Clinical trial NCT04537715: Effects of Itraconazole and Rifampin on the Blood Tazemetostat Levels
Official title: A Phase I, Open-label Multi-dose Two-part Study to Characterize the Effects of a Strong CYP3A4 Inhibitor and a Strong CYP3A4 Inducer on the Steady-State Pharmacokinetics of Tazemetostat (EPZ-6438) in Subjects With Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: All Malignancies
Advanced Malignancies
Hematologic Malignancy
Solid Tumor
Follicular Lymphoma (FL)
Non-Hodgkin Lymphoma (NHL)
Diffuse Large B-Cell Lymphoma (DLBCL)
Epithelioid Sarcoma (ES)
Synovial Sarcoma
Renal Medullary Carcinoma
Mesothelioma
Rhabdoid Tumor
Keywords: Epizyme
Tazverik
Tazemetostat (EPZ-6438)
Itraconazole
CYP3A4 inhibitor
Rifampin
CYP3A4 inducer
Drug-Drug Interaction (DDI)
Pharmacokinetics (PK)
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2020-09-03
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours of Quantifiable Concentration (AUC0-12h) of Tazemetostat
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
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of Tazemetostat
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
measure: Part 2: AUC0-12h of Tazemetostat
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
measure: Part 2: Cmax of Tazemetostat
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
Secondary outcomes:
measure: Part 1: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State
timeFrame: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 15
measure: Part 1: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole
timeFrame: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 36
measure: Part 1: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State
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
measure: Part 1: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Itraconazole
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
measure: Part 1: Observed Time at Cmax (Tmax) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State
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
measure: Part 1: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole
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
measure: Part 1: Apparent Terminal Elimination Half-Life (t1/2) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State
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
measure: Part 1: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole
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
measure: Part 2: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State
timeFrame: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 15
measure: Part 2: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin
timeFrame: Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 24
measure: Part 2: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State
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
measure: Part 2: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Rifampin
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
measure: Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State
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
measure: Part 2: Tmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin
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
measure: Part 2: T1/2 of Tazemetostat and EPZ-6930 EPZ-6930 After Tazemetostat Alone at Steady-State
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
measure: Part 2: T1/2 of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Rifampin
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
Other outcomes:
measure: Part 1: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat
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
measure: Part 1: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat
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
measure: Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Single Dose of Tazemetostat With Itraconazole
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)
measure: Part 1: Least Squares Geometric Mean Ratio of Cmax After Single Dose of Tazemetostat With Itraconazole
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)
measure: Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Tazemetostat at Steady-State With Itraconazole
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)
measure: Part 1: Least Squares Geometric Mean Ratio of Cmax After Tazemetostat at Steady-State With Itraconazole
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)
measure: Part 2: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat
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
measure: Part 2: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat
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
measure: Part 2: Least Squares Geometric Mean Ratio of AUC0-12h After Tazemetostat at Steady State With Rifampin
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)
measure: Part 2: Least Squares Geometric Mean Ratio of Cmax After Tazemetostat at Steady State With Rifampin
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)
Locations:
city: Encinitas
country: United States
facility: California Cancer Associates for Research and Excellence, Inc. (cCARE)
state: California
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute
state: California
city: Chicago
country: United States
facility: Northwestern University-Robert H. Lurie Comprehensive Cancer Center
state: Illinois
city: Grand Rapids
country: United States
facility: South Texas Accelerated Research Therapeutics (START) Midwest
state: Michigan
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Donostia
country: Spain
facility: Onkologikoa
state: Gipuzkoa
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Fundacion Jimenez Diaz
Study officials:
affiliation: Ipsen
name: Ipse Medical Director
role: STUDY_DIRECTOR
References: