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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04537715
Recruitment Status : Active, not recruiting
First Posted : September 3, 2020
Last Update Posted : May 24, 2022
Sponsor:
Information provided by (Responsible Party):
Epizyme, Inc.

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.

Condition or disease Intervention/treatment Phase
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 Drug: Tazemetostat Drug: Itraconazole Drug: Rifampin Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
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 : April 23, 2020
Estimated Primary Completion Date : July 31, 2022
Estimated Study Completion Date : December 30, 2023


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 Name: 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




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 [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 0-48 hours ]
  2. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin. [ Time Frame: 0-48 hours ]
  3. To evaluate the number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0. [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04537715


Locations
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United States, California
California Cancer Associates for Research and Excellence, Inc. (cCARE)
Encinitas, California, United States, 92024
The Angeles Clinic and Research Institute
Los Angeles, California, United States, 90025
United States, Illinois
Northwestern University-Robert H. Lurie Comprehensive Cancer Center
Chicago, Illinois, United States, 60611
United States, Michigan
South Texas Accelerated Research Therapeutics (START) Midwest
Grand Rapids, Michigan, United States, 49546
United States, Ohio
Gabrail Cancer Center
Canton, Ohio, United States, 44718
University of Cincinnati Medical Center
Cincinnati, Ohio, United States, 45267
United States, Texas
Mary Crowley Cancer Research
Dallas, Texas, United States, 75230
Spain
Onkologikoa
Donostia, Gipuzkoa, Spain, 20014
Hospital Universitario Vall d'Hebron
Barcelona, Spain, 08035
Hospital Fundacion Jimenez Diaz
Madrid, Spain, 28040
Sponsors and Collaborators
Epizyme, Inc.
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Responsible Party: Epizyme, Inc.
ClinicalTrials.gov Identifier: NCT04537715    
Other Study ID Numbers: EZH-108
First Posted: September 3, 2020    Key Record Dates
Last Update Posted: May 24, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Epizyme, Inc.:
Epizyme
Tazverik
Tazemetostat (EPZ-6438)
Itraconazole
CYP3A4 inhibitor
Rifampin
CYP3A4 inducer
Drug-Drug Interaction (DDI)
Pharmacokinetics (PK)
Additional relevant MeSH terms:
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Lymphoma
Neoplasms
Sarcoma
Lymphoma, Non-Hodgkin
Lymphoma, Large B-Cell, Diffuse
Mesothelioma
Hematologic Neoplasms
Rhabdoid Tumor
Sarcoma, Synovial
Carcinoma, Medullary
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Connective and Soft Tissue
Lymphoma, B-Cell
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms, Mesothelial
Neoplasms by Site
Hematologic Diseases
Neoplasms, Complex and Mixed
Neoplasms, Connective Tissue
Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Carcinoma