Advanced Malignancies, All Malignancies, Diffuse Large B-Cell Lymphoma (DLBCL), Epithelioid Sarcoma (ES), Follicular Lymphoma (FL), Hematologic Malignancy, Mesothelioma, Non-Hodgkin Lymphoma (NHL), Renal Medullary Carcinoma, Rhabdoid Tumor, Solid Tumor, Synovial Sarcoma
Conditions
Keywords
Epizyme, Tazverik, Tazemetostat (EPZ-6438), Itraconazole, CYP3A4 inhibitor, Rifampin, CYP3A4 inducer, Drug-Drug Interaction (DDI), Pharmacokinetics (PK)
Brief summary
The participants of this study will have advanced malignancies (also known as advanced cancer). The main aim of this trial will be to study the blood levels (known as pharmacokinetics) of the tazemtostat (the study drug) when administered in combination with another drug. Part 1 of the study will evaluate the interaction between the drugs tazemetostat and itraconazole. Part 2 of the study will evaluate the interaction between the drugs tazemetostat and rifampin For both Parts 1 and 2, safety and the level that effects of the study drug can be tolerated (known as tolerability) will be assessed throughout.
Detailed description
This two-part study is designed to characterize the steady-state PK of oral tazemetostat and its metabolite EPZ 6930 when administered as a single and twice daily dose in subjects with advanced malignancies while taken alone or in combination with either itraconazole or rifampin. Part 1: tazemetostat and Itraconazole Drug Interaction Part 1 of the study will evaluate the drug-drug interaction between tazemetostat and itraconazole in an open-label, fixed sequential cross over design. Part 2: tazemetostat and Rifampin Drug Interaction Part 2 of the study will evaluate the drug-drug interaction between tazemetostat and rifampin in an open-label, fixed sequential cross over design. For both Parts 1 and 2, safety and tolerability will be assessed throughout the subject's participation. Subjects must have an end of study visit after 30 days of the last dose of tazemetostat for safety assessment.
Interventions
DRUGTazemetostat
A single, oral, 400 mg dose of tazemetostat on Day 1, Day 15, and Day 36; and tazemetostat (oral 400 mg) tablets twice daily on Days 3 - 14 and Days 21 - 35.
DRUGItraconazole
Oral 200 mg itraconazole once daily on Days 18 - 38
DRUGRifampin
Oral 600 mg rifampin once daily on Days 17 - 25.
Sponsors
Epizyme, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥ 18 years age at the time of consent. 2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. 3. Has the ability to understand informed consent, and provide signed written informed consent. 4. Life expectancy of \> 3 months. 5. Histologically and/or cytologically confirmed advanced metastatic or unresectable solid tumors has progressed after treatment for which there are no standard therapies available OR histologically and/or cytologically confirmed hematologic malignancies that have relapsed, or refractory disease, following at least 2 standard lines of systemic therapy for which there are no standard therapies available. Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone will not be considered a separate systemic treatment regimen. 6. Must have evaluable or measurable disease. 7. Has all prior treatment (ie, chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 or are clinically stable and not clinically significant, at time of consent. 8. All subjects must have completed any prior chemotherapy, targeted therapy and major surgery ≥ 28 days before study entry. For daily or weekly chemotherapy without the potential for delayed toxicity, a washout period of 14 days or 5 half-lives, whichever is shorter may be acceptable. 9. Has normal hepatic function (per NCI-ODWG criteria) as well as adequate hematologic (bone marrow \[BM\] and coagulation factors) and renal function. 10. Able to swallow and retain orally-administered medication and without clinically significant gastrointestinal abnormalities that could alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. 11. Females of childbearing potential (FCBP) must have a negative serum pregnancy test and must either practice complete abstinence or agree to use a highly effective method of contraception. 12. Male subjects must have had a successful vasectomy OR must either practice complete abstinence or agree to use a latex or synthetic condom during sexual contact with a female of childbearing potential (FCBP) during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation. NOTE: Male subjects must not donate sperm during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation. 13. Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec.
