This is a phase I, multi-center, open-label, multi-dose, two-part PK and safety study to
characterize the DDI potential of oral Tazemetostat.
This two-part study is designed to characterize the steady-state PK of oral Tazemetostat and
its metabolite EPZ 6930 when administered as a single and twice daily dose in subjects with
advanced malignancies while taken alone or in combination with either itraconazole or
Part 1: Tazemetostat and Itraconazole Drug Interaction Part 1 of the study will evaluate the
drug-drug interaction between Tazemetostat and itraconazole in an open-label, fixed
sequential cross over design. Subjects in Cycle 1 of Part 1 will be treated for 39 days. On
Days 1, 15 and 36, a single oral dose of 400 mg Tazemetostat will be administered in the
morning. From Days 3 - 14 and 21 - 35, subjects will receive an oral 400 mg dose of
Tazemetostat twice daily (12 hours apart). From Days 18 - 38, a single dose of oral 200 mg
itraconazole will be administered daily in the morning after a meal, co-administered with
Tazemetostat when necessary. PK blood samples will be collected on Days 1 - 3, 15 - 18, 21 -
22, and 36 - 39. Sparse PK samples will be collected on Days 25, 28, 31, and 34.
Part 2: Tazemetostat and Rifampin Drug Interaction Part 2 of the study will evaluate the
drug-drug interaction between Tazemetostat and rifampin in an open-label, fixed sequential
cross over design. Subjects in Cycle 1 of Part 2 will be treated for 26 days. On Days 1, 15
and 24, a single oral dose of 800 mg Tazemetostat will be administered in the morning. From
Days 3 - 14 and 17 - 23, subjects will receive an oral 800 mg dose of Tazemetostat twice
daily (12 hours apart). From Days 17 - 25, a single dose of oral 600 mg rifampin will be
administered daily in the morning one hour before a meal, co-administered with Tazemetostat
when necessary. PK blood samples will be collected on Days 1 - 3, 15 - 17 and 24 - 26. Sparse
PK samples will be collected on Days 19 and 21.
Subjects may discontinue from the study after completion of Cycle 1 or can continue treatment
(Cycle2+ onwards) with Tazemetostat at the recommended therapeutic dose of 800 mg twice daily
until Investigator-assessed clinical disease progression per standard practice, unacceptable
toxicity, withdrawal of consent, or termination of the study by the sponsor. All subjects who
receive the recommended therapeutic dose of 800 mg Tazemetostat twice daily for 9 Cycles or
longer, and are eligible to continue receiving Tazemetostat, will transfer to a Rollover
Study (EZH-501) for monitoring and continued study drug at the Investigator and Medical
For both Parts 1 and 2, safety and tolerability will be assessed throughout the subject's
participation. Subjects must have an end of study visit after 30 days of the last dose of
Tazemetostat for safety assessment.
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 provide 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 hematologic malignancies
that have relapsed, or refractory disease, following at least 2 standard lines of
systemic therapy for which there are no standard therapies available.
Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone
will not be considered a separate systemic treatment regimen.
6. Must have evaluable or measurable disease.
7. Has all prior treatment (ie, chemotherapy, immunotherapy, radiotherapy) related
clinically significant toxicities resolve to ≤ Grade 1 per National Cancer Institute
Common Terminology Criteria for Adverse Events (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 or 5 half-lives, whichever
is shorter may be acceptable, and questions related to this can be discussed with the
9. Has normal hepatic function (per NCI-ODWG criteria) as well as adequate hematologic
(bone marrow [BM] and coagulation factors) and renal function:
- Hemoglobin: ≥9 g/dL (90 g/L)
- Platelets: ≥75,000/mm³ (≥75 × 10⁹/L)
- ANC (Hematologic malignancy subjects): ≥750/mm³ (≥0.75 × 10⁹/L)
- ANC (Solid tumor subjects): ≥1,000/mm³ (≥1.0 × 10⁹/L)
- PT: <1.5 ULN
- PTT: <1.5 ULN
- Serum creatinine: ≤1.5 × ULN
- Bilirubin and AST: ≤ ULN
Note: Laboratory results obtained during screening should be used to determine
eligibility criteria. In situations where laboratory results are outside the permitted
range, the Investigator may retest the subject and the subsequent within range
screening result may be used to determine the subject's eligibility. Subjects may be
retested once within 2 weeks of the screening test. Samples must be reanalyzed at the
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. Manual differential with no significant morphologic abnormalities on complete blood
count (CBC) testing.
12. Male subjects must refrain from donating sperm from first dose of Tazemetostat until 3
months 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 starting at signing of informed consent until 3
months following the last dose of study drug. 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 (eg,
calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal
are not acceptable methods of contraception.
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. Female subjects of childbearing potential:
1. A woman is considered to be of childbearing potential if she is postmenarchal,
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 study drug until 6 months following
the last dose of study drug.
3. Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, established and 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
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 (eg, calendar, ovulation, sympto-thermal, or
post-ovulation methods) and withdrawal are not acceptable methods of
6. 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 drug-drug interaction 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.
Subjects with primary glioblastoma multiforme are excluded.
Note: Subjects with clinically stable brain metastases are eligible to enroll in the
2. Clinically significant bleeding diathesis or coagulopathy, including known platelet
function disorders. Subjects on anticoagulation with low molecular weight heparin are
3. Known hypersensitivity to any of the components of Tazemetostat.
4. Use of 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 Tazemetostat. 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.
5. Uncontrolled concurrent illness including, but not limited to, ongoing or active
infection, 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.
Exceptions: Subjects with a history of hepatitis B or C who have normal alanine
aminotransferase (ALT) values and are hepatitis B surface antigen negative and/or have
undetectable HCV RNA.
7. Subjects taking medications that are known CYP3A4 inducers or 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 thrombocytopenia, neutropenia, or anemia of grade ≥3 (per CTCAE v5.0 criteria) or
any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
11. Has abnormalities known to be associated with MDS (e.g., del 5q, chr 7 abn) and
myeloproliferative neoplasms (MPN) (e.g., JAK2 V617F) observed in cytogenetic testing
and DNA sequencing.
12. Has a prior history of T-LBL/T-ALL.
13. Ingestion of alcohol within 72 hours prior to day 1 of Cycle 1, and until the 24, 48
or 72 hour post dose PK time point has been collected (whichever is the final sampling
time point). 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
spirits) throughout the study until the end of treatment.
14. Any form of marijuana use.
15. History of drug abuse (including alcohol) within the last 6 months prior to screening.