Trial Outcomes & Findings for Effects of Itraconazole and Rifampin on the Blood Tazemetostat Levels (NCT NCT04537715)

Results Overview

Blood samples were collected at specified timepoints. AUC0-12h was assessed using non-compartmental data analysis method. AUC0-12h was estimated by a combination of linear trapezoidal method on concentrations going up and logarithmic trapezoidal method on concentrations going down (Linear up/Log down method).

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

42 participants

Primary outcome timeframe

Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

Results posted on

2025-02-19

Participant Flow

This Phase 1, 2-part, multi-dose, open-label study was conducted in participants with advanced malignancies from 23 April 2020 to 03 April 2023 at 10 investigational sites in Spain and USA. Part 1 evaluated drug-drug interaction (DDI) between tazemetostat and itraconazole; Part 2 evaluated DDI between tazemetostat and rifampin.

This study consisted of a screening period (up to 30 days), Part 1 consisted of Cycle 1 till Day 39, Cycle 2 started on Day 40 and each subsequent cycle was of 28-day duration; Part 2 also consisted of Cycle 1 till Day 26, Cycle 2 started on Day 27 of and each subsequent cycle was of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).

Participant milestones

Participant milestones
Measure	Part 1: Tazemetostat + Itraconazole Participants received a single oral dose of 400 milligram (mg) tazemetostat on Cycle 1 Day 1, twice daily (BID) dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. A single oral dose of 200 mg itraconazole was administered daily from Day 18 to Day 20. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat co-administered with a single dose of oral 200 mg itraconazole. Itraconazole was also administered on Days 37 and 38 as a single oral 200 mg daily dose. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat co-administered with a single dose of oral 200 mg itraconazole. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).	Part 2: Tazemetostat + Rifampin Participants received a single oral dose of 800 mg tazemetostat on Cycle 1 Day 1, BID dose of 800 mg of tazemetostat from Days 3 to 14 and a single oral dose of 800 mg tazemetostat on Day 15. From Days 17 to 23, they received an 800 mg BID dose of tazemetostat co-administered with a single dose of oral 600 mg rifampin. On Day 24, subjects received a single dose of 800 mg tazemetostat co-administered with a single dose of oral 600 mg rifampin. Rifampin was also administered on Cycle 1 Day 25 as a single oral 600 mg dose. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 27 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Overall Study STARTED	21	21
Overall Study COMPLETED	10	16
Overall Study NOT COMPLETED	11	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: Tazemetostat + Itraconazole Participants received a single oral dose of 400 milligram (mg) tazemetostat on Cycle 1 Day 1, twice daily (BID) dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. A single oral dose of 200 mg itraconazole was administered daily from Day 18 to Day 20. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat co-administered with a single dose of oral 200 mg itraconazole. Itraconazole was also administered on Days 37 and 38 as a single oral 200 mg daily dose. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat co-administered with a single dose of oral 200 mg itraconazole. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).	Part 2: Tazemetostat + Rifampin Participants received a single oral dose of 800 mg tazemetostat on Cycle 1 Day 1, BID dose of 800 mg of tazemetostat from Days 3 to 14 and a single oral dose of 800 mg tazemetostat on Day 15. From Days 17 to 23, they received an 800 mg BID dose of tazemetostat co-administered with a single dose of oral 600 mg rifampin. On Day 24, subjects received a single dose of 800 mg tazemetostat co-administered with a single dose of oral 600 mg rifampin. Rifampin was also administered on Cycle 1 Day 25 as a single oral 600 mg dose. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 27 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Overall Study Death	3	1
Overall Study Withdrawal by Subject	3	1
Overall Study Other	4	3
Overall Study Progressive disease	1	0

Baseline Characteristics

Effects of Itraconazole and Rifampin on the Blood Tazemetostat Levels

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: Tazemetostat + Itraconazole n=21 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. A single oral dose of 200 mg itraconazole was administered daily from Day 18 to Day 20. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat co-administered with a single dose of oral 200 mg itraconazole. Itraconazole was also administered on Days 37 and 38 as a single oral 200 mg daily dose. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat co-administered with a single dose of oral 200 mg itraconazole. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).	Part 2: Tazemetostat + Rifampin n=21 Participants Participants received a single oral dose of 800 mg tazemetostat on Cycle 1 Day 1, BID dose of 800 mg of tazemetostat from Days 3 to 14 and a single oral dose of 800 mg tazemetostat on Day 15. From Days 17 to 23, they received an 800 mg BID dose of tazemetostat co-administered with a single dose of oral 600 mg rifampin. On Day 24, subjects received a single dose of 800 mg tazemetostat co-administered with a single dose of oral 600 mg rifampin. Rifampin was also administered on Cycle 1 Day 25 as a single oral 600 mg dose. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 27 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).	Total n=42 Participants Total of all reporting groups
Age, Continuous	60.9 years STANDARD_DEVIATION 13.45 • n=5 Participants	60.1 years STANDARD_DEVIATION 13.05 • n=7 Participants	60.5 years STANDARD_DEVIATION 13.09 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	13 Participants n=7 Participants	21 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	8 Participants n=7 Participants	21 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	19 Participants n=5 Participants	18 Participants n=7 Participants	37 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized White	18 Participants n=5 Participants	12 Participants n=7 Participants	30 Participants n=5 Participants
Race/Ethnicity, Customized Asian	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Not reported/Other	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