Exclusion criteria
1. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression or primary glioblastoma multiforme. 2. Clinically significant bleeding diathesis or coagulopathy. 3. Known hypersensitivity to any of the components of Tazemetostat, itraconazole, or rifampin. 4. Use of concurrent investigational agent or anticancer therapy. 5. Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmias, or psychiatric illness/social situations that would limit compliance with study requirements. 6. Have a known active infection with hepatitis B virus (HBV), hepatitis C virus (HCV), AND/OR human T-cell lymphotropic virus 1. 7. Subjects taking medications that are known CYP3A4 inducers or inhibitors (including St. John's Wort). 8. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from 24 hours prior to the first dose of study drug until the last dose of study drug. 9. Any condition or medical problem in addition to the underlying malignancy and organ dysfunction that the Investigator feels would pose unacceptable risk. 10. Has a prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN) or T-cell lymphoblastic lymphoma (T-LBL)/ T-cell acute lymphoblastic leukemia (T-ALL). 11. Ingestion of alcohol within 72 hours prior to day 1 of Cycle 1 until the end of Cycle 1 (Day 39 for Part 1 and Day 26 for Part 2). Regular alcohol consumption must not exceed 16 units for males and 7 units for females per week (2 units equals 40mL \[a can\] of beer, 175mL \[a standard glass\] of wine, or 50 mL \[2 small shots\] of spirits 12. Any form of marijuana use. 13. History of drug abuse (including alcohol) within the last 6 months prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Tazemetostat | 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 | Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method. |
| Part 2: Cmax of Tazemetostat | 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 | Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method. |
| Part 2: AUC0-12h of Tazemetostat | 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 | 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). |
| Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours of Quantifiable Concentration (AUC0-12h) of Tazemetostat | 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 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole | 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 | Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method. |
| Part 1: Apparent Terminal Elimination Half-Life (t1/2) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State | 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 | Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method. |
| Part 1: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole | 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 | Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method. |
| Part 2: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State | Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 15 | 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). |
| Part 2: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin | Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 24 | 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). |
| Part 2: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State | 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 | Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method. |
| Part 2: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Rifampin | 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 | Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method. |
| Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State | 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 | Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method. |
| Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin | 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 | Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method. |
| Part 2: T1/2 of Tazemetostat and EPZ-6930 EPZ-6930 After Tazemetostat Alone at Steady-State | 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 | Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method. |
| Part 2: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin | 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 | Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method. |
| Part 1: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State | Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 15 | 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). |
| Part 1: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole | Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 36 | 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). |
| Part 1: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State | 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 | Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method. |
| Part 1: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Itraconazole | 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 | Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method. |
| Part 1: Observed Time at Cmax (Tmax) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State | 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 | Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Least Squares Geometric Mean Ratio of Cmax After Tazemetostat at Steady-State With Itraconazole | 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) | Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA. |
| Part 2: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat | 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 | 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). |
| Part 2: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat | 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 | 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). |
| Part 2: Least Squares Geometric Mean Ratio of AUC0-12h After Tazemetostat at Steady State With Rifampin | 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) | Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA. |
| Part 2: Least Squares Geometric Mean Ratio of Cmax After Tazemetostat at Steady State With Rifampin | 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) | Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA. |
| Part 1: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat | 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 | 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). |
| Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Single Dose of Tazemetostat With Itraconazole | 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) | Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using analysis of variance (ANOVA). |
| Part 1: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat | 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 | 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). |
| Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Tazemetostat at Steady-State With Itraconazole | 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) | Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA. |
| Part 1: Least Squares Geometric Mean Ratio of Cmax After Single Dose of Tazemetostat With Itraconazole | 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) | Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA. |
Countries
Spain, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Tazemetostat + Itraconazole 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). | 21 |
| 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). | 21 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 1 |
| Overall Study | Other | 4 | 3 |
| Overall Study | Progressive disease | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Total | Part 1: Tazemetostat + Itraconazole | Part 2: Tazemetostat + Rifampin |
|---|---|---|---|
| Age, Continuous | 60.5 years STANDARD_DEVIATION 13.09 | 60.9 years STANDARD_DEVIATION 13.45 | 60.1 years STANDARD_DEVIATION 13.05 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 19 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not reported/Other | 5 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 30 Participants | 18 Participants | 12 Participants |
| Sex: Female, Male Female | 21 Participants | 8 Participants | 13 Participants |
| Sex: Female, Male Male | 21 Participants | 13 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 21 | 3 / 21 |
| other Total, other adverse events | 19 / 21 | 20 / 21 |
| serious Total, serious adverse events | 8 / 21 | 9 / 21 |
Outcome results
Primary
Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours of Quantifiable Concentration (AUC0-12h) of Tazemetostat
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).
