INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

Primary Objectives: Cohorts 1 (rhabdoid tumors), 3 (other INI1-negative tumors), 4 (renal medullary carcinoma) and 5 (epithelioid sarcoma): • To assess the Overall Response Rate (ORR) in subjects with rhabdoid tumors (Cohort 1), other INI1-negative tumors (Cohort 3), renal medullary carcinoma (Cohort 4) and epithelioid sarcoma (Cohort 5) following oral administration of tazemetostat 800 mg twice daily (BID) Cohort 2 (synovial sarcoma): • To determine the progression-free survival (PFS) rate after 16 weeks of treatment with tazemetostat in subjects with relapsed/refractory synovial sarcoma (Cohort 2) following oral administration of tazemetostat 800 mg BID Secondary Objectives: • To determine the PFS and overall survival (OS) at Weeks 24 and 56 and overall in subjects with rhabdoid tumors (Cohort 1), relapsed/refractory synovial sarcoma (Cohort 2) other INI1- negative tumors (Cohort 3), renal medullary carcinoma (Cohort 4) and epithelioid sarcoma (Cohort 5) following oral administration of tazemetostat 800 mg BID • To assess the ORR in subjects with synovial sarcoma (Cohort 2) • To evaluate the duration of response in subjects with rhabdoid tumors (Cohort 1), relapsed/refractory synovial sarcoma (Cohort 2), other INI1-negative tumors (Cohort 3), renal medullary carcinoma (Cohort 4) and epithelioid sarcoma (Cohort 5) and in Cohorts 1, 3, 4 and 5 combined achieving a complete response (CR) or partial response (PR) according to disease-appropriate criteria following oral administration of tazemetostat • To assess the safety and tolerability of tazemetostat • To assess the population pharmacokinetic (PK) parameters of tazemetostat • To investigate the pharmacodynamic (PD) effects of tazemetostat in tumor tissue Exploratory Objectives: • To explore the relationship between plasma PK and tumor PD markers as permitted by the data • To assess tumor tissue and blood for somatic mutations, germline variants, messenger ribonucleic acid (mRNA) and/or proteins as candidate markers of response to tazemetostat

Tazemetostat (EPZ-6438)

Tazemetostat

Tablet

Tazemetostat 200 mg in each Tablet

Primary Endpoints:
• Cohorts 1 (rhabdoid tumors), 3 (other INI1-negative tumors), 4 (renal medullary carcinoma)
and 5 (epithelioid sarcoma): ORR (confirmed CR+PR) to tazemetostat in subjects with INI1-
negative tumors using disease-appropriate standardized response criteria (primary CNS
tumors: Response Assessment for Neuro-Oncology [RANO] and all others: RECIST 1.1)
• Cohort 2 (relapsed/refractory synovial sarcoma): PFS rate after 16 weeks of treatment with
tazemetostat. This is the number of subjects with CR, PR or stable disease (SD) at the
Week 16 assessment.
Secondary Endpoints:
• ORR (confirmed CR+PR) to tazemetostat in subjects with relapsed/refractory synovial
sarcoma using RECIST 1.1
• PFS at Weeks 24 and 56 and overall for each cohort. PFS is defined as the time from date
of first dose of study treatment to the earlier of the date of first documented disease
progression or date of death due to any cause.
• OS at Weeks 24 and 56 and overall for each cohort. OS is defined as the time from the date
of the first dose of study treatment to the date of death due to any cause.
• Response duration for each cohort and Cohorts 1, 3, 4 and 5 combined. Response
duration, for the subset of subjects with a confirmed CR or PR, is defined as the time from
the first documented evidence of CR or PR to the time of first documented disease
progression or death due to any cause, using disease-appropriate standardized response
criteria
• Safety and tolerability of tazemetostat
• Population PK parameters oral clearance (CL/F), oral volume of distribution (Vd/F), and firstorder absorption rate constant (Ka) for tazemetostat
• PD effects of tazemetostat in tumor tissue in IHC assessments of changes in the level of
H3K27-Me3 following tazemetostat dosing

