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
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.
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
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
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
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
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.
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
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
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.