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A Study of Oral Tazemetostat in Subjects With Moderate and Severe Hepatic Impairment With Advanced Malignancies

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04241835
Recruitment Status : Recruiting
First Posted : January 27, 2020
Last Update Posted : June 27, 2022
Sponsor:
Collaborator:
Sponsor GmbH
Information provided by (Responsible Party):
Epizyme, Inc.

Tracking Information
First Submitted Date  ICMJE December 26, 2019
First Posted Date  ICMJE January 27, 2020
Last Update Posted Date June 27, 2022
Actual Study Start Date  ICMJE January 28, 2020
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 7, 2020)
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration [ Time Frame: 0 to 72 hours post dose on Day 1 and Day 15 ]
    When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-∞: area under the plasma concentration-time curve from time 0 extrapolated to infinity [ Time Frame: 0 to 72 hours post dose on Day 1 and Day 15 ]
    When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-72: area under the plasma concentration-time curve from time 0 to 72 hours post dose [ Time Frame: 0 to 72 hours post dose on Day 1 and Day 15 ]
    When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, Cmax: observed maximum plasma concentration [ Time Frame: 0 to 72 hours post dose on Day 1 and Day 15 ]
    When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, Tmax: observed time at Cmax [ Time Frame: 0 to 72 hours post dose on Day 1 and Day 15 ]
    When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, λz: terminal phase elimination rate constant [ Time Frame: 0 to 72 hours post dose on Day 1 and Day 15 ]
    When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, t1/2: terminal elimination half-life [ Time Frame: 0 to 72 hours post dose on Day 1 and Day 15 ]
    When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
Original Primary Outcome Measures  ICMJE
 (submitted: January 22, 2020)
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration [ Time Frame: 0 to 72 hours post dose ]
    When administered as a single oral dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-∞: area under the plasma concentration-time curve from time 0 extrapolated to infinity [ Time Frame: 0 to 72 hours post dose ]
    When administered as a single oral dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-72: area under the plasma concentration-time curve from time 0 to 72 hours post dose [ Time Frame: 0 to 72 hours post dose ]
    When administered as a single oral dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, Cmax: observed maximum plasma concentration [ Time Frame: 0 to 72 hours post dose ]
    When administered as a single oral dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, Tmax: observed time at Cmax [ Time Frame: 0 to 72 hours post dose ]
    When administered as a single oral dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, λz: terminal phase elimination rate constant [ Time Frame: 0 to 72 hours post dose ]
    When administered as a single oral dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
  • To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, T 1/2: terminal elimination half-life [ Time Frame: 0 to 72 hours post dose ]
    When administered as a single oral dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 9, 2021)
To evaluate the number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0 [ Time Frame: Through study completion, an average of 1 year ]
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
Original Secondary Outcome Measures  ICMJE
 (submitted: January 22, 2020)
  • To evaluate the number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0 [ Time Frame: Through study completion, an average of 1 year ]
    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
  • To evaluate the number of abnormalities or changes in intensity of conditions noted during the physical exam [ Time Frame: Through study completion, an average of 1 year ]
    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
  • To evaluate change in blood pressure [ Time Frame: Through study completion, an average of 1 year ]
    Investigators will note any clinically significant changes from baseline in systolic and diastolic blood pressure measured in units of millimeters of mercury (mmHg)
  • To evaluate change in heart rate [ Time Frame: Through study completion, an average of 1 year ]
    Investigators will note any clinically significant changes from baseline in heart rate measured in units of beats per minute (BPM)
  • To evaluate change in body temperature [ Time Frame: Through study completion, an average of 1 year ]
    Investigators will note any clinically significant changes from baseline in body temperature measured in degrees Fahrenheit or Celsius
  • To evaluate changes in concomitant medications [ Time Frame: Through study completion, an average of 1 year ]
    Investigators will note any changes in concomitant medications from baseline in all subjects with at least 1 dose or partial dose of tazemetostat
  • To evaluate change in electrical activity of the heartbeat, RR interval [ Time Frame: Through study completion, an average of 1 year ]
    Investigators will report any clinically significant changes from baseline in the RR interval (sec) as noted by a 12 lead electrocardiogram (ECG)
  • To evaluate change in electrical activity of the heartbeat, PR interval [ Time Frame: Through study completion, an average of 1 year ]
    Investigators will report any clinically significant changes from baseline in the PR interval (sec) as noted by a 12 lead electrocardiogram (ECG)
  • To evaluate change in electrical activity of the heartbeat, QRS complex [ Time Frame: Through study completion, an average of 1 year ]
    Investigators will report any clinically significant changes from baseline in the QRS complex (sec) as noted by a 12 lead electrocardiogram (ECG)
  • To evaluate change in electrical activity of the heartbeat, QT interval [ Time Frame: Through study completion, an average of 1 year ]
    Investigators will report any clinically significant changes from baseline in the QT interval (sec) as noted by a 12 lead electrocardiogram (ECG)
  • To evaluate changes in clinical laboratory values, hematology [ Time Frame: Through study completion, an average of 1 year ]
    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
  • To evaluate changes in clinical laboratory values, serum chemistry [ Time Frame: Through study completion, an average of 1 year ]
    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
  • To evaluate changes in clinical laboratory values, urinalysis [ Time Frame: Through study completion, an average of 1 year ]
    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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Oral Tazemetostat in Subjects With Moderate and Severe Hepatic Impairment With Advanced Malignancies
Official Title  ICMJE A Phase I, Open-label Multi-dose Pharmacokinetic and Safety Study of Oral Tazemetostat in Subjects With Moderate and Severe Hepatic Impairment With Advanced Malignancies
Brief Summary This is a phase 1, 2-part, global, multicenter, open-label, PK, safety and tolerability study of oral tazemetostat in subjects with either advanced solid tumors, or hematological malignancies and normal hepatic function or moderate, or severe hepatic impairment.
Detailed Description