Inclusion Criteria
Subjects must meet all criteria to be eligible for enrollment in this study.
1. Age (at the time of consent/assent): ≥16 years of age
2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is
considered to be ambulatory for the purpose of assessing their performance status.
3. Has provided signed written informed consent
4. Has a life expectancy of >3 months
5. Has a malignancy:
• For which there are no standard therapies available (Cohorts 1, 3, 4 & 5)
• That is relapsed or refractory after treatment with an approved therapy(ies) (Cohort 2)
6. Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical
Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or
other Sponsor-approved laboratory certification
7. For Cohort 1 (rhabdoid tumors only): The following test results must be available by
local laboratory:
• Morphology and immunophenotypic panel consistent with rhabdoid tumors, and
• Loss of INI1 or SMARCA4 confirmed by IHC, or
• Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss or mutation when
INI1 or SMARCA4 IHC is equivocal or unavailable
8. For Cohort 2 (subjects with relapsed/refractory synovial sarcoma only): The
following test results must be available by local laboratory:
• Morphology consistent with synovial sarcomas, and
• Cytogenetics or fluorescence in situ hybridization (FISH) and/or molecular
confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11)
9. For Cohorts 3 to 5 (subjects with INI1-negative tumor only): The following test
results must be available by local laboratory:
• Morphology and immunophenotypic panel consistent with INI1-negative tumors, and
• Loss of INI1 confirmed by IHC, or
• Molecular confirmation of tumor bi-allelic INI1 loss or mutation when INI1 IHC is
equivocal or unavailable
10. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related
clinically significant toxicities resolved to ≤ Grade 1 per CTCAE, version 4.03 or are
clinically stable and not clinically significant, at time of enrollment
11. Prior therapy(ies), if applicable, must be completed according to the criteria below:
12. Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing of
IHC and/or cytogenetics/FISH and/or DNA mutation analysis (required for study entry but
enrollment based on local results).
13. Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS
tumors
14. Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and
hepatic function as defined by criteria below:
15. For subjects with ATRT only: Subject must have seizures that are stable, not
increasing in frequency or severity and controlled on current anti-seizure medication(s)
for a minimum of 21 days prior to the planned first dose of tazemetostat
NOTE: Subjects may receive glucocorticoids (at stable or tapering dose) to control CNS
symptoms prior to enrollment; however, should receive stable or tapering dose for at least
7 days prior to planned first dose of tazemetostat
16. Has a shortening fraction of >27% or an ejection fraction of ≥50% by echocardiogram
(ECHO) or multi-gated acquisition (MUGA) scan and New York Heart Association
(NYHA) Class <2
17. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec
18. Female subjects of childbearing potential must:
• Have a negative beta-human chorionic gonadotropin (β-hCG) pregnancy test at time
of Screening and within 14 days prior to planned first dose of tazemetostat (urine or
serum test is acceptable however, positive urine tests must be confirmed with serum
testing), and
• Agree to use effective contraception, as defined in Section 8.5.9.4.1 , from start of
screening until 30 days following the last dose of tazemetostat and have a male
partner who uses a condom, or
• Practice true abstinence (when this is in line with the preferred and usual lifestyle of
the subject, see Section 8.5.9.4.1), or
• Have a male partner who is vasectomized
19. Male subjects with a female partner of childbearing potential must:
• Be vasectomized, or
• Agree to use condoms as defined in Section 8.5.9.4.2, from first dose of tazemetostat
until 30 days following the last dose of tazemetostat, or
• Have a female partner who is NOT of childbearing potential
20. For French subjects only: Is either affiliated with or a beneficiary of a social security
category.

Exclusion Criteria:
Subjects meeting ANY of the following criteria must NOT be enrolled in this study:
1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste
homologue-2 (EZH2)
2. Has participated in another interventional clinical study and received investigational drug
within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of
tazemetostat
3. Has known active CNS or any leptomeningeal metastasis of primary extra-cranial tumor.
Subjects with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging 4 weeks prior to the first dose of
study drug and any neurologic symptoms have stabilized), have no evidence of new or
enlarging brain metastases, and are on stable or tapering doses of steroids for at least 7
days prior to first dose of study drug.
NOTE: Only subjects with ATRT as a primary CNS tumor are permitted.
4. Has had a prior malignancy other than the malignancies under study
Exception: A subject who has been disease-free for 5 years, or a subject with a history of a
completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is
eligible.
5. Has had major surgery within 3 weeks prior to enrollment
NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter
placement, shunt revision) is permitted within 3 weeks prior to enrollment.
6. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all
foods that contain those fruits from time of enrollment to while on study.
7. Has cardiovascular impairment, history of congestive heart failure greater than NYHA
Class 2, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or
stroke within 6 months prior to the planned first dose of tazemetostat; or ventricular
cardiac arrhythmia requiring medical treatment
8. Is currently taking any prohibited medication(s)
9. Has an active infection requiring systemic treatment
10. Is immunocompromised (i.e., has a congenital immunodeficiency), including subjects
known history of infection with human immunodeficiency virus (HIV)
NOTE: HIV positive subjects who are taking antiretroviral therapy are ineligible due to
potential PK interactions with tazemetostat.
11. Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen
positive) or hepatitis C virus (detectable HCV RNA)
12. Has had a symptomatic venous thrombosis within the 3 months prior to study enrollment.
NOTE: Subjects with a history of a deep vein thrombosis >3 months prior to study
enrollment who are on anticoagulation therapy with low molecular weight heparin are
eligible for this study.
13. For subjects with CNS involvement (primary tumor or metastatic disease): Have
any active bleeding, or new intratumoral hemorrhage of more than punctate size on
screening MRI obtained within 14 days of starting study drug or known bleeding diathesis
or treatment with anti-platelet or anti-thrombotic agents.