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Tazemetostat (TAZ), a selective inhibitor of EZH2, was administered intravenously and orally (unlabeled and [14C]-labeled) to patients (pts) with B-Cell lymphomas (BCL) or advanced solid tumors (AdvST) to characterize its pharmacokinetic (PK) (oral TAZ only) and safety profile in an open-label, 2-part phase 1 study (NCT03010982). In Part A, pts received oral TAZ (800 mg twice daily) for ≥14 days plus 1 dose of [14C]-labeled TAZ (12 μg TAZ containing 500 nCi of [14C]-TAZ) as an IV bolus on Day 15. Serial blood samples were collected for 24 hours after the Day 15 oral dose. In part B, pts received oral TAZ solution (800 mg twice daily) containing ~400 μCi (14.8 MBq) of [14C]-TAZ on Day 16. Blood, plasma, urine, and fecal samples were collected for up to 120 hours after administration. Pts could continue receiving oral TAZ until disease progression/unacceptable toxicity. Part A primary endpoints included PK parameters for oral TAZ, metabolite EPZ-6930, and IV [14C]-TAZ. Part B primary endpoints included total and relative radioactivity excretion. Secondary endpoints included safety (both parts), TAZ bioavailability (Part A), and additional PK parameters (Part B). As of May 7, 2019, 3 lymphoma pts were enrolled and received study treatment as planned. The pts were of >50 years of age and had received ≥3 prior lines of systemic therapy. The half-life of TAZ and its metabolite EPZ-6930 was 3-4 hours regardless of the route of administration. Cumulatively, 93.25%-94.7% of the administered TAZ dose was excreted through urine and feces. Two pts discontinued TAZ due to disease progression and the remaining pt entered a rollover study. All pts experienced ≥1 treatment-related (TR) treatment-emergent adverse events (TEAEs); 2 experienced ≥1 Grade 3/4 TR TEAEs. No TEAE resulted in dose reduction/interruption. All pts experienced ≥1 serious TEAEs; 2 experienced serious TR TEAEs. PK and safety in this small sample size are consistent with those previously reported.

TAZEPZ-6930[14C]-TAZ
PK Parameter (Unit)Day 15 (oral TAZ: tablets) (n=3)Day 16 (oral TAZ: solution) (n=3)Day 15 (oral TAZ: tablets) (n=3)Day 16 (oral TAZ: solution) (n=3)Day 16 (TAZ IV bolus) (n=3
Cmax (ng/mL)a 1110 (37.5) 1780 (51.5) 1670 (25) 2190 (25.3) 0.702 (0.0154) 
tmax (h)b 1.05 (1.02-2.92) 0.917 (0.583-0.967) 1.05 (1.02-4.92) 1.97 (0.917-1.98) 0.0167 (0.0167-0.0333) 
AUC0-last (h•ng/mL)a 4390 (74.1) 6950 (65.7) 9750 (54.5) 13200 (46.8) 210 (27.6) 
AUC0-∞ (h•ng/mL)a 5110 (69.2) 7620 (64.9) 12000 (46.9) 14900 (50.4) 218 (26.4) 
AUC0-12 (h•ng/mL)a 4620 (69.5) 6950 (65.6) 10400 (47.9) 13200 (46.7) 206 (21.8) 
t½ (h)a 3.52 (12.4) 3.66 (20.5) 3.91 (15.7) 3.53 (8.99) 3.39 (23.8) 
λza 0.197 (12.6) 0.189 (18.5) 0.177 (14.5) 0.196 (9.18) 0.204 (22.4) 
CL/F (L/h)a ND ND ND ND 55.0 (23.2) 
Vz/F (L)a ND ND ND ND 269 (12.5) 
MPRa NA NA 2.36 (0.193) 2.00 (0.166) NA 
TAZEPZ-6930[14C]-TAZ
PK Parameter (Unit)Day 15 (oral TAZ: tablets) (n=3)Day 16 (oral TAZ: solution) (n=3)Day 15 (oral TAZ: tablets) (n=3)Day 16 (oral TAZ: solution) (n=3)Day 16 (TAZ IV bolus) (n=3
Cmax (ng/mL)a 1110 (37.5) 1780 (51.5) 1670 (25) 2190 (25.3) 0.702 (0.0154) 
tmax (h)b 1.05 (1.02-2.92) 0.917 (0.583-0.967) 1.05 (1.02-4.92) 1.97 (0.917-1.98) 0.0167 (0.0167-0.0333) 
AUC0-last (h•ng/mL)a 4390 (74.1) 6950 (65.7) 9750 (54.5) 13200 (46.8) 210 (27.6) 
AUC0-∞ (h•ng/mL)a 5110 (69.2) 7620 (64.9) 12000 (46.9) 14900 (50.4) 218 (26.4) 
AUC0-12 (h•ng/mL)a 4620 (69.5) 6950 (65.6) 10400 (47.9) 13200 (46.7) 206 (21.8) 
t½ (h)a 3.52 (12.4) 3.66 (20.5) 3.91 (15.7) 3.53 (8.99) 3.39 (23.8) 
λza 0.197 (12.6) 0.189 (18.5) 0.177 (14.5) 0.196 (9.18) 0.204 (22.4) 
CL/F (L/h)a ND ND ND ND 55.0 (23.2) 
Vz/F (L)a ND ND ND ND 269 (12.5) 
MPRa NA NA 2.36 (0.193) 2.00 (0.166) NA 

Note: Day 15 included oral administration of 800 mg TAZ and Day 16 included oral administration of 800 mg TAZ containing 400 μCi of [14C]-TAZ.

aData reported as geometric mean (CV%).

bData reported as median (minimum-maximum). λz = apparent first-order terminal elimination rate constant; AUC0-∞ = area under the concentration-time curve from time 0 extrapolated to infinity time; AUC0-12 = area under the concentration-time curve from time 0 to 12 hours; AUC0-last = area under the concentration-time curve from time 0 to last; CL/F = apparent clearance; Cmax = maximum plasma concentration; CV% = percent coefficient of variation; IV = intravenous; MPR = metabolite-to-parent ratio; NA = not applicable; ND = not determined; PK = pharmacokinetic; t½ = half-life; TAZ = tazemetostat; tmax = time to maximum plasma concentration; Vz/F = apparent volume of distribution.

Citation Format: Evren Kocabas Argon, Felicia Nguyen, Anand Rajarethinam, Vikram Kansra, Andrew Pettitt. Phase 1 study to characterize the pharmacokinetics and safety of tazemetostat in b-cell lymphomas or advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT170.

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