Background: Absence of integrase interactor 1 (INI1) expression is a defining molecular feature of rhabdoid tumors (RT), epithelioid sarcoma (ES), and chordomas, inducing dependence on enhancer of zeste homolog-2 (EZH2). Tazemetostat (TAZ) is a selective EZH2 inhibitor approved by the FDA for treatment of patients (pts) ≥16 yrs with metastatic or locally advanced ES ineligible for complete resection. Data from a Phase 1 (Ph1) pediatric dose-escalation study (Ph1a) of TAZ were previously reported; herein we report interim efficacy and safety from the Ph1 pediatric dose-expansion study (Ph1b). Methods: NCT02601937 is a Ph1, multicenter study in pts 6 months – 18 yrs evaluating TAZ administered BID at 1200 mg/m² in Ph1b, per Ph1a recommendation. Ph1b cohorts enrolled pts based on tumor type: Atypical teratoid RT (ATRT), RT, and other INI1-negative tumors (including ES and chordoma). The Ph1b primary endpoint was overall response rate (ORR). Secondary endpoints included safety/tolerability, duration of response (DOR), and survival. Results: Ph1b has enrolled 47 pts who received TAZ oral suspension. Across all tumor types, ORR was 17% (Table). Responses were observed in ATRT (4/21), chordoma (2/4), and ES (2/7); 1 pt dosed at 520mg/m² and 7pts at 1200mg/m². In the ATRT cohort, 19% of pts responded to TAZ with a median DOR of 6.5 months. The median DOR has not yet been reached in the other cohorts, with ongoing responses in 3 pts. TAZ was generally well tolerated with no drug-related deaths. Most common adverse events (AE) include vomiting, nausea, and cough. During Ph1b enrollment, 1 pt with chordoma (dosed at TAZ 900 mg/m² for 15 months in Ph1a) developed a secondary malignancy (T-cell lymphoblastic lymphoma). In response, the pediatric recommended Ph2 dose was revised to limit exposure in pts without CNS involvement to 520 mg/m² TAZ (maximum dosing of 1 yr after response, pts to go off-treatment until disease progression). Conclusions: Interim results indicate TAZ is generally well tolerated in children with an AE profile similar to adults. Pt enrollment in the non-ATRT, INI1-negative cohorts is ongoing. TAZ shows promising anti-tumor activity in a subset of pediatric tumors, including ATRT, chordoma, and ES. Clinical trial information: NCT02601937

^a15 pts across additional tumor types did not show a response. ^bNot estimable

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