DDRE-12. DETERMINATION OF TOTAL AND UNBOUND LEVELS OF A POTENT INHIBITOR OF FIBROBLAST GROWTH FACTOR RECEPTOR, INFIGRATINIB, IN HUMAN PLASMA, CEREBROSPINAL FLUID AND BRAIN TUMOR BY A VALIDATED LC-MS/MS ASSAY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi76-vi77
Author(s):  
Tigran Margaryan ◽  
Nader Sanai ◽  
Artak Tovmasyan
Keyword(s):  
Clinical Trial ◽  
Cerebrospinal Fluid ◽  
Growth Factor ◽  
Human Plasma ◽  
Fibroblast Growth Factor Receptor ◽  
Potent Inhibitor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Phase 0

Abstract BACKGROUND Infigratinib is an orally available potent inhibitor of fibroblast growth factor receptor (FGFR) under investigation in a Phase 0 clinical trial for recurrent high-grade gliomas harboring oncogenic FGFR mutation or translocation (NCT04424966). Here, we report on our development and validation of an LC-MS/MS method for determination of total and unbound levels of infigratinib in human plasma, cerebrospinal fluid (CSF) and glioblastoma tissue. METHODS Infigratinib was extracted from human plasma, CSF and glioblastoma homogenate samples by protein precipitation with methanol. Unbound fractions of infigratinib in plasma and brain tissues were determined by equilibrium dialysis. Validation was performed using Sciex ExionLC UHPLC system coupled with Sciex QTRAP 6500+ MS/MS detector using positive electrospray ionization mode. The method was validated according to FDA guidelines and CAP/CLIA regulations. RESULTS The method was validated for 0.2-1000 nmol/L concentration range using plasma as matrix for all biospecimens. The analytical separation was optimized on Phenomenex Kinetex™ F5 column with total run time of 3.5 min using isocratic mode. Maximum coefficient of variation for intra- and inter-day precision was 12.7% and the accuracy was within 88.5-115.0% in all matrixes. The analyte is stable in plasma for at least 19 hours at room temperature (RT). Plasma stability at -20°C was demonstrated for at least 119 days. Stability of stock and working solutions was demonstrated for at least 15 hours (RT) and 60 days (2-8°C). The unbound fraction of infigratinib in pooled human plasma and brain were determined to be 0.01. CONCLUSIONS A sensitive and rapid bioanalytical method is successfully developed and validated to quantify total and unbound infigratinib levels in human plasma, CSF and glioblastoma tissue. The method is presently employed to evaluate plasma pharmacokinetics and CNS penetration of infigratinib in recurrent glioblastoma patients in an ongoing Phase 0 clinical trial.

scholarly journals Markedly Increased Ocular Side Effect Causing Severe Vision Deterioration After Chemotherapy Using New or Investigational Epidermal or Fibroblast Growth Factor Receptor Inhibitors.

2019 ◽  
Author(s):  
Eunhae Shin ◽  
Dong Hui Lim ◽  
Jisang Han ◽  
Do-Hyun Nam ◽  
Keunchil Park ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Visual Acuity ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Eye Drops ◽  
Fibroblast Growth ◽  
Ocular Complication ◽  
Corneal Epithelial

Abstract Background To describe corneal epithelial changes after using epidermal (EGFR) or fibroblast growth factor receptor (FGFR) inhibitors as chemotherapy and to clarify incidence and prognosis. Materials Retrospective chart review. Results Among 6,871 patients and 17 EGFR or FGFR inhibitors, 1,161 patients (16.9%) referred for ophthalmologic examination. Authors identified that in twelve patients, 3 EGFR inhibitors and 2 FGFR inhibitors that caused corneal epithelial lesions. Vandetanib, Osimertinib, and an EGFR agent under clinical trial (ABT-414) caused vortex keratopathy in nine patients and ASP5878 and FPA144, the FGFR inhibitors of clinical trial caused epithelial changes resembling corneal dysmaturation in three patients. Mean interval until symptoms appear was 246 days with Vandetanib, 196 days with Osimertinib, 30 days with ABT-414, 55 days with ASP5878 and 70 days with FPA144. Mean of lowest logarithm of minimal angle of resolution units (logMAR) visual acuity of right eye after chemotherapy was 0.338 and 0.413 in left eye. Incidence of epithelial changes were 15.79% with Vandetanib, 0.005% with Osimertinib, 100% with ABT414, 50.0% with ASP5878 and 18.2% with FPA144. After excluding deceased patients, or were lost to follow-up or were still undergoing treatment, we confirmed the reversibility of corneal lesions after discontinuation of each agent. Although patients diagnosed with glioblastoma used prophylactic topical steroids before and during ABT-414 therapy, all developed vortex keratopathy. Conclusions EGFR and FGFR inhibitors are well known chemotherapy agents and could make corneal epithelial changes. Contrary to low probability of ocular complication with old EGFR drugs, recently introduced EGFR and FGFR agents showed high incidence of ocular complication with severe vision distortion. Doctors should forewarn patients planning chemotherapy with EGFR or FGFR inhibitors that decreased visual acuity could develop due to corneal epithelial changes, and also reassure them that the condition could be improved after the end of treatment without the use of steroid eye drops.

