Comparing blood levels and safety of tazemetostat in cancer patients with liver impairment and normal liver function

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

This study is testing how the cancer drug tazemetostat works and its safety in people with liver problems compared to those with normal liver function.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Ipsen (Industry-sponsored)
• Drugs / interventions: chemotherapy, immunotherapy
• Locations: 18 sites (Lake Mary, Florida and 17 other locations)
• Trial ID: NCT04241835 on ClinicalTrials.gov

What this trial studies

This trial aims to compare the pharmacokinetics and safety of tazemetostat in participants with advanced solid tumors who have moderate or severe liver impairment against those with normal liver function. Participants will receive a single oral dose of tazemetostat followed by a twice-daily regimen, with blood samples collected for analysis. The study is divided into two parts, focusing on both the initial pharmacokinetic assessment and ongoing treatment until disease progression or unacceptable toxicity occurs. Safety assessments will be conducted 30 days after the last dose.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with advanced solid tumors or hematological malignancies who have experienced disease progression after standard therapies.

Not a fit: Patients with early-stage cancer or those who have not yet undergone standard treatment options may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide critical insights into the safe use of tazemetostat for patients with liver impairment, potentially expanding treatment options for this population.

How similar studies have performed: While there have been studies on tazemetostat, this specific comparison in patients with liver impairment is novel and has not been extensively tested.

Eligibility 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 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. Subjects 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 myeloproliferative 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.

Where this trial is running

Lake Mary, Florida and 17 other locations

• Florida Cancer Specialists & Research Institute — Lake Mary, Florida, United States (Recruiting)
• Robert H. Lurie Comprehensive Cancer Center of Northwestern University — Chicago, Illinois, United States (Terminated)
• Hematology Oncology Consultants — Royal Oak, Michigan, United States (Recruiting)
• Comprehensive Cancer Center of Nevada — Las Vegas, Nevada, United States (Terminated)
• Rutgers Cancer Institute — New Brunswick, New Jersey, United States (Recruiting)
• Gabrail Cancer Center — Canton, Ohio, United States (Terminated)
• Mary Crowley Cancer Research — Dallas, Texas, United States (Terminated)
• Oncology Consultants - Texas Medical Center — Houston, Texas, United States (Withdrawn)
• Virginia Cancer Specialists — Fairfax, Virginia, United States (Recruiting)
• Antwerp University Hospital — Edegem, Antwerp, Belgium (Recruiting)
• Cliniques Universitaires Saint-Luc — Brussels, Belgium (Withdrawn)
• Institut Bergonie — Bordeaux Cedex, France (Recruiting)
• Centre Oscar Lambret — Lille, France (Recruiting)
• Hopital de la Timone — Marseille, France (Withdrawn)
• Institut de Cancérologie Strasbourg Europe — Strasbourg, France (Recruiting)
• Biokinetica S.A Przychodnia Jozefow — Józefów, Mazowieckie, Poland (Withdrawn)
• MedPolonia — Poznań, Wielkopolskie, Poland (Recruiting)
• Summit Clinical Research, s.r.o — Bratislava, Slovakia (Recruiting)

Study contacts

• Study coordinator: Ipsen Recruitment Enquiries

Conditions Hepatic Impairment; Advanced Malignant Solid Tumor