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First-in-human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors.
- Source :
-
Cancer science [Cancer Sci] 2020 Feb; Vol. 111 (2), pp. 571-579. - Publication Year :
- 2020
-
Abstract
- Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first-in-human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1-3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1-180 mg) was carried out to assess dose-limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25-(OH) <subscript>2</subscript> -vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140-mg dose; one patient in the 180-mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose-dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose-dependent increases were observed in all pharmacodynamic markers and plateaued at 100-140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow-up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.<br /> (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Subjects :
- Administration, Oral
Adult
Aged
Antineoplastic Agents adverse effects
Antineoplastic Agents pharmacokinetics
Drug Administration Schedule
Female
Humans
Japan
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms genetics
Protein Kinase Inhibitors adverse effects
Protein Kinase Inhibitors pharmacokinetics
Antineoplastic Agents administration & dosage
Neoplasms drug therapy
Protein Kinase Inhibitors administration & dosage
Receptors, Fibroblast Growth Factor antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1349-7006
- Volume :
- 111
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer science
- Publication Type :
- Academic Journal
- Accession number :
- 31797489
- Full Text :
- https://doi.org/10.1111/cas.14265