Dataset Information

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.

ABSTRACT:

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.

SUBMITTER: Voss MH

PROVIDER: S-EPMC9014845 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring <i>FGFR</i> Gene Alterations.

Voss Martin H MH Hierro Cinta C Heist Rebecca S RS Cleary James M JM Meric-Bernstam Funda F Tabernero Josep J Janku Filip F Gandhi Leena L Iafrate A John AJ Borger Darrell R DR Ishii Nobuya N Hu Youyou Y Kirpicheva Yulia Y Nicolas-Metral Valerie V Pokorska-Bocci Anna A Vaslin Chessex Anne A Zanna Claudio C Flaherty Keith T KT Baselga Jose J

Clinical cancer research : an official journal of the American Association for Cancer Research 20190211 9

<h4>Purpose</h4>To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.<h4>Patients and methods</h4>This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring <i>FGFR1-3</i> 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 o ...[more]

PMID: 30745300

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