Abstract CT028: Drug-drug interaction potential of EZH2 inhibitor tazemetostat (TAZ)

Abstract

TAZ, a selective, oral EZH2 inhibitor, is in the phase 2 clinical investigation stage for the treatment of advanced solid tumors (AdvST) and B-cell non-Hodgkin lymphoma (NHL). Drug-drug interaction (DDI) potential of TAZ was investigated in study EZH-105, a phase 1, open-label, 2-part study in adults with AdvST or NHL. In Part A, patients received TAZ 400 mg twice-daily (BID) days 1-24, then 800 mg BID continuously. Moderate CYP3A inhibitor fluconazole 400 mg was administered once daily (QD) days 16-19. Serial blood samples for pharmacokinetic analysis were collected on days 15 and 19. Patients in Part B received TAZ 800 mg BID continuously starting day 2. The CYP2C8 probe repaglinide 0.25 mg and CYP2C19 probe omeprazole 20 mg were administered on day 1 and 1 hour following TAZ administration on day 16. Omeprazole 20 mg QD continued days 17-19. Serial blood samples were collected on days 1, 16, and 19. DDIs were evaluated based on AUC and Cmax. Other primary endpoints included safety of TAZ. As of August 14, 2018, 27 patients were enrolled (n=17 AdvST, n=10 NHL). Median age was 60 years. Preliminary pharmacokinetic results are displayed in the Table. Median treatment exposure was 70 days in Part A and 57 days in Part B. Two patients, both in Part B, discontinued due to treatment emergent adverse events (TEAEs). Grade ≥3 TEAEs were reported in 12 patients. The most frequent treatment-related TEAEs (any grade) included diarrhea (n=6), fatigue (n=6), and nausea (n=3). In conclusion, the likelihood of a clinically significant DDI in the presence of TAZ is minimal. Table.Preliminary study EZH-105 PK resultsPart A. The effect of fluconazole on TAZParameterTAZ alone Day 15 Mean (%CV)TAZ + fluconazole Day 19 Mean (%CV)TAZ, n=14Cmax, ng/ml426 (95)968 (80)AUC0-12h, ng*h/mL1590 (81)5180 (66)Part B. The effect of TAZ on REP and OMPREP + OMP Day 1 Mean (%CV)REP + OMP + TAZ Day 16 Mean (%CV)REP, n=12Cmax, ng/ml5 (109)10 (78)AUC0-7h, ng*h/mL9 (110)17 (65)OMP, n=12Cmax, ng/ml263 (266)220 (250)AUC0-7h, ng*h/mL677 (340)558 (231)Part B. The effect of OMP on TAZTAZ prior to OMP Day 16 Mean (%CV)TAZ + OMP Day 19 Mean (%CV)TAZ, n=9Cmax, ng/ml613 (91)663 (68)AUC0-12h, ng*h/mL2200 (58)2820 (62)AUC, area under the concentration curve; CI, confidence interval; Cmax, maximum plasma concentration; CV, coefficient of variation; REP, repaglinide; OMP, omeprazole; PK, pharmacokinetic; TAZ, tazemetostat. Citation Format: Jennifer E. Amengual, Gary K. Schwartz, Lora Inclan, Abhijeet Kumar, Patricia Robles-Medina, Shahnaz Singh-Kandah, Benjamin Suttle, Melissa Beelen, Daniel Persky. Drug-drug interaction potential of EZH2 inhibitor tazemetostat (TAZ) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT028.