TAZVERIK Film coated tablet Ref.[10219] Active ingredients:

Tazemetostat exposure-response relationships and the time course of pharmacodynamic responses are unknown.

Cardiac Electrophysiology

The effect of orally administered TAZVERIK, at doses ranging from 100 mg to 1600 mg twice daily (0.125 to 2 times the approved recommended dosage) for 15 days, on the heart-rate corrected QT (QTc) interval was evaluated in a dose-finding study in 38 patients with advanced malignancies. Tazemetostat and its metabolite EPZ-6930 did not cause a large mean increase (i.e. >20 ms) on the QTc interval at the 800 mg twice daily dose. The largest mean increase (upper bound of 90% confidence interval) in QTc were 6.1 ms (8.5 ms) and 9.3 ms (12.5 ms) at a dose of 800 mg twice daily and 1600 mg twice daily, respectively.

The systemic exposure of tazemetostat is approximately dose proportional over the dose range of 200 mg to 1600 mg twice daily of TAZVERIK (0.25 to 2 times the approved recommended dosage). Following TAZVERIK 800 mg orally twice daily, steady-state was reached by Day 15. The mean (coefficient of variation [CV]) steady-state peak plasma concentration (C_max) was 829 (56) ng/mL and AUC_0-12h was 3340 (49%) ng•h/mL. Tazemetostat exhibited time-dependent pharmacokinetics (PK). The mean accumulation ratio (measured by AUC) was 0.58.

Absorption

The mean absolute oral bioavailability of tazemetostat is approximately 33%. The median time to reach the peak plasma concentration of tazemetostat is 1 to 2 hours.

Effect of Food

A high-fat, high-calorie (approximately 800 to 1000 calories) meal does not have a significant effect on tazemetostat exposure.

Distribution

The mean (CV%) apparent volume of distribution at steady-state (V_ss/F) is 1230 L (46%). Tazemetostat is 88% bound to human plasma proteins in vitro. The blood-to-plasma ratio is 0.73.

Elimination

At steady-state, the estimated mean (CV%) terminal elimination half-life of tazemetostat is 3.1 hours (14%) and the apparent total clearance (CL_ss/F) is 274 L/h (49%).

Metabolism

In vitro, tazemetostat is metabolized by CYP3A to form the inactive major metabolites M5 (EPZ-6930) and M3 (EPZ006931). M5 undergoes further metabolism by CYP3A.

Excretion

Following a single oral dose of radiolabeled tazemetostat, 94% of the total radioactivity was recovered over 12 days, with 15% excreted into urine and 79% into feces.

Specific Populations

Age (16 to 91 years), sex, race (White, Black, Asian), body weight (37.3 to 173 kg), mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN) and renal impairment, including end stage renal disease, have no clinically meaningful effect on the pharmacokinetics of tazemetostat. The effect of moderate to severe hepatic impairment has not been studied.

Drug Interaction Studies

Clinical Studies

Effect of CYP3A Inhibitors on Tazemetostat: Coadministration of fluconazole (a moderate CYP3A inhibitor) with TAZVERIK 400 mg twice daily in patients increased tazemetostat steady-state AUC_0-8h by 3.1-fold and C_max by 2.3-fold.

Effect of Gastric Acid Reducing Agents on Tazemetostat: Coadministration of omeprazole (a proton pump inhibitor) with TAZVERIK 800 mg twice daily in patients increased tazemetostat steady-state AUC_0-8h by 26% and C_max by 25%, which is not expected to have clinically relevant impact.

Effect of Tazemetostat on CYP3A Substrate: Coadministration of TAZVERIK 800 mg twice daily with oral midazolam (a sensitive CYP3A substrate) in patients decreased midazolam AUC_0-12h by 40% and C_max by 21%.

Effect of Tazemetostat on CYP2C8 and CYP2C19 Substrates: Coadministration of TAZVERIK 800 mg twice daily with repaglinide (a sensitive CYP2C8 substrate) and omeprazole (a sensitive CYP2C19 substrate) in patients increased repaglinide AUC_0-8h by 80% and C_max by 51%; and had no effect on the exposure of omeprazole.

In Vitro Studies

Metabolic Enzymes: Tazemetostat does not inhibit CYP1A2, CYP2B6, CYP2C9, and CYP2D6 at clinically relevant concentrations.

Drug Transporters: Tazemetostat is a substrate of p-glycoprotein (P-gp). Tazemetostat is not a substrate of breast cancer resistance protein (BCRP); renal transporters organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), and multidrug and toxin extrusion transporter 1 (MATE1); or hepatic transporters organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3).

Tazemetostat is an inhibitor of MATE1 and multidrug and toxin extrusion transporter 2-K (MATE2-K). Tazemetostat does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, organic cation transporter 1 (OCT1), OCT2, organic anion transporter 1 (OAT1), OAT3, or bile salt export pump (BSEP) at clinically relevant concentrations.

Dedicated carcinogenicity studies were not conducted with tazemetostat, but T-LBL, MDS, and AML have been reported clinically and T-LBL occurred in juvenile and adult rats after ~9 or more weeks of tazemetostat administration during 13-week toxicity studies. Based on nonclinical studies in rats, the risk of T-LBL appears to be greater with longer duration dosing.

