A Study of Oral Tazemetostat in Subjects With Moderate and Severe Hepatic Impairment With Advanced Malignancies
Study Details
Study Description
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 |
|---|---|---|
| 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Open label Tazemetostat Single and BID doses of oral tazemetostat 800 mg |
Drug: Tazemetostat
200 mg and 400 mg tablets
Round, red, biconvex, film-coated tablets
Duration: continuous
Other Names:
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Outcome Measures
Primary Outcome Measures
- 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 [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 [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 [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 [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 [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 [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 [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
- To evaluate the number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0 [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
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male or female ≥ 18 years age at the time of consent.
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Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
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Has the ability to understand informed consent and provided signed written informed consent.
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Life expectancy of > 3 months.
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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.
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Must have evaluable or measurable disease.
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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.
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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.
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Has adequate hematologic (bone marrow [BM] and coagulation factors), and renal function.
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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.
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Subjects with abnormal hepatic function will be eligible and will be grouped according to established criteria. Subjects with active hemolysis will be excluded.
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Manual differential with no significant morphologic abnormalities on complete blood count (CBC) testing.
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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.
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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.
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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.
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Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec.
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Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in the study if they meet established criteria.
Exclusion Criteria:
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Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
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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.
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Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders. Subjects on anticoagulation with low molecular weight heparin are allowed.
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Known hypersensitivity to any of the components of tazemetostat.
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Concurrent investigational agent or anticancer therapy. NOTE: Megestrol (Megace) if used as an appetite stimulant is allowed.
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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.
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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.
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Subjects taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John's Wort).
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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.
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Any condition or medical problem in addition to the underlying malignancy and organ dysfunction that the Investigator feels would pose unacceptable risk.
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Has thrombocytopenia, neutropenia, or anemia of grade ≥3 (per CTCAE 5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
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Has abnormalities known to be associated with MDS and multiple primary neoplasms (MPN) observed in cytogenetic testing and DNA sequencing.
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Has a prior history of T-LBL/T-ALL.
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Ingestion of alcohol and smoking is not permitted any time during the study.
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History of drug abuse (including alcohol) within the last 6 months prior to screening.
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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.
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History of liver transplantation.
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Advanced ascites or ascites that require drainage and albumin supplementation, as judged by the Investigator.
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Acute damage of the liver with Grade 4 AST/ALT values at screening or admission.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Robert H. Lurie Comprehensive Cancer Center of Northwestern University | Chicago | Illinois | United States | 60611 |
| 2 | Comprehensive Cancer Center of Nevada | Las Vegas | Nevada | United States | 89014 |
| 3 | Gabrail Cancer Center | Canton | Ohio | United States | 44718 |
| 4 | Mary Crowley Cancer Research | Dallas | Texas | United States | 75230 |
| 5 | Oncology Consultants - Texas Medical Center | Houston | Texas | United States | 77030 |
| 6 | Antwerp University Hospital | Edegem | Antwerp | Belgium | 2650 |
| 7 | Cliniques Universitaires Saint-Luc | Brussels | Belgium | 1200 | |
| 8 | Institut Bergonie | Bordeaux Cedex | France | 33076 | |
| 9 | Centre Oscar Lambret | Lille | France | 59020 | |
| 10 | Hopital de la Timone | Marseille | France | 13005 | |
| 11 | Biokinetica S.A Przychodnia Jozefow | Józefów | Mazowieckie | Poland | 05410 |
| 12 | MedPolonia | Poznań | Wielkopolskie | Poland | 60693 |
| 13 | Summit Clinical Research, s.r.o | Bratislava | Slovakia | 831 01 |
Sponsors and Collaborators
- Epizyme, Inc.
- Sponsor GmbH
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- EZH-1201