A phase II, multicenter study of the EZH2 inhibitor tazemetostat in adults (rhabdoid tumor cohort) (NCT02601950)

Abstract

Background: Malignant rhabdoid tumors (MRTs), including small cell carcinoma of the ovary hypercalcemic type (SCCOHT) and thoracic sarcoma (TS; distinct, aggressive SMARCA4 negative tumors with rhabdoid features), are highly aggressive with limited response to conventional systemic therapy. Dysfunction of the SWI/SNF complex, due to loss of INI1 or SMARCA4, leads to oncogenic dependence on EZH2 through transcriptional repression caused by aberrant H3K27me3. Tazemetostat, a potent, selective, oral inhibitor of EZH2, demonstrated antitumor activity in both INI1 and SMARCA4-negative preclinical models. Methods: Tazemetostat (800 mg BID) was studied in adults with MRT (confirmed by histology and INI1 loss) in this phase 2 multicenter, open-label, single arm, 2-stage Green-Dahlberg design study. Futility assessment was performed at stage 1 after the first 15 pts completed ≥24-weeks dosing, the final study visit, or terminated early. Success at stage 1 required ≥1 pt achieving a PR or CR. Stage 2 success required confirmed PR or CR in≥5 treated pts. The primary endpoint was overall response rate. Key secondary endpoints included safety/tolerability. Results: With enrollment complete (N=31; median age of 32 years; 58% female; n=10 SCCOHT; n=10 TS; n=11 other INI1-neg tumors), futility was passed for stage 1, but not for stage 2. There were a total of 2/31 PRs; 1 pt with SCCOHT with a duration of response of 32 weeks and 1 pt with TS with an ongoing response at 8 weeks. Stable disease as best overall response was observed in 7 (23%) pts. Adverse events (AEs) were generally mild. Vomiting (42%), nausea (32%), cancer pain (26%), fatigue (23%), and abdominal pain (23%) were the most frequently reported AEs of any grade. Grade ≥3 AEs, regardless of relationship to study drug, included: death (19%; not treatment-related), anemia (16%), and abdominal pain (10%). No pts discontinued due to treatment-related AEs. Conclusions: Tazemetostat demonstrated clinical activity in 2 difficult to treat tumors (SCCOHT and TS), with generally mild tomoderate AEs. Although stage 2 futility was not passed, further understanding of the heterogeneity of these highly aggressive tumors may help to build upon the PR seen in 2 pts.