Tazemetostat did not cause genetic damage in a standard battery of studies including a screening and pivotal bacterial reverse mutation (Ames) assay, an in vitro micronucleus assessment in human peripheral blood lymphocytes, and an in vivo micronucleus assessment in rats after oral administration.

Fertility and early embryonic development studies have not been conducted with tazemetostat; however, an assessment of male and female reproductive organs were included in 4- and 13-week repeat-dose toxicity studies in rats and Cynomolgus monkeys. Oral daily administration of tazemetostat did not result in any notable effects in the adult male and female reproductive organs [see Use in Specific Populations (8.3)].

14.1 Epithelioid Sarcoma

The efficacy of TAZVERIK was evaluated in an open-label, single-arm cohort (Cohort 5) of a multi-center study (Study EZH-202, NCT02601950) in patients with histologically confirmed, metastatic or locally advanced epithelioid sarcoma. Patients were required to have INI1 loss, detected using local tests, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2. Patients received TAZVERIK 800 mg orally twice daily until disease progression or unacceptable toxicity. Tumor response assessments were performed every 8 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by blinded independent central review (BICR) and duration of response (DOR). Median duration of follow-up was 14 months (range 0.4 to 31).

Among the 62 patients who received TAZVERIK, median age was 34 years (range 16 to 79); 63% were male, 76% were White, 11% were Asian, 44% had proximal disease, 92% had an ECOG PS of 0 or 1, and 8% had an ECOG PS of 2. Prior surgery occurred in 77% of patients; 61% received prior systemic chemotherapy.

Efficacy results are summarized in Table 8.

Table 8. Efficacy Results for Patients with Epithelioid Sarcoma Enrolled in Cohort 5 of Study EZH-202:

CI = Confidence Interval
* Time to response ranged from 1.4 to 18.4 months.

14.2 Relapsed or Refractory Follicular Lymphoma

The efficacy of TAZVERIK was evaluated in two open-label, single-arm cohorts (Cohorts 4 and 5) of a multi-center study (Study E7438-G000-101, NCT01897571) in patients with histologically confirmed follicular lymphoma after at least 2 prior systemic therapies. Patients were required to have ECOG PS of 0-2 and were enrolled based on EZH2 mutation status. EZH2 mutations were identified prospectively using formalin-fixed, paraffin-embedded tumor samples, which were centrally tested using the cobas EZH2 Mutation Test; the cobas EZH2 Mutation test is designed to detect the following mutations: Y646X [S,H,C], Y646F, Y646N, A682G, and A692V. Patients received TAZVERIK 800 mg orally twice daily until confirmed disease progression or unacceptable toxicity. Tumor response assessments were performed every 8 weeks through Week 24 and then every 12 weeks. The major efficacy outcome measures were ORR and DOR according to the International Working Group Non-Hodgkin Lymphoma (IWG-NHL) criteria ¹ as assessed by Independent Review Committee. Median duration of follow-up was 22 months (range 3 months to 44 months) for patients with EZH2 MT positive tumors and 36 months (range 32 months to 39 months) for patients whose tumors did not have an EZH2 mutation detected.

A total of 99 patients were enrolled, including 45 patients whose tumors had one of these EZH2 mutations (mutant) and 54 patients whose tumors did not have one of these mutations (wild-type).

Among the 45 patients with EZH2 mutant follicular lymphoma, median age was 62 years (range 38 to 80), 58% were female, 42% had early progression following front-line therapy (POD24), and all had an ECOG PS of 0
or 1. Race was reported in 84% of patients; of these patients, 82% were White. Based on the cobas EZH2 Mutation test, 36%, 29%, 27%, 11% and 2% of patients had the following mutations: Y646X [S,H,C], Y646F, Y646N, A682G, and A692V, respectively. The median number of lines of prior systemic therapy was 2 (range 1 to 11), with 49% refractory to rituximab, 49% refractory to their last therapy, and 9% had received prior stem cell transplant.

Among the 54 patients with EZH2 wild-type follicular lymphoma, median age was 61 years (range 36 to 87), 63% were male, 59% had POD24, and 91% had an ECOG PS of 0 or 1. Race was reported in 57% of patients; of these patients, 48% were White and 3% were Asian. The median number of lines of prior systemic therapy was 3 (range 1 to 8), with 59% refractory to rituximab, 41% refractory to their last therapy, and 39% had received prior stem cell transplant.

The approval of TAZVERIK was based upon the efficacy in 95 patients (42 EZH2 Mutant, 53 EZH2 Wild-Type) who had received at least 2 prior systemic therapies and is presented in Table 9.

Table 9. Efficacy Results for Patients with Relapsed or Refractory Follicular Lymphoma Enrolled into Cohorts 4 and 5 of Study E7438-G000-101:

CI = Confidence Interval; NE = Not Estimable.
* Median time to response for patients with EZH2 MT follicular lymphoma was 3.7 months (range 1.6 to 10.9) and for patients with EZH2 WT follicular lymphoma was 3.9 months (range 1.6 to 16.3).