SWOG S1400D (NCT02965378), a Phase II Study of the Fibroblast Growth Factor Receptor Inhibitor AZD4547 in Previously Treated Patients With Fibroblast Growth Factor Pathway-Activated Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy).
S1400D is a biomarker-driven therapeutic substudy Lung-MAP evaluate fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with squamous cell FGF-activated pathway.
This is the first Phase II trials to evaluate AZD4547 as a targeted approach in previously treated patients with squamous cell NSCLC FGFR-altered and is the first demonstration of the successful execution and behavior of a national umbrella protocol in this disease setting.Eligible patients had tumoral FGFR change or mutations and have progressive disease after at least one line of platinum-based systemic therapy.
Patients received AZD4547 80 mg twice a day orally. The primary endpoint was the response by Response Evaluation Criteria in Solid Tumors version 1.1; Secondary endpoints included progression-free survival, overall survival, and duration of response (DOR) .Ninety-two patients assigned to S1400D, 43 were enrolled, and 27 patients were treated AZD4547 was evaluated. evaluable patients was predominantly white (n = 24, 89%), median age 66 years (range, 49-88 years old) and women (n = 7, 26%). FGFR changes include FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%).
Treatment with ADZ4547 tolerated; Grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of the 27 patient-evaluated response, one patient with FGFR3 S249C had an unconfirmed partial response with dor 1.5 months and 1 patient with FGFR1 amplification has confirmed partial response with a bang of 2.9 months (7%, 95% confidence interval [CI ]: 0% -17%). Median progression-free survival and overall survival for AZD4547-treated cohort of 2.7 months (95% CI: 1.4 to 4.5 months) and 7.5 months (95% CI: 3.7 to 9.3 months). AZD4547 has an acceptable safety profile but minimal activity in this group is dominated FGFR1 / FGFR3-reinforced. Evaluation of other targeted agents in Lung-MAP is underway.
SWOG S1400D (NCT02965378), a Phase II Study of the Fibroblast Growth Factor Receptor Inhibitor AZD4547 in Previously Treated Patients With Fibroblast Growth Factor Pathway-Activated Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy).
the important role of fibroblast growth factor signaling pathways in Ewing sarcoma octamer binding transcription factor 4 -mediated cell proliferation and tumorigenesis.
certain bone and soft tissue (BST) tumors harbor chromosomal translocation [t (6; 22) (p21; q12)], which fuses Ewing’s sarcoma (EWS) gene at 22q12 with octamer binding transcription factor 4 (Oct-4) gene on the 6p21 , resulting chimeric EWS-Oct-4 protein that has the ability of high transactivation.
Although the abnormal activation of signaling pathways can lead to the development of human cancer, pathways that underlie this process in tumor BST humans remain poorly explored. Here, we investigate the functional significance of fibroblast growth factor (FGF) signaling in human tumor BST. To identify the gene (s) involved in the FGF signaling pathway and potentially regulated by EWS-Oct-4 (also called EWS-POU5F1) we did an analysis of RNA-Seq, electrophoretic mobility shift test, chromatin immunoprecipitation test, and test xenograft.
Treating the cells expressing GBS6 or ZHBTc4-EWS-Oct-4 with a small molecule FGF receptor (FGFR) inhibitor PD173074, NVPBGJ398, ponatinib, and dovitinib suppressed cell proliferation. Gene expression analysis revealed that, among the 22 FGF and four family members Fgfr, FGF-4 showed the highest upregulation (by 145-fold) in cells expressing EWS ZHBTc4-October-4. computer-aided analysis to identify sites EWS-October-4-binding allegedly at + 3017 / + 3024, shows that the EWS-October-4 Organize FGF-4 expression in human tumor BST.
FGF-4 enhancer construction showed that EWS-October-4 transactivated reporter FGF-4 gene in vitro, and that overexpression of EWS-Oct-4 stimulates endogenous FGF-4 gene expression in vivo. \
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