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Found 2 Presentations For Request "Abs: 550P"
550P - Preclinical characterization of CPL304110 as a potential selective inhibitor of fibroblast growth factors 1/2/3 in solid cancers
- Delfina Popiel (Kielpin-Lomianki, Poland)
Abstract
Background
Fibroblast Growth Factor Receptor (FGFR), a family of receptor tyrosine kinases (RTK) contains four members – FGFR1, FGFR2, FGFR3, FGFR4. FGFRs play a critical role in cell proliferation, migration, angiogenesis and survival. Dysregulation of FGF/FGFR signaling can result in formation of different tumour types including bladder, gastric, endometrial and lung cancer. Therefore, targeting FGFRs represents an attractive strategy for anticancer therapy for patients with FGFR-dependent tumours. Here we present CPL304110, a potent and selective small molecule that acts as FGFR 1/2/3 inhibitor. It can be a potential therapy for FGFRs dependent cancers.
Methods
Activity of CPL304110 was evaluated against FGFRs in ADP-based enzymatic test and its selectivity was tested on KINOMEscan® screening platform. The biological potency of compound was evaluated in a number of cancer cell-based models using Western Blot and cell viability assay (ATPliteTM). Our inhibitor was also characterized in BioMAP Diversity PLUS panel.
Results
CPL304110 was designed as a novel, potent and selective FGFR1-3 inhibitor. CPL304110 showed strong inhibitory effect on FGFR2 (IC50 = 1.44 nM), FGFR1 (4.08 nM) and lower on FGFR3 (10.55 nM). Compound selectivity was evaluated on KINOMEscan® panel of 468 kinases at 1μM. We confirmed potent inhibitory activity on several FGFR-dependent cancer cell lines with low nanomolar IC50 values, without significant effect on viability of FGFR-independent cells (up to 33.7 μM). Cells treated with CPL304110 showed substantial decrease in activation of FGFR-mediated signaling. In the Diversity PLUS panel CPL304110 showed broad antiproliferative and anti-inflammatory impact.
Conclusions
Presented preclinical studies indicated that CPL304110 can be qualified as a good clinical candidate for the treatment of FGFR-dependent tumours. Our drug is currently under clinical investigation – Phase I (NCT04149691).
Editorial acknowledgement
The research was co-financed by the National Center of Research and Development and Celon Pharma S.A., project "CELONKO", grant number STRATEGMED2/266776/17/NCBR/2015.
Legal entity responsible for the study
Celon Pharma S.A.
Funding
Celon Pharma S.A and NCBR grant.
Disclosure
D. Popiel: Full/Part-time employment: Celon Pharma S.A. A. Mikołajczyk: Full/Part-time employment: Celon Pharma S.A. M.M. Skupinska: Full/Part-time employment: Celon Pharma S.A. J. Hucz-Kalitowska: Full/Part-time employment: Celon Pharma S.A. P. Stańczak: Full/Part-time employment: Celon Pharma S.A. N. Piotrkowska: Full/Part-time employment: Celon Pharma S.A. A. Yamani: Full/Part-time employment: Celon Pharma S.A. K. Dubiel: Full/Part-time employment: Celon Pharma S.A. J. Pieczykolan: Full/Part-time employment: Celon Pharma S.A.M. Wieczorek: Full/Part-time employment: Celon Pharma S.A. A. Stancza: Full/Part-time employment: Celon Pharma S.A.
1165P - Subgroup analysis by Ki-67 and primary tumour origins of the randomized, placebo-controlled phase III study of surufatinib in advanced well-differentiated extrapancreatic neuroendocrine tumours (SANET-ep)
- Zhiwei Zhou (Guangzhou, China)
Abstract
Background
Surufatinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (1,2,3), fibroblast growth factor receptor 1 and colony stimulating factor 1 receptor, has demonstrated superior efficacy in extrapancreatic neuroendocrine tumors (NETs) in a phase III study (SANET-ep, ESMO 2019 Abs. LBA76). The proliferation marker Ki-67 and primary tumor origins are the major prognostic factors in NETs.
Methods
The post-hoc efficacy analysis of surufatinib versus placebo was conducted by Ki-67 subcategory (<3%, 3-10%, >10%) and primary tumor origins (foregut, midgut, hindgut, others or unknown) in patients (pts) with advanced well-differentiated (grade 1 or 2) extrapancreatic NETs. The primary endpoint (progression-free survival [PFS]) and secondary endpoint (objective response rate [ORR]) both by investigator assessment (RECIST1.1) were analyzed.
Results
Median PFS was significantly prolonged with surufatinib compared to placebo in subgroups of Ki-67 3-10% (7.6 vs 4.6 months [mo], hazard ratio [HR] 0.47,
Conclusions
Surufatinib demonstrated clinically significant benefits for pts with advanced well-differentiated extrapancreatic NETs compared to placebo. Results of this exploratory analysis were consistent with those reported for the SANET-ep primary analysis, and improved outcomes were observed across major subgroups.
Clinical trial identification
NCT02588170.
Legal entity responsible for the study
Hutchison MediPharma Limited.
Funding
Hutchison MediPharma Limited.
Disclosure
J. Li, J. He: Full/Part-time employment: Hutchison MediPharma Limited. W. Su: Shareholder/Stockholder/Stock options, Full/Part-time employment: Hutchison MediPharma Limited. All other authors have declared no conflicts of interest.