The study will be conducted in 2 parts for subjects with advanced malignancies and either normal liver function, or advanced malignancies and moderate, or severe hepatic impairment. Subjects in Part 1 of the study will receive a single oral, 800 mg dose of tazemetostat on Day 1 and Day 15. In addition, the subjects will receive tazemetostat (oral 800 mg dose) tablets to be taken twice daily from Day 5 to Day 14. Blood samples for PK analysis will be obtained on Day 1 through Day 4 and again on Day 15 through Day 18. Part 1 ends on Day 18.

Subjects continuing treatment in Part 2 will receive tazemetostat (oral 800 mg dose) tablets to be taken twice daily in repeated 28-day cycles beginning on Day 19 until Investigator-assessed clinical progression per standard practice, or unacceptable toxicity, or until another discontinuation criterion is met. Subjects must have an end of study visit after 30 days of the last dose of tazemetostat for safety assessment. Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying procedure manuals (i.e., laboratory, pharmacy, ECG manuals). Such manuals will provide the site personnel with administrative and detailed technical information that does not impact subject safety.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hepatic Impairment
  • Advanced Malignant Solid Tumor
Intervention  ICMJE Drug: Tazemetostat

200 mg and 400 mg tablets

Round, red, biconvex, film-coated tablets

Duration: continuous

Other Name: EPZ-6438
Study Arms  ICMJE Experimental: Open label Tazemetostat
Single and BID doses of oral tazemetostat 800 mg
Intervention: Drug: Tazemetostat
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 22, 2020)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2022
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 provided 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 hematological malignancies that have relapsed, or refractory disease following at least 2 standard lines of systemic therapy for which there are no standard therapies available.
  6. Must have evaluable or measurable disease.
  7. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1 per 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 may be acceptable, and questions related to this can be discussed with the Medical Monitor.
  9. Has 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. Subjects with abnormal hepatic function will be eligible and will be grouped according to established criteria. Subjects with active hemolysis will be excluded.
  12. Manual differential with no significant morphologic abnormalities on complete blood count (CBC) testing.
  13. 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 from the first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.
  14. Females of childbearing potential must have a negative serum pregnancy test at screening and within 24 hours prior to the first dose of study drug. All females will be considered of childbearing potential unless they are naturally postmenopausal or have been sterilized.
  15. Females of childbearing potential (FCBP) must either practice complete abstinence or agree to use a highly effective method of contraception beginning at least 28 days prior to the first dose of study drug, during study treatment (including during dose interruptions), and for 6 months after study drug discontinuation.
  16. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec.
  17. Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in the study if they meet established criteria.

Exclusion Criteria:

  1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
  2. 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. Subject's with primary glioblastoma multiforme are excluded.
  3. Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders. Subjects on anticoagulation with low molecular weight heparin are allowed.
  4. Known hypersensitivity to any of the components of tazemetostat.
  5. Concurrent investigational agent or anticancer therapy. NOTE: Megestrol (Megace) if used as an appetite stimulant is allowed.
  6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmias, or psychiatric illness/social situations that would limit compliance with study requirements.
  7. 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.
  8. Subjects taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John's Wort).
  9. 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.
  10. Any condition or medical problem in addition to the underlying malignancy and organ dysfunction that the Investigator feels would pose unacceptable risk.
  11. Has thrombocytopenia, neutropenia, or anemia of grade ≥3 (per CTCAE 5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
  12. Has abnormalities known to be associated with MDS and multiple primary neoplasms (MPN) observed in cytogenetic testing and DNA sequencing.
  13. Has a prior history of T-LBL/T-ALL.
  14. Ingestion of alcohol and smoking is not permitted any time during the study.
  15. History of drug abuse (including alcohol) within the last 6 months prior to screening.
  16. Severe hepatic encephalopathy (Grade >2) or degree of CNS impairment which the Investigator considers sufficiently serious to interfere with the informed consent, the conduct, the completion, or the results of this trial, or constitutes an unacceptable risk to the subject.
  17. History of liver transplantation.
  18. Advanced ascites or ascites that require drainage and albumin supplementation, as judged by the Investigator.
  19. Acute damage of the liver with Grade 4 AST/ALT values at screening or admission.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Clinical Trial Medical Affairs +1 (855) 500-1011 clinicaltrials@epizyme.com
Listed Location Countries  ICMJE Belgium,   France,   Poland,   Slovakia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04241835
Other Study ID Numbers  ICMJE EZH-1201
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Epizyme, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Epizyme, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Sponsor GmbH
Investigators  ICMJE Not Provided
PRS Account Epizyme, Inc.
Verification Date June 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP