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• W2890660749 startingPage "TPS2619" @default.
• W2890660749 abstract "TPS2619 Background: NOTCH signalling is a key development pathway whose aberrant activation is recognised to play an oncogenic role in human cancers. When NOTCH signalling is inappropriately activated by genetic alterations, it becomes an oncogenic driver for NOTCH-dependent cancers, while upregulation of NOTCH receptors is linked to resistance to standard of care. CB-103 is a new small molecule protein-protein interaction (PPI) inhibitor able to target assembly of the NOTCH transcription complex in the cell nucleus leading to downregulation of NOTCH target genes (c-MYC, CCND1, HES1) and inhibition of NOTCH signalling independently of NOTCH mechanisms of activation. CB-103 has demonstrated efficacy and tolerability in different preclinical tumor models derived from various NOTCH-driven cancer indications and in blood from NOTCH-activated leukemia pts. Methods: This study is a multi-centre, open label, non-randomised, phase 1-2A dose escalation study in adult patients (pts), with expansion arms of oral CB-103. Aim of phase 1 is to find the MTD/RP2D. The starting dose is targeting a plasma exposure (daily AUC) that has reasonable safety margin and allows reliable determination of pharmacokinetics (PK). An adaptive Bayesian logistic regression model for dose escalation is implemented in phase 1 to guide determination of MTD/RP2D. Full PK sampling profiles will be taken on days 1 & 8 of cycle one (28 days) and day 1 of cycle two. NOTCH-related PD and Biomarker exploratory analyses are planned on tumour biopsies, hair follicles and blood samples (liquid biopsy). Administration schedule (once-daily) may be adapted depending on PK and safety. 3-6 eligible pts regardless of NOTCH pathway activation status are enrolled per dose group in phase 1, while pts in phase 2A will be selected for NOTCH pathway genetic alterations. Phase 2A will assess preliminary efficacy of CB-103 in expansion arms across different indications using Bayesian design. Enrolment into 1st dose group (15mg) started with first pt treated on 20Dec17: 7 pts registered with 2 screen failures, 1 discontinued due to early cancer progression and 4 in treatment in their first treatment cycle. Clinical trial information: NCT03422679." @default.
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• W2890660749 date "2018-05-20" @default.
• W2890660749 modified "2023-10-08" @default.
• W2890660749 title "First-in-human phase 1-2A study of CB-103, an oral Protein-Protein Interaction Inhibitor targeting pan-NOTCH signalling in advanced solid tumors and blood malignancies." @default.
• W2890660749 doi "https://doi.org/10.1200/jco.2018.36.15_suppl.tps2619" @default.
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