Background: The prognosis for children with INI1-negative cancers is dismal, with historic 5-year overall survival <30%. These cancers (including malignant rhabdoid tumors [MRT], atypical teratoid rhabdoid tumors [ATRT], epithelioid sarcomas [ES], and poorly differentiated chordomas) have few novel treatment options. These tumors exhibit a heightened dependence on the Polycomb Repressive Complex, whereby EZH2 is the catalytic subunit. Two recent pediatric phase 1/2 trials with EZH2 inhibitor tazemetostat (EZH-102, NCT02601937 and APEC1621C, NCT03213665) demonstrated 17% overall objective response rate, with 19% response in ATRT patients and higher response rates in patients with chordoma and ES. One patient had PR on the phase 2 Pediatric MATCH study and 5 patients had prolonged SD. Studies of INI1-deficient tumors have shown significant immune infiltration, including T-cells with high levels of inhibitory checkpoint receptors. As EZH2 has a role in tumor immunity and tazemetostat increases MHC presentation and immune signaling, we hypothesized that combining EZH2 inhibitor with checkpoint inhibitors may provide benefit for pediatric patients with INI1- or SMARCA4-deficient tumors. Methods: TAZNI is a phase 1/2, multi-center trial of Tazemetostat, Nivolumab and Ipilimumab for children with INI1- or SMARCA4-deficient tumors after upfront therapy. All patients receive standard pediatric nivolumab and ipilimumab doses/dosing schedule with continuous tazemetostat dosing determined by disease strata: Stratum A- subjects with ATRT; Stratum B for all other (non-ATRT) INI1/SMARCA4-deficient tumors. Each stratum is subdivided by disease status: A1/B1- subjects with refractory disease after upfront therapy; A2/B2- subjects with relapsed disease; and A3/B3: subjects with no evidence of disease (NED) after upfront therapy. The study is conducted in 2 parts: Part 1 will be two concurrent “rolling six” phase 1 studies to identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) by disease stratum. Starting dose level 1 for Stratum A is 900mg/m² orally BID and for Stratum B: 520mg/m² orally BID, with one dose escalation and one dose de-escalation planned. Part 2 will be two phase 2 studies to estimate the overall response rate (ORR) in Substrata A1 and A2 (with refractory disease or with relapse, respectively), based on a primary endpoint of ORR (CR+PR) in a Simon’s 2-stage design at the RP2D. All other substrata will be descriptive analyses. Patients may receive up to 26 cycles of therapy. Key inclusion/exclusion criteria include INI1 loss by immunohistochemistry (IHC) or molecular confirmation; age between 6 mo and 21 yo; no prior immunotherapy; limited corticosteroid; and no history or concern for hematologic malignancy. To date, 4 patients have enrolled, and the study is ongoing in the United States. Clinical trial information: NCT05407441.