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | 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 hours*nanogram/milliliter (h*ng/mL) | Geometric Coefficient of Variation 55.3 |
| Part 1: Tazemetostat | 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 hours*nanogram/milliliter (h*ng/mL) | Geometric Coefficient of Variation 37.6 |
Primary
Part 1: Maximum Observed Plasma Concentration (Cmax) of Tazemetostat
Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | Part 1: Maximum Observed Plasma Concentration (Cmax) of Tazemetostat | Cycle 1 Day 1 | 704 ng/mL | Geometric Coefficient of Variation 56.5 |
| Part 1: Tazemetostat | Part 1: Maximum Observed Plasma Concentration (Cmax) of Tazemetostat | Cycle 1 Day 15 | 543 ng/mL | Geometric Coefficient of Variation 63.3 |
Primary
Part 2: AUC0-12h of Tazemetostat
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).
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | Part 2: AUC0-12h of Tazemetostat | Cycle 1 Day 1 | 4420 h*ng/mL | Geometric Coefficient of Variation 83.2 |
| Part 1: Tazemetostat | Part 2: AUC0-12h of Tazemetostat | Cycle 1 Day 15 | 3610 h*ng/mL | Geometric Coefficient of Variation 70.3 |
Primary
Part 2: Cmax of Tazemetostat
Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | Part 2: Cmax of Tazemetostat | Cycle 1 Day 1 | 1330 ng/mL | Geometric Coefficient of Variation 67.4 |
| Part 1: Tazemetostat | Part 2: Cmax of Tazemetostat | Cycle 1 Day 15 | 1100 ng/mL | Geometric Coefficient of Variation 78.7 |
Secondary
Part 1: Apparent Terminal Elimination Half-Life (t1/2) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State
Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Tazemetostat | Part 1: Apparent Terminal Elimination Half-Life (t1/2) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State | Tazemetostat | 8.21 hour |
| Part 1: Tazemetostat | 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 |
Secondary
Part 1: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State
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).
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Tazemetostat | Part 1: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State | 3650 h*ng/mL | Geometric Coefficient of Variation 26.4 |
Secondary
Part 1: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With 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).
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | 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: Tazemetostat | 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
Part 1: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State
Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Tazemetostat | Part 1: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State | 780 ng/mL | Geometric Coefficient of Variation 38.2 |
Secondary
Part 1: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Itraconazole
Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | 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 |
| Part 1: Tazemetostat | 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 |
Secondary
Part 1: Observed Time at Cmax (Tmax) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State
Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | 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: Tazemetostat | 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
Part 1: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole
Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Tazemetostat | Part 1: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole | Tazemetostat | 12.8 hour |
| Part 1: Tazemetostat | Part 1: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole | EPZ-6930 | 13.9 hour |
Secondary
Part 1: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole
Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | 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: Tazemetostat | 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
Part 2: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State
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).
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Tazemetostat | Part 2: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State | 7010 h*ng/mL | Geometric Coefficient of Variation 72 |
Secondary
Part 2: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With 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).
