Study to Describe the Interaction Between Tazemetostat and Itraconazole and Between Tazemetostat and Rifampin in Participants With Advanced Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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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

Intervention / Treatment
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* Drug: Tazemetostat
* Drug: Itraconazole
* Drug: Tazemetostat
* Drug: Rifampin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Male or female ≥ 18 years age at the time of consent. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Has the ability to understand informed consent, and provide signed written informed consent. Life expectancy of > 3 months. 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. Must have evaluable or measurable disease. 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. 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. Has normal hepatic function (per NCI-ODWG criteria) as well as adequate hematologic (bone marrow [BM] and coagulation factors) and renal function. 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. 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. 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. Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec. EXCLUSION CRITERIA: Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression or primary glioblastoma multiforme. Clinically significant bleeding diathesis or coagulopathy. Known hypersensitivity to any of the components of Tazemetostat, itraconazole, or rifampin. Use of concurrent investigational agent or anticancer therapy. 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. Have a known active infection with hepatitis B virus (HBV), hepatitis C virus (HCV), AND/OR human T-cell lymphotropic virus 1. Subjects taking medications that are known CYP3A4 inducers or inhibitors (including St. John's Wort). 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. Any condition or medical problem in addition to the underlying malignancy and organ dysfunction that the Investigator feels would pose unacceptable risk. 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). 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 Any form of marijuana use. History of drug abuse (including alcohol) within the last 6 months prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Tazemetostat and Itraconazole Drug Interaction Cycle 1<br>Participants in Part 1 of the study will receive a single oral, 400 mg dose of tazemetostat on Day 1, 15, and Day 36. The study participants will receive tazemetostat (oral 400 mg) tablets to be taken twice daily on Days 3 - 14 and Days 21 - 35. In addition, the participants will receive oral 200 mg itraconazole once daily on Days 18 - 38. Study participants may continue tazemetostat from Day 40+ at the recommended therapeutic dose (oral 800 mg twice daily) in 28-day cycles. | Drug: Tazemetostat<br>* 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.<br>* Other names: Tazverik;Drug: Itraconazole<br>* Oral 200 mg itraconazole once daily on Days 18 - 38<br>* Other names: Sporanox;|
| Experimental: Part 2:Tazemetostat and Rifampin Drug Interaction Cycle 1<br>Participants in Part 2 of the study will receive a single oral, 800 mg dose of tazemetostat on Days 1, 15, and Day 36. The study participants will receive tazemetostat (oral 800 mg dose) tablets to be taken twice daily on Days 3 - 14 and Days 17 - 23. In addition, the participants will receive oral 200 mg rifampin once daily on Days 17 - 25. Study participants may continue tazemetostat from Day 27+ at the recommended therapeutic dose (oral 800 mg twice daily) in 28-day cycles. | Drug: Tazemetostat<br>* 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.<br>* Other names: Tazverik;Drug: Rifampin<br>* Oral 600 mg rifampin once daily on Days 17 - 25.<br>* Other names: Rimactane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Pharmacokinetics (PK) of tazemetostat administered as a single and twice daily: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t) |  | 0-72 hours | 
| Part 1: PK of tazemetostat administered as a single and twice daily: area under the plasma concentration-time curve from time 0 to 72 hours post-dose (AUC0-72) |  | 0-72 hours | 
| Part 1: PK of tazemetostat administered as a single and twice daily: observed maximum plasma of concentration (Cmax) |  | 0-72 hours | 
| Part 2: PK of tazemetostat administered as a single and twice daily: AUC0-t |  | 0-48 hours | 
| Part2: PK of tazemetostat administered as a single and twice daily: area under the plasma concentration-time curve from time 0 to 48 hours post-dose (AUC0-48) |  | 0-48 hours | 
| Part 2: PK of tazemetostat administered as a single and twice daily: Cmax |  | 0-48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants experiencing Adverse Events (AEs) | Severity of adverse events experienced by all subjects with at least 1 dose or partial dose of tazemetostat will be evaluated by the Investigator based on the CTCAE, version 5.0. | Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. | 
| Percentage of Participants With Clinically Significant Changes in Physical Examination | Percentage of participants with clinically significant changes in physical examination findings will be reported. The clinical significance will be graded by the investigator. | Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. | 
| Percentage of Participants With Clinically Significant Changes in Vital Signs | Percentage of participants with clinically significant changes in Vital Signs will be reported. The clinical significance will be decided by the investigator. | Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. | 
| Percentage of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Readings | Percentage of participants with clinically significant changes in ECG readings will be reported. The clinical significance will be graded by the investigator. | Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. | 
| Performance status evaluated by Eastern Cooperation Oncology Group (ECOG) | ECOG is a 4-point performance status scale used to assess performance as a key indicator (e.g., 0 = fully active, 2 = up and about more than 50% of walking hours, 4 = Completely disabled). Performance status will be assessed per usual clinical practice and will be recorded in the medical record. | Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. | 
| Concomitant medication monitoring | All prior medications administered 30 days before study drug administration will be recorded. | Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. | 
| Part 1: PK of tazemetostat and its metabolites after administration alone and with itraconazole: AUC0-t |  | 0-48 hours | 
| Part 1: PK of tazemetostat and its metabolites after administration alone and with itraconazole: Cmax |  | 0-48 hours | 
| Part 1: PK of tazemetostat and its metabolites after administration alone and with itraconazole: Tmax |  | 0-48 hours | 
| Part 1: PK of tazemetostat and its metabolites after administration alone and with itraconazole: terminal phase elimination rate constant (λz) |  | 0-48 hours | 
| Part 1: PK of tazemetostat and its metabolites after administration alone and with itraconazole: terminal elimination half-life (t1/2) |  | 0-48 hours | 
| Part 2: PK of tazemetostat and its metabolites after administration alone and with rifampin: AUC0-t |  | 0-48 hours | 
| Part 2: PK of tazemetostat and its metabolites after administration alone and with rifampin: Cmax |  | 0-48 hours | 
| Part 2: PK of tazemetostat and its metabolites after administration alone and with rifampin: Tmax |  | 0-48 hours | 
| Part 2: PK of tazemetostat and its metabolites after administration alone and with rifampin: λz |  | 0-48 hours | 
| Part 2: PK of tazemetostat and its metabolites after administration alone and with rifampin: t1/2 |  | 0-48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epizyme, Tazverik, Tazemetostat (EPZ-6438), Itraconazole, CYP3A4 inhibitor, Rifampin, CYP3A4 inducer, Drug-Drug Interaction (DDI), Pharmacokinetics (PK)