scholarly journals Markedly Increased Ocular Side Effect Causing Severe Vision Deterioration After Chemotherapy Using New or Investigational Epidermal or Fibroblast Growth Factor Receptor Inhibitors.

2019 ◽  
Author(s):  
Eunhae Shin ◽  
Dong Hui Lim ◽  
Jisang Han ◽  
Do-Hyun Nam ◽  
Keunchil Park ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Topical Steroids ◽  
Eye Drops ◽  
Fibroblast Growth ◽  
Ocular Complication ◽  
Corneal Epithelial

Abstract Background To describe corneal epithelial changes after using epidermal (EGFR) or fibroblast growth factor receptor (FGFR) inhibitors as chemotherapy and to clarify incidence and prognosis. Materials Retrospective chart review. Results Among 6,871 patients and 17 EGFR or FGFR inhibitors, authors identified five EGFR inhibitors and two FGFR inhibitors that cause such corneal lesions. Unlike other old EGFR agents with rare ocular complications, Vandetanib, Osimertinib, and 3 EGFR agents under clinical trial (ABT-414, ASP5878, FPA144) caused vortex keratopathy in nine patients and ASP5878 and FPA144, the FGFR inhibitors of clinical trial caused epithelial changes resembling corneal dysmaturation in three patients. ABT-414 showed a remarkably short interval from the start of therapy to initiation of keratopathy. After excluding deceased patients, or were lost to follow-up or were still undergoing treatment, we confirmed the reversibility of corneal lesions after discontinuation of each agent. Although patients diagnosed with glioblastoma used prophylactic topical steroids before and during ABT-414 therapy, all developed vortex keratopathy. Conclusions EGFR and FGFR inhibitors are well known chemotherapy agents and could make corneal epithelial changes. Contrary to low probability of ocular complication with old EGFR drugs, recently introduced EGFR and FGFR agents showed high incidence of ocular complication with severe vision distortion. Doctors should forewarn patients planning chemotherapy with EGFR or FGFR inhibitors that decreased visual acuity could develop due to corneal epithelial changes, and also reassure them that the condition is reversible after the end of treatment without the use of steroid eye drops.

scholarly journals Electrochemical sensor for rapid determination of fibroblast growth factor receptor 4 in raw cancer cell lysates

PLoS ONE ◽  
2017 ◽  
Vol 12 (4) ◽  
pp. e0175056 ◽  
Author(s):  
Rebeca M. Torrente-Rodríguez ◽  
Víctor Ruiz-Valdepeñas Montiel ◽  
Susana Campuzano ◽  
María Pedrero ◽  
Meryem Farchado ◽  
...  
Keyword(s):  
Growth Factor ◽  
Electrochemical Sensor ◽  
Fibroblast Growth Factor ◽  
Cancer Cell ◽  
Fibroblast Growth Factor Receptor ◽  
Rapid Determination ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Cell Lysates

scholarly journals Targeting the Fibroblast Growth Factor Receptor (FGFR) in Advanced Cholangiocarcinoma: Clinical Trial Progress and Future Considerations

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1706
Author(s):  
Patrick C. Lee ◽  
Andrew Hendifar ◽  
Arsen Osipov ◽  
May Cho ◽  
Daneng Li ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Molecular Profiling ◽  
Clinical Development ◽  
Fibroblast Growth ◽  
Emerging Issues ◽  
Treatment Refractory

Landmark molecular profiling efforts have identified multiple targetable alterations in cholangiocarcinoma. Among the molecular-driven subsets of cholangiocarcinoma, targeting the fibroblast growth factor receptor (FGFR) has shown promise and represents the first targeted therapy to be approved in treatment-refractory, advanced cholangiocarcinoma. In this review, we provide an up-to-date overview of the clinical development of FGFR inhibitors in advanced cholangiocarcinoma. We review the FGFR pathway and discuss emerging issues including resistance to FGFR inhibitors. We end with a discussion on future considerations to optimize the potential of this class of therapeutics in advanced cholangiocarcinoma.

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