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | 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 |
| Part 1: Tazemetostat | 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 |
Secondary
Part 2: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State
Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Tazemetostat | Part 2: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State | 1530 ng/mL | Geometric Coefficient of Variation 49.5 |
Secondary
Part 2: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Rifampin
Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | 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 1: Tazemetostat | 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
Part 2: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin
Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Tazemetostat | Part 2: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin | Tazemetostat | 5.24 hour |
| Part 1: Tazemetostat | Part 2: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin | EPZ-6930 | 8.07 hour |
Secondary
Part 2: T1/2 of Tazemetostat and EPZ-6930 EPZ-6930 After Tazemetostat Alone at Steady-State
Blood samples were collected at specified timepoints. T1/2 was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Tazemetostat | Part 2: T1/2 of Tazemetostat and EPZ-6930 EPZ-6930 After Tazemetostat Alone at Steady-State | Tazemetostat | 7.21 hour |
| Part 1: Tazemetostat | Part 2: T1/2 of Tazemetostat and EPZ-6930 EPZ-6930 After Tazemetostat Alone at Steady-State | EPZ-6930 | 8.38 hour |
Secondary
Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State
Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State | Tazemetostat | 1.25 hour | Geometric Coefficient of Variation 47 |
| Part 1: Tazemetostat | 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
Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin
Blood samples were collected at specified timepoints. Tmax was assessed using non-compartmental data analysis method.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Tazemetostat | Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin | Tazemetostat | 1.40 hour | Standard Deviation 1.1 |
| Part 1: Tazemetostat | Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin | EPZ-6930 | 1.85 hour | Standard Deviation 0.934 |
Other Pre-specified
Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Single Dose of Tazemetostat With Itraconazole
Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using analysis of variance (ANOVA).
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Tazemetostat | Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Single Dose of Tazemetostat With Itraconazole | 3.12 ratio |
Other Pre-specified
Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Tazemetostat at Steady-State With Itraconazole
Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Tazemetostat | Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Tazemetostat at Steady-State With Itraconazole | 2.47 ratio |
Other Pre-specified
Part 1: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat
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).
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Tazemetostat | Part 1: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat | 0.771 ratio |
Other Pre-specified
Part 1: Least Squares Geometric Mean Ratio of Cmax After Single Dose of Tazemetostat With Itraconazole
Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Tazemetostat | Part 1: Least Squares Geometric Mean Ratio of Cmax After Single Dose of Tazemetostat With Itraconazole | 2.00 ratio |
Other Pre-specified
Part 1: Least Squares Geometric Mean Ratio of Cmax After Tazemetostat at Steady-State With Itraconazole
Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Tazemetostat | Part 1: Least Squares Geometric Mean Ratio of Cmax After Tazemetostat at Steady-State With Itraconazole | 1.86 ratio |
Other Pre-specified
Part 1: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat
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).
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Tazemetostat | Part 1: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat | 0.842 ratio |
Other Pre-specified
Part 2: Least Squares Geometric Mean Ratio of AUC0-12h After Tazemetostat at Steady State With Rifampin
Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Tazemetostat | Part 2: Least Squares Geometric Mean Ratio of AUC0-12h After Tazemetostat at Steady State With Rifampin | 0.163 ratio |
Other Pre-specified
Part 2: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat
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).
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Tazemetostat | Part 2: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat | 0.828 ratio |
Other Pre-specified
Part 2: Least Squares Geometric Mean Ratio of Cmax After Tazemetostat at Steady State With Rifampin
Blood samples were collected at specified timepoints. Drug-drug interaction was assessed using ANOVA.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Tazemetostat | Part 2: Least Squares Geometric Mean Ratio of Cmax After Tazemetostat at Steady State With Rifampin | 0.164 ratio |
Other Pre-specified
Part 2: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat
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).
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Tazemetostat | Part 2: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat | 0.816 ratio |