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

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ClinicalTrials.gov Identifier: NCT04537715
Recruitment Status : Recruiting
First Posted : September 3, 2020
Last Update Posted : May 27, 2021
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. Subjects in Cycle 1 of Part 1 will be treated for 39 days. On Days 1, 15 and 36, a single oral dose of 400 mg Tazemetostat will be administered in the morning. From Days 3 - 14 and 21 - 35, subjects will receive an oral 400 mg dose of Tazemetostat twice daily (12 hours apart). From Days 18 - 38, a single dose of oral 200 mg itraconazole will be administered daily in the morning after a meal, co-administered with Tazemetostat when necessary. PK blood samples will be collected on Days 1 - 3, 15 - 18, 21 - 22, and 36 - 39. Sparse PK samples will be collected on Days 25, 28, 31, and 34.

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. Subjects in Cycle 1 of Part 2 will be treated for 26 days. On Days 1, 15 and 24, a single oral dose of 800 mg Tazemetostat will be administered in the morning. From Days 3 - 14 and 17 - 23, subjects will receive an oral 800 mg dose of Tazemetostat twice daily (12 hours apart). From Days 17 - 25, a single dose of oral 600 mg rifampin will be administered daily in the morning one hour before a meal, co-administered with Tazemetostat when necessary. PK blood samples will be collected on Days 1 - 3, 15 - 17 and 24 - 26. Sparse PK samples will be collected on Days 19 and 21.

Subjects may discontinue from the study after completion of Cycle 1 or can continue treatment (Cycle2+ onwards) with Tazemetostat at the recommended therapeutic dose of 800 mg twice daily until Investigator-assessed clinical disease progression per standard practice, unacceptable toxicity, withdrawal of consent, or termination of the study by the sponsor. All subjects who receive the recommended therapeutic dose of 800 mg Tazemetostat twice daily for 9 Cycles or longer, and are eligible to continue receiving Tazemetostat, will transfer to a Rollover Study (EZH-501) for monitoring and continued study drug at the Investigator and Medical Monitor's discretion.

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 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 in Part 1 of the study will receive a single oral 400 mg dose of Tazemetostat on Day 1, 15 and 36. The subjects will receive Tazemetostat (oral 400 mg dose) tablets to be taken twice daily from Day 3 - 14 and Day 21 - 35. In addition, the subjects will receive oral 200 mg itraconazole daily from Day 18 - 38.

Subjects may discontinue from the study after completion of Cycle 1 or can continue treatment (Cycle 2+ onwards) until Investigator-assessed clinical progression per standard practice, or unacceptable toxicity, or until another discontinuation criterion is met. For subjects continuing Tazemetostat treatment at the recommended therapeutic dose (oral 800 mg Tazemetostat twice daily [12 hours apart]), Cycle 2 will begin on day 40 (Cycle 2 Day 1) and each subsequent cycle from Cycle 2+ onwards will be of 28-day duration. 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

Information regarding brand itraconazole (Sporanox) is provided here as an example only. 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.

Dosage form: 100 mg capsule

Physical description: Capsules contain itraconazole-coated sugar spheres within a blue opaque cap and pink transparent body, imprinted with "JANSSEN" and "SPORANOX 100", supplied in unit-dose blister packs of 3 × 10 capsules, bottles of 30 capsules, or in the PulsePak® containing 7 blister packs × 4 capsules each.

Other Name: Sporanox

Experimental: Part 2:Tazemetostat and Rifampin Drug Interaction Cycle 1

Subjects in Part 2 of the study will receive a single oral 800 mg dose of Tazemetostat on Day 1, 15 and 24. The subjects will receive Tazemetostat (oral 800 mg dose) tablets to be taken twice daily from Day 3 - 14 and Day 17 - 23. In addition, the subjects will receive oral 600 mg rifampin daily from Day 17 - 25.

Subjects may discontinue from the study after completion of Cycle 1 or can continue treatment (Cycle 2+ onwards) until Investigator-assessed clinical progression per standard practice, or unacceptable toxicity, or until another discontinuation criterion is met. For subjects continuing Tazemetostat treatment at the recommended therapeutic dose (800 mg Tazemetostat twice daily [12 hours apart]), Cycle 2 will begin on day 27 (Cycle 2 Day 1) and each subsequent cycle from Cycle 2+ onwards will be of 28-day duration. 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

Information regarding brand rifampin (Rifadin) is provided here as an example only. 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.

Dosage form: 150 mg and 300 mg capsules

Physical description: 150 mg maroon and scarlet capsules imprinted "RIFADIN 150" in bottles of 30. 300 mg maroon and scarlet capsules imprinted "RIFADIN 300" in bottles of 60.

