TRLS-15. “TAZNI”: A PHASE I/II COMBINATION TRIAL OF TAZEMETOSTAT WITH NIVOLUMAB AND IPILIMUMAB FOR CHILDREN WITH INI1-NEGATIVE OR SMARCA4-DEFICIENT TUMORS (NCT05407441)

Abstract

Abstract BACKGROUND Recent pediatric trials with EZH2 inhibitor tazemetostat monotherapy have demonstrated efficacy and disease stabilization in children with relapsed INI1/SMARCA4-deficient tumors: overall response rate (ORR) 14% in all patients (dose expansion cohort), and 24%, 33% and 22% response rates in ATRT, chordoma and epithelioid sarcoma, respectively (NCT02601937); and prolonged disease stabilization >6 months (NCT03213665). Leveraging the role of EZH2 in tumor immunity and increased immune signaling by tazemetostat, we hypothesized that combining this EZH2 inhibitor with checkpoint inhibitors may benefit pediatric patients with these rare cancers. METHODS “TAZNI” is a phase 1/2, multi-center trial of tazemetostat, nivolumab and ipilimumab for children with INI1/ SMARCA4-deficient tumors, administered either after standard upfront therapy or in the relapsed setting. All patients will receive standard nivolumab and ipilimumab doses/dosing schedule, with continuous tazemetostat dosing determined by disease strata: Stratum A- subjects with ATRT; Stratum B- all other (non-ATRT) tumors. Each stratum is subdivided by disease status: A1/B1- refractory disease; A2/B2- relapsed disease; and A3/B3- no evidence of disease. Part 1 of the study consists of two concurrent “rolling six” phase 1 studies to identify the recommended phase 2 dose (RP2D) by disease stratum. Two dose levels are planned, with one dose de-escalation. Part 2 will consist of two phase 2 studies to estimate the ORRs in substrata A1 and A2, in a Simon’s 2-stage design at the RP2D. All other substrata will have descriptive analyses. Patients may receive up to 26 cycles of therapy. Key inclusion/exclusion criteria include INI1 or SMARCA4 loss (by immunohistochemistry or molecular confirmation); age 6 mo - 21 yo; no prior immunotherapy; limited corticosteroid usage; and no concern for hematologic malignancy. This trial is currently ongoing and open to accrual. To date, four patients have enrolled and additional sites across the US are anticipated to open for enrollment (NCT05407441).