Population: The Pharmacokinetic (PK) population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. AUC0-12h was assessed using non-compartmental data analysis method. AUC0-12h was estimated by a combination of linear trapezoidal method on concentrations going up and logarithmic trapezoidal method on concentrations going down (Linear up/Log down method).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours of Quantifiable Concentration (AUC0-12h) of Tazemetostat Cycle 1 Day 1	2180 hoursnanogram/milliliter (hng/mL) Geometric Coefficient of Variation 55.3
Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours of Quantifiable Concentration (AUC0-12h) of Tazemetostat Cycle 1 Day 15	1830 hoursnanogram/milliliter (hng/mL) Geometric Coefficient of Variation 37.6

PRIMARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, 48, and 72 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Maximum Observed Plasma Concentration (Cmax) of Tazemetostat Cycle 1 Day 1	704 ng/mL Geometric Coefficient of Variation 56.5
Part 1: Maximum Observed Plasma Concentration (Cmax) of Tazemetostat Cycle 1 Day 15	543 ng/mL Geometric Coefficient of Variation 63.3

PRIMARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. AUC0-12h was assessed using non-compartmental data analysis method. AUC0-12h was estimated by a combination of linear trapezoidal method on concentrations going up and logarithmic trapezoidal method on concentrations going down (Linear up/Log down method).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: AUC0-12h of Tazemetostat Cycle 1 Day 1	4420 h*ng/mL Geometric Coefficient of Variation 83.2
Part 2: AUC0-12h of Tazemetostat Cycle 1 Day 15	3610 h*ng/mL Geometric Coefficient of Variation 70.3

PRIMARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: Cmax of Tazemetostat Cycle 1 Day 1	1330 ng/mL Geometric Coefficient of Variation 67.4
Part 2: Cmax of Tazemetostat Cycle 1 Day 15	1100 ng/mL Geometric Coefficient of Variation 78.7

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. AUC0-12h was assessed using non-compartmental data analysis method. AUC0-12h was estimated by a combination of linear trapezoidal method on concentrations going up and logarithmic trapezoidal method on concentrations going down (Linear up/Log down method).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State	3650 h*ng/mL Geometric Coefficient of Variation 26.4

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 36

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. AUC0-12h was assessed using non-compartmental data analysis method. AUC0-12h was estimated by a combination of linear trapezoidal method on concentrations going up and logarithmic trapezoidal method on concentrations going down (Linear up/Log down method).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole EPZ-6930	5450 h*ng/mL Geometric Coefficient of Variation 46.6
Part 1: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole Tazemetostat	4530 h*ng/mL Geometric Coefficient of Variation 64.5

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, and 72 hours post-dose on Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State	780 ng/mL Geometric Coefficient of Variation 38.2

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, and 72 hours post-dose on Cycle 1 Day 36

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Itraconazole EPZ-6930	792 ng/mL Geometric Coefficient of Variation 44.7
Part 1: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Itraconazole Tazemetostat	1010 ng/mL Geometric Coefficient of Variation 76.3

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, and 72 hours post-dose on Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Observed Time at Cmax (Tmax) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State Tazemetostat	1.34 hour Geometric Coefficient of Variation 72.1
Part 1: Observed Time at Cmax (Tmax) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State EPZ-6930	1.70 hour Geometric Coefficient of Variation 51.4

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, and 72 hours post-dose on Cycle 1 Day 36

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole Tazemetostat	1.55 hour Geometric Coefficient of Variation 63.4
Part 1: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole EPZ-6930	1.82 hour Geometric Coefficient of Variation 49.9

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, and 72 hours post-dose on Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole. Only data from the participants analyzed were reported.

Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Apparent Terminal Elimination Half-Life (t1/2) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State Tazemetostat	8.21 hour Interval 4.67 to 19.8
Part 1: Apparent Terminal Elimination Half-Life (t1/2) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State EPZ-6930	15.8 hour Interval 8.1 to 22.8

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, and 72 hours post-dose on Cycle 1 Day 36

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole. Only data from the participants analyzed were reported.

Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole Tazemetostat	12.8 hour Interval 6.4 to 22.0
Part 1: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole EPZ-6930	13.9 hour Interval 7.19 to 21.6

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. AUC0-12h was assessed using non-compartmental data analysis method. AUC0-12h was estimated by a combination of linear trapezoidal method on concentrations going up and logarithmic trapezoidal method on concentrations going down (Linear up/Log down method).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State	7010 h*ng/mL Geometric Coefficient of Variation 72.0

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 24

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. AUC0-12h was assessed using non-compartmental data analysis method. AUC0-12h was estimated by a combination of linear trapezoidal method on concentrations going up and logarithmic trapezoidal method on concentrations going down (Linear up/Log down method).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin EPZ-6930	3070 h*ng/mL Geometric Coefficient of Variation 34.1
Part 2: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin Tazemetostat	588 h*ng/mL Geometric Coefficient of Variation 65.2

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours post-dose on Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State	1530 ng/mL Geometric Coefficient of Variation 49.5

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 hours post-dose on Cycle 1 Day 24

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Rifampin Tazemetostat	181 ng/mL Geometric Coefficient of Variation 71.7
Part 2: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Rifampin EPZ-6930	857 ng/mL Geometric Coefficient of Variation 40.5

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours post-dose on Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State Tazemetostat	1.25 hour Geometric Coefficient of Variation 47.0
Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State EPZ-6930	1.47 hour Geometric Coefficient of Variation 59.1

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 hours post-dose on Cycle 1 Day 24

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin Tazemetostat	1.40 hour Standard Deviation 1.10
Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin EPZ-6930	1.85 hour Standard Deviation 0.934

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours post-dose on Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin. Only data from the participants analyzed were reported.

Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: T1/2 of Tazemetostat and EPZ-6930 EPZ-6930 After Tazemetostat Alone at Steady-State Tazemetostat	7.21 hour Interval 5.55 to 10.6
Part 2: T1/2 of Tazemetostat and EPZ-6930 EPZ-6930 After Tazemetostat Alone at Steady-State EPZ-6930	8.38 hour Interval 6.44 to 13.8

SECONDARY outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 hours post-dose on Cycle 1 Day 24

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin. Only data from the participants analyzed were reported.

Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=15 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin Tazemetostat	5.24 hour Interval 2.45 to 8.19
Part 2: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin EPZ-6930	8.07 hour Interval 3.7 to 10.3

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. AUC0-12h accumulation ratio was assessed using non-compartmental data analysis method. AUC0-12h accumulation ratio was calculated as the ratio of AUC0-12h at steady state (Cycle 1 Day 15) divided by AUC0-12 during the initial dosing interval (Cycle 1 Day 1).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat	0.842 ratio Interval 0.726 to 0.976

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8,12, 36, 48 post-dose on Cycle 1 Day 1, and 72 hours post-dose on Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. Cmax accumulation ratio was assessed using non-compartmental data analysis method. Cmax accumulation ratio was calculated as the ratio of Cmax at steady state (Cycle 1 Day 15) divided by Cmax during the initial dosing interval (Cycle 1 Day 1).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat	0.771 ratio Interval 0.662 to 0.897

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 1 (without itraconazole) and Cycle 1 Day 21 (with itraconazole)

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using analysis of variance (ANOVA).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Single Dose of Tazemetostat With Itraconazole	3.12 ratio Interval 2.44 to 3.99

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours post-dose on Cycle 1 Day 1 (without itraconazole) and Cycle 1 Day 21 (with itraconazole)

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Least Squares Geometric Mean Ratio of Cmax After Single Dose of Tazemetostat With Itraconazole	2.00 ratio Interval 1.6 to 2.48

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 15 (without itraconazole) and Cycle 1 Day 36 (with itraconazole)

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Tazemetostat at Steady-State With Itraconazole	2.47 ratio Interval 2.02 to 3.02

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, and 72 hours post-dose on Cycle 1 Day 15 (without itraconazole) and Cycle 1 Day 36 (with itraconazole)

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 1 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or itraconazole.

Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 1: Least Squares Geometric Mean Ratio of Cmax After Tazemetostat at Steady-State With Itraconazole	1.86 ratio Interval 1.49 to 2.31

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8,12, 24, 36, and 48 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. AUC0-12h accumulation ratio was assessed using non-compartmental data analysis method. AUC0-12h accumulation ratio was calculated as the ratio of AUC0-12h at steady state (Cycle 1 Day 15) divided by AUC0-12h during the initial dosing interval (Cycle 1 Day 1).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat	0.816 ratio Interval 0.638 to 1.04

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8,12, 24, 36, and 48 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. Cmax accumulation ratio was assessed using non-compartmental data analysis method. Cmax accumulation ratio was calculated as the ratio of Cmax at steady state (Cycle 1 Day 15) divided by Cmax during the initial dosing interval (Cycle 1 Day 1).

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat	0.828 ratio Interval 0.635 to 1.08

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 15 (without rifampin) and Cycle 1 Day 24 (with rifampin)

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: Least Squares Geometric Mean Ratio of AUC0-12h After Tazemetostat at Steady State With Rifampin	0.163 ratio Interval 0.128 to 0.208

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours post-dose on Cycle 1 Day 15 (without rifampin) and Cycle 1 Day 24 (with rifampin)

Population: The PK population included all participants who had sufficient PK concentration data to calculate steady-state PK parameters in Part 2 and did not have any major protocol deviation that was deemed to greatly alter the steady-state exposure to tazemetostat or rifampin.

Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA.

Outcome measures

Outcome measures
Measure	Part 1: Tazemetostat n=16 Participants Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Part 2: Least Squares Geometric Mean Ratio of Cmax After Tazemetostat at Steady State With Rifampin	0.164 ratio Interval 0.122 to 0.219

Adverse Events

Part 1: Tazemetostat + Itraconazole

Serious events: 8 serious events

Other events: 19 other events

Deaths: 10 deaths

Part 2: Tazemetostat + Rifampin

Serious events: 9 serious events

Other events: 20 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Lead or Designee

Epizyme, Inc.

Phone: (855) 500-1011

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER

Measure	Part 1: Tazemetostat + Itraconazole n=21 participants at risk Participants received a single oral dose of 400 mg tazemetostat on Cycle 1 Day 1, BID dose of tazemetostat 400 mg on Days 3 to 14 and single dose of tazemetostat 400 mg on Day 15. A single oral dose of 200 mg itraconazole was administered daily from Day 18 to Day 20. From Days 21 to 35, they received a 400 mg BID dose of tazemetostat co-administered with a single dose of oral 200 mg itraconazole. Itraconazole was also administered on Days 37 and 38 as a single oral 200 mg daily dose. On Cycle 1 Day 36, they received a single dose of 400 mg tazemetostat co-administered with a single dose of oral 200 mg itraconazole. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 40 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).	Part 2: Tazemetostat + Rifampin n=21 participants at risk Participants received a single oral dose of 800 mg tazemetostat on Cycle 1 Day 1, BID dose of 800 mg of tazemetostat from Days 3 to 14 and a single oral dose of 800 mg tazemetostat on Day 15. From Days 17 to 23, they received an 800 mg BID dose of tazemetostat co-administered with a single dose of oral 600 mg rifampin. On Day 24, subjects received a single dose of 800 mg tazemetostat co-administered with a single dose of oral 600 mg rifampin. Rifampin was also administered on Cycle 1 Day 25 as a single oral 600 mg dose. Participants continued to receive tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat BID), from Day 27 (Cycle 2 Day 1) for each subsequent cycle of 28-day duration until Investigator assessed clinical progression per standard practice, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure).
Gastrointestinal disorders Colitis	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Cardiac disorders Pericardial effusion	9.5% 2/21 • Number of events 2 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Gastrointestinal disorders Diarrhoea	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Gastrointestinal disorders Vomiting	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
General disorders Oedema peripheral	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
General disorders Pain	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Infections and infestations Pneumonia	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Infections and infestations Sepsis	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	9.5% 2/21 • Number of events 2 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Infections and infestations Abdominal infection	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Infections and infestations COVID-19	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Infections and infestations Enterocolitis infectious	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Infections and infestations Urinary tract infection	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Investigations Blood bilirubin increased	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Nervous system disorders Hemiparesis	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Renal and urinary disorders Acute kidney injury	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 2 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	9.5% 2/21 • Number of events 2 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Respiratory, thoracic and mediastinal disorders Respiratory failure	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.
Vascular disorders Superior vena cava syndrome	4.8% 1/21 • Number of events 1 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.	0.00% 0/21 • Treatment-emergent adverse events and all-cause mortality were reported from the first dose of study treatment (Day 1) through 30 days after the end of study treatment (approximately 33 months). The Safety population included all participants in the Enrolled population who received at least 1 dose or partial dose of the study treatments and had 1 post-dose safety observation recorded.