A Two-part Study to Characterize Drug-Drug Interaction Effects on Steady-State Pharmacokinetics of Oral Tazemetostat

Sponsor
Epizyme, Inc. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT04537715
Collaborator
(none)
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2
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Study Details

Study Description

Brief Summary

This is a phase I, multi-center, open-label, multi-dose, two-part PK and safety study to characterize the DDI potential of oral Tazemetostat.

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
42 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Apr 23, 2020
Anticipated Primary Completion Date :
Jul 31, 2022
Anticipated Study Completion Date :
Dec 30, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part 1: Tazemetostat and Itraconazole Drug Interaction Cycle 1

Subjects may discontinue from the study after completion of Cycle 1 or can continue (Cycle 2+ onwards) Tazemetostat treatment at the recommended therapeutic dose (oral 800 mg Tazemetostat twice daily [12 hours apart]) in 28 day cycles. Safety and tolerability will be assessed throughout the subject's participation.

Drug: Tazemetostat
Physical description: Red, round, and biconvex film-coated tablets packaged in white high-density polyethylene bottle with a child resistant, tamper-evident polypropylene screw cap.
Other Names:
  • EPZ-6438
  • Tazverik
  • Drug: Itraconazole
    During this study, the use of either brand or generic forms of itraconazole is acceptable. Please refer to manufacturer's prescribing information for drug form selected prior to administration.
    Other Names:
  • Sporanox
  • Experimental: Part 2:Tazemetostat and Rifampin Drug Interaction Cycle 1

    Subjects may discontinue from the study after completion of Cycle 1 or can continue (Cycle 2+ onwards) Tazemetostat treatment at the recommended therapeutic dose (800 mg Tazemetostat twice daily [12 hours apart]), in 28 day cycles. Safety and tolerability will be assessed throughout the subject's participation.

    Drug: Tazemetostat
    Physical description: Red, round, and biconvex film-coated tablets packaged in white high-density polyethylene bottle with a child resistant, tamper-evident polypropylene screw cap.
    Other Names:
  • EPZ-6438
  • Tazverik
  • Drug: Rifampin
    During this study, the use of either brand or generic forms of rifampin is acceptable. Please refer to manufacturer's prescribing information for drug form selected prior to administration.
    Other Names:
  • RIF
  • Rifampicin
  • Rifadin
  • Rimactane
  • Outcome Measures

    Primary Outcome Measures

    1. Part 1: To evaluate the effect of CYP3A4 inhibition by itraconazole on the steady-state pharmacokinetics (PK) of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, AUC0-t, Cmax [0-72 hours]

    2. Part 2: To evaluate the effect of CYP3A4 induction by rifampin on the steady-state PK of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, AUC0-t, Cmax. [0-48 hours]

    Secondary Outcome Measures

    1. Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, AUC0-t. [0-48 hours]

    2. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin. [0-48 hours]

    3. To evaluate the number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0. [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.]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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.

    1. Must have evaluable or measurable disease.

    2. 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.

    3. 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.

    4. Has normal hepatic function (per NCI-ODWG criteria) as well as adequate hematologic (bone marrow [BM] and coagulation factors) and renal function.

    5. 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.

    6. 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.

    7. 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.

    1. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 California Cancer Associates for Research and Excellence, Inc. (cCARE) Encinitas California United States 92024
    2 The Angeles Clinic and Research Institute Los Angeles California United States 90025
    3 Northwestern University-Robert H. Lurie Comprehensive Cancer Center Chicago Illinois United States 60611
    4 South Texas Accelerated Research Therapeutics (START) Midwest Grand Rapids Michigan United States 49546
    5 Gabrail Cancer Center Canton Ohio United States 44718
    6 University of Cincinnati Medical Center Cincinnati Ohio United States 45267
    7 Mary Crowley Cancer Research Dallas Texas United States 75230
    8 Onkologikoa Donostia Gipuzkoa Spain 20014
    9 Hospital Universitario Vall d'Hebron Barcelona Spain 08035
    10 Hospital Fundacion Jimenez Diaz Madrid Spain 28040

    Sponsors and Collaborators

    • Epizyme, Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Epizyme, Inc.
    ClinicalTrials.gov Identifier:
    NCT04537715
    Other Study ID Numbers:
    • EZH-108
    First Posted:
    Sep 3, 2020
    Last Update Posted:
    May 24, 2022
    Last Verified:
    May 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Epizyme, Inc.
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of May 24, 2022