Clinical trial NCT04241835: A Study to Compare the Blood Levels and Safety of Tazemetostat in Participants With Advanced Cancer and Moderate/Severe Liver Impairment to Participants With Advanced Cancer and Normal Liver Function
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Hepatic Impairment
Advanced Malignant Solid Tumor
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
Collaborators: name: Sponsor GmbH
First posted: 2020-01-27
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This main aim of this trial will be to study the blood levels (known as pharmacokinetics) of the study drug tazemetostat.

The pharmacokinetics of the study drug in participants with advanced solid tumors and moderate or severe hepatic (liver) impairment will be compared with participants with advanced malignancies and normal hepatic function.

An advanced malignancy is a cancer that has recurred (come back) after prior treatment or hasn't controlled with treatment.

The trial will also study the safety of the study drug in participants (how well it is tolerated).

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 for safety assessment 30 days after the last dose of tazemetostat or prior to initiation of a subsequent anticancer therapy, whichever occurs first. 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.

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.

Primary outcomes:
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
timeFrame: 0 to 72 hours post dose on Day 1 and Day 15
measure: 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
timeFrame: 0 to 72 hours post dose on Day 1 and Day 15
measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-8: area under the plasma concentration-time curve from time 0 to 8 hours post dose
timeFrame: 0 to 8 hours post dose on Day 1 and Day 15
measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, Cmax: observed maximum plasma concentration
timeFrame: 0 to 72 hours post dose on Day 1 and Day 15
measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, Tmax: observed time at Cmax
timeFrame: 0 to 72 hours post dose on Day 1 and Day 15
measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, t1/2: terminal elimination half-life
timeFrame: 0 to 72 hours post dose on Day 1 and Day 15
measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, fu: unbound fraction of drug in plasma
timeFrame: Pre-dose, 3 hours, 24 hours, and 72 hours post-dose
Secondary outcomes:
measure: To evaluate the number of participants with adverse events (AEs) as assessed by CTCAE v5.0
timeFrame: Through study completion, an average of 1 year
Other outcomes:
Locations:
city: Lake Mary
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
state: Illinois
city: Royal Oak
country: United States
facility: Hematology Oncology Consultants
state: Michigan
city: Las Vegas
country: United States
facility: Comprehensive Cancer Center of Nevada
state: Nevada
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute
state: New Jersey
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Houston
country: United States
facility: Oncology Consultants - Texas Medical Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Edegem
country: Belgium
facility: Antwerp University Hospital
state: Antwerp
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Bordeaux Cedex
country: France
facility: Institut Bergonie
city: Lille
country: France
facility: Centre Oscar Lambret
city: Marseille
country: France
facility: Hopital de la Timone
city: Strasbourg
country: France
facility: Institut de Cancérologie Strasbourg Europe
city: Józefów
country: Poland
facility: Biokinetica S.A Przychodnia Jozefow
state: Mazowieckie
city: Poznań
country: Poland
facility: MedPolonia
state: Wielkopolskie
city: Bratislava
country: Slovakia
facility: Summit Clinical Research, s.r.o
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References: