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

To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor. This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring gene alterations. Eligible patients received oral Debio 1347 at escalating...

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Bibliographic Details
Published in:Clinical cancer research Vol. 25; no. 9; p. 2699
Main Authors: Voss, Martin H, Hierro, Cinta, Heist, Rebecca S, Cleary, James M, Meric-Bernstam, Funda, Tabernero, Josep, Janku, Filip, Gandhi, Leena, Iafrate, A John, Borger, Darrell R, Ishii, Nobuya, Hu, Youyou, Kirpicheva, Yulia, Nicolas-Metral, Valerie, Pokorska-Bocci, Anna, Vaslin Chessex, Anne, Zanna, Claudio, Flaherty, Keith T, Baselga, Jose
Format: Journal Article
Language:English
Published: United States 01.05.2019
Subjects:
Adult
Aged
Benzimidazoles - pharmacokinetics
Benzimidazoles - therapeutic use
Drug Administration Schedule
Female
Follow-Up Studies
Gene Fusion
Humans
Male
Maximum Tolerated Dose
Middle Aged
Mutation
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - pathology
Prognosis
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - therapeutic use
Pyrazoles - pharmacokinetics
Pyrazoles - therapeutic use
Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 1 - genetics
Receptor, Fibroblast Growth Factor, Type 2 - antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 2 - genetics
Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 3 - genetics
Signal Transduction
Tissue Distribution
ISSN:1557-3265, 1557-3265
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Summary:To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor. This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring 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. 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 amplifications (40%) and mutations in (12%) and (17%); 12 patients (21%) showed 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 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. 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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ISSN:1557-3265
1557-3265
DOI:10.1158/1078-0432.CCR-18-1959