Pharmacokinetics, Drug Interaction, and Exposure-Safety Analyses of Tazemetostat When Co-Administered with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Phase 1b Results of Symphony-1

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved in the US for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or who have no satisfactory alternative treatment options. EZH2 modulates the B-cell tumor microenvironment, supporting combination approaches to treatment. SYMPHONY-1 (EZH-302; NCT04224493) is a Phase 1b/3 study designed to determine the phase 3 dose (RP3D), pharmacokinetics, efficacy, and safety of TAZ + lenalidomide and rituximab (R ²) in patients with R/R FL after ≥1 prior therapy. We report here the pharmacokinetics; drug interaction, and exposure-safety analysis of TAZ in combination with R ², which are used to support the dose selection for RP3D.

Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg, bid) in 28-day cycles with standard-dose R ². Primary endpoints of the Phase 1b portion were safety and determination of the recommended phase 3 dose (RP3D). PK of Taz and drug-drug interaction (DDI) with R ² were also evaluated. The AEs Grade 3 or greater of treatment emergent AE (TEAE3), gastro-intestinal AE (GIAE3), neutropenia (NEU3), hepatotoxic event (HEP3), anemia (ANEM3) and thrombosis (THRM3) were assessed, and their relationships with Taz exposure when combined with R ² were explored.

Results: The PK results are based on thirty-nine (39) patients with no major protocol deviations. TAZ PK are characterized by rapid absorption with a Tmax 1.00 hours; and a short half-life which ranged from 3.2 to 3.8 hours across all dose levels. Both Cmax and AUC increased with increasing Taz doses over the dose range. Exposures of 800 mg TAZ at steady state are similar to those found in TAZVERIK Prescribing Information. These results suggest that the PK of TAZ doses 400 mg to 800 mg BID are not altered by concomitant administration of a daily oral dose of 20 mg lenalidomide. Lenalidomide PK (Cmax and AUC) are similar to those found in Revlimid FDA's Biopharm Review (fda.gov). Taken together these data suggest there is no DDI when TAZ is given in combination with R ². The Taz exposure at 800 mg bid in the presence of R ² is over the target engagement of > 80%. No clear increasing AE trend with increasing exposure (AUC) was observed with TEAE3. More importantly, there is no increasing trend of other AEs of gastro-intestinal AE (GIAE3), neutropenia (NEU3), hepatotoxic event (HEP3), and thrombosis (THRM3) with increasing exposure (AUC) or dose was observed. However, there is no ANEM3 observed with the available database.

Conclusions: TAZ + R ² combination demonstrates consistent and unaltered PK for TAZ and lenalidomide, and delivered an optimal target engagement, and favorable safety profile. There is no DDI when TAZ is given in combination with R ². The exposure safety analysis demonstrated that there were no obvious trends in increasing Grade ≥3 AEs with increasing exposure when combined with R ². Based on the totality of the PK, target engagement and exposure-safety analysis, the RP3D of TAZ was determined to be 800 mg BID in combination with R ². The 2-arm randomized phase 3 portion is currently ongoing to further explore the efficacy and safety of TAZ 800 mg + R ² in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.