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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 : April 9, 2020
Sponsor:
Collaborator:
Sponsor GmbH
Information provided by (Responsible Party):
Epizyme, Inc.

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.

Condition or disease Intervention/treatment Phase
Hepatic Impairment Advanced Malignant Solid Tumor Drug: Tazemetostat Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 28, 2020
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2021

Arm Intervention/treatment
Experimental: Open label Tazemetostat
Single and BID doses of oral tazemetostat 800 mg
Drug: Tazemetostat

200 mg and 400 mg tablets

200 mg: Round, red, biconvex, film-coated tablets 400 mg: Oval, red, biconvex, film-coated tablets Dose/Route/Schedule/Duration: Oral/twice daily/continuous

Other Name: EPZ-6438




Primary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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)

  4. 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)

  5. 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

  6. 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

  7. 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)

  8. 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)

  9. 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)

  10. 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)

  11. 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

  12. 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

  13. 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



Information from the National Library of Medicine

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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
  1. Male or female ≥ 18 years age at the time of consent.
  2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 (Appendix 1).
  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 refrain from donating sperm starting at least 7 days before the planned first dose of tazemetostat until 3 months following the last dose of tazemetostat.
  14. Male subjects with a female partner of childbearing potential must:

    1. Be vasectomized, or
    2. Remain abstinent or use a condom starting at least 7 days before the planned first dose of IP until 3 months following the last dose of IP
  15. 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.
  16. Women of childbearing potential:

    1. 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 IP until 6 months following the last dose of IP
    2. 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.
    3. Barrier methods must always be supplemented with the use of a spermicide.
  17. Females of childbearing potential must have a negative serum pregnancy test at screening.
  18. Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec.
  19. 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 DDI 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. Subject's 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. 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 study therapy. 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 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.
  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 ALT and are hepatitis B surface antigen negative and/or have undetectable HCV RNA.
  7. Subjects taking medications that are known potent CYP3A4 inducers/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 5.0 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 multiple primary 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, until the 72 hour PK time point has been collected. 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).
  14. History of drug abuse (including alcohol) within the last 6 months prior to screening.
  15. Severe hepatic encephalopathy (Grade >2) or degree of central nervous system (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.
  16. History of liver transplantation.
  17. Advanced ascites or ascites that require drainage and albumin supplementation, as judged by the Investigator.
  18. Acute damage of the liver with Grade 4 AST/ALT values at screening or admission

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): NCT04241835


Contacts
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Contact: Shefali Agarwal, MD 855-500-1011 clinicaltrials@epizyme.com

Locations
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United States, Nevada
Comprehensive Cancer Center of Nevada Recruiting
Las Vegas, Nevada, United States, 89014
Contact: Fadi Braiteh, MD         
United States, Texas
Mary Crowley Cancer Research Recruiting
Dallas, Texas, United States, 75230
Contact: James Strauss, MD         
Sponsors and Collaborators
Epizyme, Inc.
Sponsor GmbH
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Responsible Party: Epizyme, Inc.
ClinicalTrials.gov Identifier: NCT04241835    
Other Study ID Numbers: EZH-1201
First Posted: January 27, 2020    Key Record Dates
Last Update Posted: April 9, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Diseases
Digestive System Diseases