Effects of Itraconazole and Rifampin on the Blood Tazemetostat Levels

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.

• Tazemetostat (Drug), also known as EPZ-6438, Tazverik: 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.
• Itraconazole (Drug), also known as Sporanox: Oral 200 mg itraconazole once daily on Days 18 - 38
• Tazemetostat (Drug), also known as EPZ-6438, Tazverik: A single, oral, 800 mg dose of tazemetostat on Days 1, 15, and Day 24 ; and tazemetostat (oral 800 mg) twice daily on Days 3 - 14 and on Days 17 - 23.
• Rifampin (Drug), also known as RIF, Rifampicin, Rifadin, Rimactane: Oral 600 mg rifampin once daily on Days 17 - 25.

Primary outcomes

• 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).
• 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: 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 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.

Secondary outcomes

• 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.
• 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.

Other outcomes

• 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 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 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 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.
• 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 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.

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours of Quantifiable Concentration (AUC0-12h) of Tazemetostat (Primary), Geometric mean, hours*nanogram/milliliter (h*ng/mL): Part 1: Tazemetostat 2180 +/- 55.3
• Part 1: Maximum Observed Plasma Concentration (Cmax) of Tazemetostat (Primary), Geometric mean, ng/mL: Part 1: Tazemetostat 704 +/- 56.5
• Part 2: AUC0-12h of Tazemetostat (Primary), Geometric mean, h*ng/mL: Part 2: Tazemetostat 4420 +/- 83.2
• Part 2: Cmax of Tazemetostat (Primary), Geometric mean, ng/mL: Part 2: Tazemetostat 1330 +/- 67.4
• Part 1: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State (Secondary), Geometric mean, h*ng/mL: Part 1: Tazemetostat 3650 +/- 26.4
• Part 1: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole (Secondary), Geometric mean, h*ng/mL: Part 1: Tazemetostat + Itraconazole 4530 +/- 64.5
• Part 1: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State (Secondary), Geometric mean, ng/mL: Part 1: Tazemetostat 780 +/- 38.2
• Part 1: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Itraconazole (Secondary), Geometric mean, ng/mL: Part 1: Tazemetostat + Itraconazole 1010 +/- 76.3
• Part 1: Observed Time at Cmax (Tmax) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State (Secondary), Geometric mean, hour: Part 1: Tazemetostat 1.34 +/- 72.1
• Part 1: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole (Secondary), Geometric mean, hour: Part 1: Tazemetostat + Itraconazole 1.55 +/- 63.4
• Part 1: Apparent Terminal Elimination Half-Life (t1/2) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State (Secondary), Median, hour: Part 1: Tazemetostat 8.21 (4.67 to 19.8)
• Part 1: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole (Secondary), Median, hour: Part 1: Tazemetostat + Itraconazole 12.8 (6.40 to 22.0)
• Part 2: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State (Secondary), Geometric mean, h*ng/mL: Part 2: Tazemetostat 7010 +/- 72.0
• Part 2: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin (Secondary), Geometric mean, h*ng/mL: Part 2: Tazemetostat + Rifampin 588 +/- 65.2
• Part 2: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State (Secondary), Geometric mean, ng/mL: Part 2: Tazemetostat 1530 +/- 49.5
• Part 2: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Rifampin (Secondary), Geometric mean, ng/mL: Part 2: Tazemetostat + Rifampin 181 +/- 71.7
• Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State (Secondary), Geometric mean, hour: Part 2: Tazemetostat 1.25 +/- 47.0
• Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin (Secondary), Mean, hour: Part 2: Tazemetostat + Rifampin 1.40 +/- 1.10
• Part 2: T1/2 of Tazemetostat and EPZ-6930 EPZ-6930 After Tazemetostat Alone at Steady-State (Secondary), Median, hour: Part 2: Tazemetostat 7.21 (5.55 to 10.6)
• Part 2: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin (Secondary), Median, hour: Part 2: Tazemetostat + Rifampin 5.24 (2.45 to 8.19)
• 10 more outcome measures not shown.

Adverse events

Time frame: 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).

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2021-08-31)
• Statistical Analysis Plan (PDF, 2022-11-21)

• Ipse Medical Director, Study director, Ipsen