Phase I study of tazemetostat, an enhancer of zeste homolog-2 inhibitor, in pediatric pts with relapsed/refractory integrase interactor 1-negative tumors.
Susan Chi, Franck Bourdeaut, Theodore W. Laetsch, Maryam Fouladi, Margaret E. Macy, Guy Makin, Neerav Shukla, Cynthia Wetmore, Ashley Margol, Michela Casanova, Lindsay Kilburn, Joanna Yi, Darren Hargrave, Geoffrey McCowage, Navin Pinto, David Ebb, Giles Robinson, Laura Sierra, Melinda S. Merchant, Karsten Nysom
Abstract
10525 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/m 2 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/m 2 and 7pts at 1200mg/m 2 . 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/m 2 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/m 2 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. [Table: see text]