Abstract CT031: The effect of food on the pharmacokinetics (pk) of tazemetostat in patients with cancer
Authors: Suttle Benjamin , Smith Sherri A. , Waters Nigel L. , Ribrag Vincent , Italiano Antoine , Michot Jean-Marie , Postel-Vinay Sophie , Toulmonde Maud , Cousin Sophie , Roche Maria , Pimentel Patricia , Thomson Blythe , Ho Peter 
Published: July 2016

Tazemetostat is a selective oral small molecule inhibitor of enhancer of zeste homolog 2 (EZH2). In preclinical evaluations of tazemetostat in monkeys, oral administration (30 mg/kg) with concomitant food decreased Cmax and AUC by 10- and 5-fold, respectively, relative to the fasted state. Therefore, a food interaction sub-study was performed as part of the ongoing study E7438-G000-101 (NCT01897571).

Purpose: To investigate the effect of food on the PK of tazemetostat in patients with advanced solid tumors or B-cell lymphomas.

Methods: Patients (n = 13; 5 B-cell lymphoma, 8 solid tumor) received 200 mg tazemetostat fasted and immediately after a high-fat breakfast in a randomized crossover fashion with 7 days between doses. Serial blood samples for analysis of plasma tazemetostat were collected over 24 hours after each dose. Patients received 400 mg twice daily after completing the food effect component of the study.

Results: Preliminary tazemetostat PK data (n = 11) are displayed below. Meal StateCmaxa(ng/mL)AUC(0-∞)a(ng*h/mL)Tmaxb(h)t1/2a(h)Fed232 (107)1080 (85.3)4.0 (1.0 – 6.0)4.38 (26.3)(65.7 – 752)(317.7 – 3070)(2.63 – 6.23)Fasted322 (130)1140 (135)1.04.40 (26.6)(59.6 – 1470)(179 – 6250)(0.5 – 6.0)(2.72 – 7.17)Ratio (90% CI)c0.72 (0.52, 1.00)0.93 (0.66, 1.30)aData are presented as geometric mean [(%CV) (range)]bTmax presented as median (range)cData presented as geometric mean ratio and 90% CI

In contrast to results from monkeys, administration of tazemetostat with a high-fat meal decreased AUC(0-?) and Cmax 7% and 28%, respectively, relative to administration in the fasted state. Administration with a high-fat meal resulted in a 4-fold increase in median Tmax relative to the fasted state. Mean t1/2 values were nearly identical after administration in the fed and fasted states. All Cmax and AUC(0-?) values observed after administration of tazemetostat after a high-fat meal were within the range of the respective values observed after administration in the fasted state.

Conclusions: The effect of food on the PK tazemetostat observed in monkeys did not predict the results observed in cancer patients, possibly due to inter-species differences in gastric residence time and pH. Administration of tazemetostat with a high fat breakfast results in slower absorption with no clinically relevant effect on systemic disposition or overall systemic exposure. These results support administration of tazemetostat without regards to meals.

Citation Format: Benjamin Suttle, Sherri A. Smith, Nigel L. Waters, Vincent Ribrag, Antoine Italiano, Jean-Marie Michot, Sophie Postel-Vinay, Maud Toulmonde, Sophie Cousin, Maria Roche, Patricia Pimentel, Blythe Thomson, Peter Ho. The effect of food on the pharmacokinetics (pk) of tazemetostat in patients with cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT031.