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.
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.
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
