Clinical Trials /

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

NCT04241835

Description:

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.

Related Conditions:
  • Hematopoietic and Lymphoid Malignancy
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Oral Tazemetostat in Subjects With Moderate and Severe Hepatic Impairment With Advanced Malignancies
  • Official Title: A Phase I, Open-label Single-dose Pharmacokinetic and Safety Study of Oral Tazemetostat in Subjects With Moderate and Severe Hepatic Impairment With Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: EZH-1201
  • NCT ID: NCT04241835

Conditions

  • Hepatic Impairment
  • Advanced Malignant Solid Tumor

Interventions

DrugSynonymsArms
TazemetostatEPZ-6438Open label Tazemetostat

Purpose

This is a phase 1, 2-part, global, multicenter, open-label, parallel cohort, 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. Part 1 is an evaluation of the PK of a single 800 mg
      dose of tazemetostat in subjects with advanced malignancies and either normal liver function,
      or advanced malignancies and moderate, or severe hepatic impairment. Part 1 ends on day 8.
      Subjects continuing onto Part 2 of the study must begin dosing on day 9, cycle 1. There is no
      window between Part 1 and Part 2 for dosing. In Part 2, subjects are eligible to continue
      receiving 800 mg tazemetostat twice daily in 28 day cycles until Investigator-assessed
      clinical progression or unacceptable toxicity, or until another discontinuation criterion is
      met. Subjects must have a post-treatment follow-up visit within 30 days of the last dose of
      tazemetostat. Supplementary study conduct information not mandated to be present in this
      protocol is provided in the accompanying procedure manuals (ie, laboratory, pharmacy, ECG
      manuals). Such manuals will provide the site personnel with administrative and detailed
      technical information that does not impact subject safety.
    

Trial Arms

NameTypeDescriptionInterventions
Open label TazemetostatExperimentalPart 1: Single dose Oral Tazemetostat, 800mg Part 2: Oral Tazemetostat 800mg BID
  • Tazemetostat

Eligibility Criteria

        1. Male or female ≥ 18 years age at the time of consent.

          2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (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 (See Appendix 4 and Appendix 5 for disease
             assessment criteria in solid tumors and hematological malignancies respectively).

          7. Has all prior treatment (ie, 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. Male subjects must refrain from donating sperm starting at the planned first dose of
             tazemetostat until 30 days 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

         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. 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
                  the planned first dose of IP until 30 days 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 30 days after discontinuation of study
                  treatment.

               3. 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 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.

          2. Clinically significant bleeding diathesis or coagulopathy, including known platelet
             function disorders. Patients 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 patients 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.

          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 a prior history of T-LBL/T-ALL.

         11. 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).

         12. History of drug abuse (including alcohol) within the last 6 months prior to screening.

         13. 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.

         14. History of liver transplantation.

         15. Advanced ascites or ascites that require drainage and albumin supplementation, as
             judged by the Investigator.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description: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
Measure:To evaluate change in blood pressure
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Investigators will note any clinically significant changes from baseline in systolic and diastolic blood pressure measured in units of millimeters of mercury (mmHg)
Measure:To evaluate change in heart rate
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Investigators will note any clinically significant changes from baseline in heart rate measured in units of beats per minute (BPM)
Measure:To evaluate change in body temperature
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Investigators will note any clinically significant changes from baseline in body temperature measured in degrees Fahrenheit or Celsius
Measure:To evaluate changes in concomitant medications
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Investigators will note any changes in concomitant medications from baseline in all subjects with at least 1 dose or partial dose of tazemetostat
Measure:To evaluate change in electrical activity of the heartbeat, RR interval
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Investigators will report any clinically significant changes from baseline in the RR interval (sec) as noted by a 12 lead electrocardiogram (ECG)
Measure:To evaluate change in electrical activity of the heartbeat, PR interval
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Investigators will report any clinically significant changes from baseline in the PR interval (sec) as noted by a 12 lead electrocardiogram (ECG)
Measure:To evaluate change in electrical activity of the heartbeat, QRS complex
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Investigators will report any clinically significant changes from baseline in the QRS complex (sec) as noted by a 12 lead electrocardiogram (ECG)
Measure:To evaluate change in electrical activity of the heartbeat, QT interval
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Investigators will report any clinically significant changes from baseline in the QT interval (sec) as noted by a 12 lead electrocardiogram (ECG)
Measure:To evaluate changes in clinical laboratory values, hematology
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description: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
Measure:To evaluate changes in clinical laboratory values, serum chemistry
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description: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
Measure:To evaluate changes in clinical laboratory values, urinalysis
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description: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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Epizyme, Inc.

Last Updated

January 22, 2020