 clinical medicine Oncology Tolerability Pharmacokinetics 030220 oncology & carcinogenesis Pharmacodynamics Internal medicine Toxicity medicine FGFR Inhibitor Debio 1347 Adverse effect business Stomatitis |
| Zdroj: | Clinical Cancer Research. 25:2699-2707 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective 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 (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks. Results: A total of 71 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 six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic 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, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. 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. |
| Databáze: | OpenAIRE |
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