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. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
    AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration

  2. 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, AUC0-72. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
    AUC0-72: area under the plasma concentration-time curve from time 0 to 72 hours post dose

  3. 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, Cmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
    Cmax: observed maximum plasma concentration

  4. 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. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21. ]
    AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration

  5. 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, AUC0-48. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21. ]
    AUC0-48: area under the plasma concentration-time curve from time 0 to 48 hours post dose

  6. 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, Cmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21. ]
    Cmax: observed maximum plasma concentration


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 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
    AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration

  2. 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, Cmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
    Cmax: observed maximum plasma concentration

  3. 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, Tmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
    Tmax: observed time at Cmax

  4. 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, λz. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
    λz: terminal phase elimination rate constant

  5. 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, t1/2. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
    t1/2: terminal elimination half-life

  6. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, AUC0-t. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21. ]
    AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration

  7. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, Cmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21. ]
    Cmax: observed maximum plasma concentration

  8. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, Tmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21. ]
    Tmax: observed time at Cmax

  9. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, λz. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21. ]
    λz: terminal phase elimination rate constant

  10. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, t1/2. [ Time Frame: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21. ]
    t1/2: terminal elimination half-life

  11. 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.

  12. To evaluate the number of abnormalities or changes in intensity of conditions noted during the physical exam. [ 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. ]
    Investigators will note any new clinically significant findings (e.g., not noted at screening) or changes in intensity of conditions that occurred after the initial tazemetostat administration.

  13. To evaluate change in blood pressure. [ 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. ]
    Investigators will note any clinically significant changes from baseline in systolic and diastolic blood pressure measured in units of millimeters of mercury (mmHg).

  14. To evaluate change in heart rate [ 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. ]
    Investigators will note any clinically significant changes from baseline in heart rate measured in units of beats per minute (BPM).

  15. To evaluate change in body temperature. [ 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. ]
    Investigators will note any clinically significant changes from baseline in body temperature measured in degrees Fahrenheit or Celsius.

  16. To evaluate changes in concomitant medications. [ 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. ]
    Investigators will note any changes in concomitant medications from baseline in all subjects with at least 1 dose or partial dose of tazemetostat.

  17. To evaluate change in electrical activity of the heartbeat, RR interval. [ 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. ]
    Investigators will report any clinically significant changes from baseline in the RR interval (sec) as noted by a 12 lead electrocardiogram (ECG).

  18. To evaluate change in electrical activity of the heartbeat, PR interval. [ 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. ]
    Investigators will report any clinically significant changes from baseline in the PR interval (sec) as noted by a 12 lead electrocardiogram (ECG).

  19. To evaluate change in electrical activity of the heartbeat, QRS complex. [ 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. ]
    Investigators will report any clinically significant changes from baseline in the QRS complex (sec) as noted by a 12 lead electrocardiogram (ECG).

  20. To evaluate change in electrical activity of the heartbeat, QT interval. [ 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. ]
    Investigators will report any clinically significant changes from baseline in the QT interval (sec) as noted by a 12 lead electrocardiogram (ECG).

  21. To evaluate changes in clinical laboratory values, hematology. [ 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. ]
    Investigators will note any clinically significant changes in hematological clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges.

  22. To evaluate changes in clinical laboratory values, serum chemistry. [ 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. ]
    Investigators will note any clinically significant changes in serum chemistry clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges.

  23. To evaluate changes in clinical laboratory values, urinalysis. [ 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. ]
    Investigators will note any clinically significant changes in urinalysis clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges.



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Layout table for eligibility information
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, and questions related to this can be discussed with the Medical Monitor.
  9. Has normal hepatic function (per NCI-ODWG criteria) as well as adequate hematologic (bone marrow [BM] and coagulation factors) and renal function:

    • Hemoglobin: ≥9 g/dL (90 g/L)
    • Platelets: ≥75,000/mm³ (≥75 × 10⁹/L)
    • ANC (Hematologic malignancy subjects): ≥750/mm³ (≥0.75 × 10⁹/L)
    • ANC (Solid tumor subjects): ≥1,000/mm³ (≥1.0 × 10⁹/L)
    • PT: <1.5 ULN
    • PTT: <1.5 ULN
    • Serum creatinine: ≤1.5 × ULN
    • Bilirubin and AST: ≤ ULN

    Note: Laboratory results obtained during screening should be used to determine eligibility criteria. In situations where laboratory results are outside the permitted range, the Investigator may retest the subject and the subsequent within range screening result may be used to determine the subject's eligibility. Subjects may be retested once within 2 weeks of the screening test. Samples must be reanalyzed at the local laboratory.

