This is a multicenter, open-label, Phase 1/2 study that is being conducted in two parts. The
Phase 1 part (closed to accrual as of January 25, 2016) comprised dose escalation and
expansion parts to establish the MTD and/or the recommended Phase 2 dose (RP2D) when
tazemetostat was given BID (twice daily) orally on a continuous basis. Additionally, in
separate cohorts in Phase 1, the effect of food on the bioavailability of tazemetostat as
well as the drug-drug interaction (DDI) potential of tazemetostat were evaluated. The Phase 2
part was initiated once the MTD and /or RP2D was established. Phase 2 enrolls subjects with
DLBCL (Cohorts 1-3 and 6) and FL (Cohorts 4 and 5) for the determination of efficacy and
safety of tazemetostat monotherapy (Cohorts 1-5and of tazemetostat in combination with
prednisolone (Cohort 6) with placement determined by centrally confirmed histology, cell of
origin (COO), and EZH2 mutation status.
1. Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Phase
2: ECOG performance status of 0 to 2.
2. Life expectancy ≥ 3 months before starting tazemetostat.
3. Subjects with Hepatitis B or C are eligible on the condition that subjects have
adequate liver function as defined by Inclusion Criterion #6 and are hepatitis B
surface antigen negative and/or have undetectable hepatitis C virus (HCV) RNA.
4. Adequate renal function defined as calculated creatinine clearance ≥40 mL/min per the
Cockcroft and Gault formula or the local institutional standard formula.
5. Adequate bone marrow function:
a. Absolute neutrophil count (ANC) ≥750/mm^3 (≥0.75 x 10^9/L) - Without growth factor
support (filgrastim or pegfilgrastim) for at least 14 days
b. Platelets greater ≥ 75,000/mm^3 (≥75 x 10^9/L) - Evaluated after at least 7 days
since last platelet transfusion
c. Hemoglobin greater than or equal to 9.0 g/dL - May receive transfusion
6. Adequate liver function:
1. Total bilirubin ≤1.5 x the upper limit of normal (ULN) except for unconjugated
hyperbilirubinemia of Gilbert's syndrome
2. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine
aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3 x ULN (≤5 x ULN
if subject has liver metastases)
7. Time between prior anticancer therapy and first dose of tazemetostat as below:
1. Cytotoxic chemotherapy - At least 21 days
2. Non-cytotoxic chemotherapy (eg. Small molecule inhibitor) - At least 14 days
3. Nitrosoureas - At least 6 weeks
4. Monoclonal antibody (ies) - At least 28 days
5. Radiotherapy- At least 14 days from local site radiation therapy/At least 6 weeks
from prior radioisotope therapy/At least 12 weeks from 50% pelvic or total body
6. High dose therapy with autologous hematopoietic cell infusion - At least 60 days
7. High dose therapy with allogeneic transplant - At least 90 days (if graft versus
host disease [GVHD] is present, must be < Grade 2) and no prohibited medications
per Exclusion Criteria #3)
Note: Starting at Cycle 1 Day 1, subjects may receive no more than 10 mg of prednisone
daily (or equivalent corticosteroid, excluding protocol-defined prednisolone dosing
for subjects enrolled in Cohort 6) when used for treatment of lymphoma related
symptoms, with the intent to taper by the end of Cycle 1.
8. Males or females aged ≥ 18 years at the time of informed consent (Phase 2). Males or
females aged ≥ 16 years at time of informed consent (Phase 1).
9. Females must not be lactating or pregnant at screening or baseline (as documented by a
negative beta-human chorionic gonadotropin [beta-hCG] test with a minimum sensitivity
of 25 IU/L or equivalent units of beta-hCG). A separate baseline assessment is
required if a negative screening pregnancy test was obtained more than 72 hours before
the first dose of study drug. All females will be considered to be of childbearing
potential unless they are postmenopausal (at least 12 months consecutive amenorrheic,
in the appropriate age group, and without other known or suspected cause) or have been
sterilized surgically (ie, bilateral tubal ligation, total hysterectomy or bilateral
oophorectomy, all with surgery at least 1 month before dose). Females of childbearing
potential must not have had unprotected sexual intercourse within 30 days prior to
study entry and must agree to use a highly effective method of contraception, from the
last menstrual period prior to randomization, during Treatment Cycles, and for 6
months after the last final dose of study drug; any male partner must use a condom.
Highly effective contraception is one that results in a failure rate of <1% per year
when used consistently and correctly and includes:
1. Double barrier methods of contraception such as condom plus diaphragm or
cervical/vault cap with spermicide.
2. Placement of an intrauterine device.
3. Established hormonal contraceptive methods: oral, injectable, or implant. Females
who are using hormonal contraceptives must have been on a stable dose of the same
hormonal contraceptive product for at least 4 weeks prior to dosing and must
continue to use the same contraceptive during the study and for 6 months after
study drug discontinuation.
Female subjects exempt from this requirement are subjects who practice total
abstinence or have a male partner who is vasectomized. If currently abstinent, the
subject must agree to use a highly effective method of contraception as described
above if they become sexually active during the Treatment Cycles, and for 6 months
after study drug discontinuation.
10. Male subjects must have had a successful vasectomy (with confirmed azoospermia) or
they and their female partner must meet the criteria above (ie, not of childbearing
potential or practicing highly effective contraception and use a condom throughout the
study period and for 3 months after study drug discontinuation). Nonvasectomized male
subjects must also agree to refrain from donating sperm from first dose of
tazemetostat until 3 months following the last dose of tazemetostat.
11. Voluntary agreement to provide written informed consent and the willingness and
ability to comply with all aspects of the protocol.
12. Phase 1 only: Histologically and/or cytologically confirmed advanced or metastatic
solid tumor or B-cell lymphomas that have progressed after treatment with approved
therapies or for which there are no standard therapies available.
13. Phase 2, Cohorts 1-6 only: Subjects must satisfy all of the following criteria:
1. Have histologically confirmed DLBCL (including primary mediastinal B-cell
lymphoma), with relapsed or refractory disease following at least 2 lines of
prior standard therapy, including alkylator/anthracycline (unless
anthracycline-based chemotherapy is contraindicated)/anti-CD20-based therapy
(rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone
[R-CHOP] or equivalent) AND must be considered unable to benefit from
intensification treatment with autologous hematopoietic stem cell transplantation
(ASCT) as defined by meeting at least 1 of the following criteria:
- Relapsed following, or refractory to, previous ASCT
- Did not achieve at least a partial response to a standard salvage regimen
(eg, rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE] or
rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP])
- Ineligible for intensification treatment due to age or significant
- Ineligible for intensification treatment due to failure to mobilize an
acceptable number of hematopoietic stem cells
- Refused intensification treatment and/or ASCT or
b .Have histologically confirmed FL, all grades. Subjects may have relapsed/refractory
disease following at least 2 standard prior systemic treatment regimens where at least 1
anti-CD20-based regimen was used. Subjects with prior radiotherapy will be included;
however, radiotherapy alone will not be considered a systemic treatment regimen.
c. Have provided sufficient archival tumor tissue that has been successfully tested for
EZH2 mutation status and cell of origin (DLBCL only) at study specific laboratories
allowing for allocation into an open cohort.
d. Have measurable disease as defined by International Working Group-Non-Hodgkin's Lymphoma
(IWG-NHL [Cheson, 2007])
1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
2. Subjects with leptomeningeal metastases or brain metastases or history of previously
treated brain metastases.
3. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) and
any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
4. Has a prior history of T-cell lymphoblastic lymphoma(T-LBL) or T-cell lymphoblastic
5. Subjects taking medications that are known strong CYP3A inhibitors and strong or
moderate CYP3A inducers (including St. Johns Wort) (see
6. Subjects unwilling to remove Seville oranges, grapefruit juice and grapefruit from
7. Any prior treatment-related (i.e. chemotherapy, immunotherapy, radiotherapy)
clinically significant toxicities that have not resolved to ≤ Grade 1 per CTCAE
version 4.03 or prior treatment-related toxicities that are clinically unstable and
clinically significant at time of enrollment.
8. Major surgery within 4 weeks before the first dose of study drug. Note: Minor surgery
(eg. minor biopsy of extracranial site, central venous catheter placement, shunt
revision) is permitted within 3 weeks prior to enrollment.
9. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled
gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the
bioavailability of tazemetostat.
10. Significant cardiovascular impairment: history of congestive heart failure greater
than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension,
unstable angina, myocardial infarction, or stroke within 6 months of the first dose of
study drug; or cardiac ventricular arrhythmia.
11. Prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 msec.
12. Venous thrombosis or pulmonary embolism within the last 3 months before starting
13. Active infection requiring systemic therapy.
14. Known hypersensitivity to any component of tazemetostat, prednisolone/prednisone
(combination cohort only), or inability to be treated with a Pneumocystis prophylaxis
medication (combination cohort only).
15. Immunocompromised patients, including patients known to be infected with human
immunodeficiency virus (HIV).
16. Any other major illness that, in the investigator's judgment, will substantially
increase the risk associated with the subject's participation in this study.
17. Females who are pregnant or breastfeeding.
18. Subjects who have undergone an organ transplant.
19. Phase 2 only: Subjects with noncutaneous malignancies other than B-cell lymphomas.
Exception: Subjects with another malignancy who have been disease-free for 5 years, or
subjects with a history of a completely resected non-melanoma skin cancer or
successfully treated in situ carcinoma are eligible.