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• W2785484811 abstract "Abstract Background: The defining molecular feature of rhabdoid tumors, epithelioid sarcoma (ES), and poorly differentiated chordomas is the absence of tumor expression of INI1 (SMARCB1), a subunit of the SWI/SNF chromatin remodeling complex. INI1 loss impairs SWI/SNF activity and induces a dependence on the activity of EZH2, the catalytic subunit of PRC2, a separate complex responsible for chromatin remodeling and transcriptional repression through trimethylation of lysine 27 on histone H3 (H3K27me3). Tazemetostat, a potent and selective EZH2 inhibitor, has demonstrated tumor regressions in INI1-negative preclinical malignant rhabdoid tumor (MRT) models and durable objective responses in adults with certain INI1-negative ES or chordoma. Interim results from dose escalation (DEsc) cohorts of a Phase (Ph) 1 pediatric study are reported. Methods: EZH-102 (NCT02601937) is a Ph 1, multicenter study of tazemetostat dosed continuously as an oral suspension administered twice daily (BID) in patients (pts) aged 6 months to 21 years with synovial sarcoma, or INI1-negative tumors including atypical teratoid rhabdoid tumors (ATRT), MRT, ES, chordoma, and others. A “Rolling 6” design was used for DEsc. Objective response was assessed every 8 weeks using disease-appropriate response criteria, i.e., RANO or RECIST 1.1. Primary endpoints included identification of dose-limiting toxicities (DLT) and recommended Ph 2 dose (RP2D). Secondary endpoints included characterization of safety/tolerability, pharmacokinetics (PK), and duration of response. Exploratory endpoints included assessing the relationship between tazemetostat exposure and the pharmacodynamic (PD) marker H3K27me3 in peripheral blood. Results: Forty-six pts have been treated in 7 dose cohorts: 240 (n=8), 300 (n=6), 400 (n=6), 520 (n=7), 700 (n=6), 900 (n=6), and 1200 mg/m2 BID (n=7). One pt at 300 mg/m2 had DLTs of dyspnea (grade 4)/hypoxia (grade 3), but no DLTs were observed in any other cohort. Adverse events were generally mild to moderate, consistent with the safety profile observed in adults. Plasma concentrations were generally dose-proportional across the dose range studied and were lower at steady-state on Day 15 vs. those measured on Day 1. Mean systemic exposure in the 1200 mg/m2 cohort was ~ 4-fold greater than that at the adult RP2D of 800 mg BID. A PK:PD relationship between C1D15 tazemetostat exposure and H3K27me3 levels in peripheral blood monocytes and granulocytes was observed with consistent and significant post-dose reductions in H3K27me3 at the 900 and 1200 mg/m2 doses. Confirmed complete or partial responses (CR/PR) per RECIST/RANO were observed in pts with ES (n=1), chordoma (n=2), and ATRT (n=1) at dose levels ranging from 520 to 900 mg/m2. Conclusion: Tazemetostat was generally well tolerated in children and showed promising antitumor activity including CRs in pts with INI1-negative tumors. The RP2D of 1200 mg/m2 BID was defined on the basis of PK, PD, and clinical safety, and resulted in higher systemic exposure than in adults. Dose expansion cohorts are currently enrolling. Citation Format: Susan Chi, Maryam Fouladi, Neerav Shukla, Franck Bourdeaut, Ashley Margol, Guy Makin, Geoff McCowage, Cynthia Wetmore, Margaret Macy, Ted Laetsch, Darren Hargrave, Navin Pinto, Joanna Yi, Dave Ebb, Giles Robinson, Maria Roche, Benjamin Suttle, Alicia Clawson, Peter Ho, Jill Rodstrom, Scott Daigle, Karsten Nysom. Phase 1 study of the EZH2 inhibitor, tazemetostat, in children with relapsed or refractory INI1-negative tumors including rhabdoid tumors, epithelioid sarcoma, chordoma, and synovial sarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A175." @default.
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• W2785484811 date "2018-01-01" @default.
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• W2785484811 title "Abstract A175: Phase 1 study of the EZH2 inhibitor, tazemetostat, in children with relapsed or refractory INI1-negative tumors including rhabdoid tumors, epithelioid sarcoma, chordoma, and synovial sarcoma" @default.
• W2785484811 doi "https://doi.org/10.1158/1535-7163.targ-17-a175" @default.
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