  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. Manual differential with no significant morphologic abnormalities on complete blood count (CBC) testing.
  12. Male subjects must refrain from donating sperm from first dose of Tazemetostat until 3 months following the last dose of Tazemetostat.
  13. Male subjects with a female partner of childbearing potential must:

    1. Be vasectomized, or
    2. Remain abstinent or use a condom starting at signing of informed consent until 3 months following the last dose of study drug. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  14. Female partners of male subjects who are of childbearing potential must also adhere to one of the following:

    1. Placement of an intrauterine device or intrauterine system.
    2. Established use of oral, injected, or implanted hormonal methods of contraception plus an additional barrier method.
    3. Progesterone-only oral contraception, where inhibition of ovulation is not the primary mode of action.
  15. Female subjects of childbearing potential:

    1. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
    2. Must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year starting at least 7 days before the planned first dose of study drug until 6 months following the last dose of study drug.
    3. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
    4. Due to the potential of enzyme induction with Tazemetostat, female subjects who use hormonal contraceptives should use an additional barrier method of birth control while on study treatment and for 6 months after discontinuation of study treatment.
    5. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    6. Barrier methods must always be supplemented with the use of a spermicide.
  16. Females of childbearing potential must have a negative serum pregnancy test at screening.
  17. Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec.
  18. Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in the study if they meet the following criteria:

    1. No history of AIDS-defining opportunistic infections, or have not had an opportunistic infection within the past 12 months prior to enrollment.
    2. No history of AIDS-defining cancers (eg, Kaposi's sarcoma, aggressive B-cell lymphoma, and invasive cervical cancer).
    3. Subjects may take prophylactic antimicrobials, however subjects that are taking specific antimicrobial drugs where there may be drug-drug interaction or overlapping toxicities should be excluded from study participation.
    4. Subjects should be on established anti-retroviral therapy for at least 4 weeks, and have an HIV viral load of < 400 copies/mL prior to enrollment.

EXCLUSION CRITERIA:

  1. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression as documented by CT or MRI scan, analysis of cerebrospinal fluid or neurological exam. Subjects with primary glioblastoma multiforme are excluded.

    Note: Subjects with clinically stable brain metastases are eligible to enroll in the study.

  2. Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders. Subjects on anticoagulation with low molecular weight heparin are allowed.
  3. Known hypersensitivity to any of the components of Tazemetostat.
  4. Use of concurrent investigational agent or anticancer therapy. Note: megestrol (Megace) if used as an appetite stimulant is allowed.

    1. Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of Tazemetostat. Prophylactic use of bisphosphonates in subjects without bone disease is not permitted, except for the treatment of osteoporosis.
    2. The concurrent use of all herbal supplements is prohibited during the study as the composition, PK, and metabolism of many herbal supplements are unknown.
  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), as measured by positive hepatitis B surface antigen, hepatitis C virus (HCV, as measured by positive hepatitis C antibody), OR human T-cell lymphotropic virus 1.

    Exceptions: Subjects with a history of hepatitis B or C who have normal alanine aminotransferase (ALT) values and are hepatitis B surface antigen negative and/or have undetectable HCV RNA.

  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 thrombocytopenia, neutropenia, or anemia of grade ≥3 (per CTCAE v5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
  11. Has abnormalities known to be associated with MDS (e.g., del 5q, chr 7 abn) and myeloproliferative neoplasms (MPN) (e.g., JAK2 V617F) observed in cytogenetic testing and DNA sequencing.
  12. Has a prior history of T-LBL/T-ALL.
  13. Ingestion of alcohol within 72 hours prior to day 1 of Cycle 1, and until the 24, 48 or 72 hour post dose PK time point has been collected (whichever is the final sampling time point). Regular alcohol consumption must not exceed 16 units for males and 7 units for females per week (1 unit equals 340mL of beer, 115mL of wine, or 43 mL of spirits) throughout the study until the end of treatment.
  14. Any form of marijuana use.
  15. 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


Contacts
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Contact: Deyaa Adib, MD 617-229-7575 clinicaltrials@epizyme.com

Locations
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United States, California
California Cancer Associates for Research and Excellence, Inc. (cCARE) Recruiting
Encinitas, California, United States, 92024
Contact: Alberto Bessudo, MD    760-452-3909    abessudo@ccare.com   
The Angeles Clinic and Research Institute Recruiting
Los Angeles, California, United States, 90025
Contact: Omid Hamid, MD    310-231-2121 ext 2185    ohamid@theangelesclinic.org   
United States, Illinois
Northwestern University-Robert H. Lurie Comprehensive Cancer Center Recruiting
Chicago, Illinois, United States, 60611
Contact: Devalingam Mahalingam, MD    312-695-1300    Mahalingam@nm.org   
United States, Michigan
South Texas Accelerated Research Therapeutics (START) Midwest Recruiting
Grand Rapids, Michigan, United States, 49546
Contact: Manish Sharma, MD    616-954-5554    manish.sharma@startmidwest.com   
United States, Ohio
Gabrail Cancer Center Recruiting
Canton, Ohio, United States, 44718
Contact: Nashat Gabrail, MD    330-492-3345    ngabrailMD@gabrailcancercenter.com   
University of Cincinnati Medical Center Recruiting
Cincinnati, Ohio, United States, 45267
Contact: Trisha Wise-Draper, MD, PhD    513-558-2826    wiseth@uc.edu   
United States, Texas
Mary Crowley Cancer Research Recruiting
Dallas, Texas, United States, 75230
Contact: James Strauss, MD    214-739-4175    jstrauss@marycrowley.org   
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 27, 2021
Last Verified: May 2021
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