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

• Status: Recruiting
• Trial end date: 2022-07-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Epizyme, Inc.
• Collaborator: Sponsor GmbH

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. A woman is considered to be of childbearing potential if she is post menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).

2. 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

3. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

4. 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.

5. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.

6. 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) ≤480 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. 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. Subject's with primary glioblastoma multiforme are excluded. NOTE: Subjects with clinically stable brain metastases are eligible to enroll in the study.

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.

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.

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. 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.

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 (e.g. del 5q, chr 7 abn) and multiple primary neoplasms (MPN) (e.g. JAK2 V617F) 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 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.

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