A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

This study will include participants with various types of cancer known as soft-tissue
sarcomas.

Tissues that can be affected by soft tissue sarcomas include fat, muscle, blood vessels, deep
skin tissues, tendons and ligaments.

Soft tissue cancers are rare and can occur almost anywhere in the body.

Part 1 of this trial will study the safety and the level that adverse effects of the study
drug tazemetostat in combination with doxorubicin (current front line treatment) can be
tolerated (known as tolerability).

It is also designed to establish a recommended study drug dosage for the next part of the
study.

Part 2 will evaluate and compare how long participants live without their disease getting
worse when receiving the study drug plus doxorubicin versus doxorubicin plus placebo (dummy
treatment).

Inclusion Criteria:

1. Age (at the time of consent/assent): ≥18 years of age

2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

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 and 5)

- That is relapsed or refractory after treatment with an approved therapy(ies),
defined as metastatic or non-resectable, locally advanced disease that has
previously been treated with and progressed following approved therapy(ies)
(Cohort 2)

- That has progressed within 6 months prior to study enrollment (Cohort 5
Expansion, Cohort 6 and Cohort 8 ONLY)

6. Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical
Laboratory Improvement Amendments (CLIA/College of American Pathologists (CAP) or
equivalent 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
tests 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 Cohort 3, 4, 5, 7 and 8 (subjects with INI1-negative/aberrant tumors or any solid
tumor with EZH2 GOF mutation only), the following test results must be available by
local laboratory: Morphology and immunophenotypic panel consistent with INI1-negative
tumors (not applicable for solid tumors with EZH2 GOF mutation), 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, or molecular evidence of EZH2 GOF mutation

10. For Cohort 6 (subjects with ES undergoing optional tumor biopsy) only:

- Morphology and immunophenotypic panel consistent with ES (e.g., CD34, EMA,
Keratin, and INI1)

11. Has all prior treatment (i.e. chemotherapy, immunotherapy, radiotherapy) related
clinically significant toxicities resolve to ≤Grade 1 per CTCAE version 4.0.3 or are
clinically stable and not clinically significant, at time of enrollment.

12. Prior anti-cancer therapy(ies), if applicable, must be completed according to the
criteria below:

- Chemotherapy: cytotoxic (At least 14 days since last dose of chemotherapy prior
to first dose of tazemetostat)

- Chemotherapy: nitrosoureas (At least 6 weeks since last dose of nitrosoureas
prior to first dose of tazemetostat)

- Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) (At least 14 days
since last dose of non-cytotoxic chemotherapy prior to first dose of
tazemetostat)

- Monoclonal antibody(ies) (At least 28 days since the last dose of any monoclonal
antibody prior to first dose of tazemetostat)

- Immunotherapy (e.g. tumor vaccine) (At least 42 days since last dose of
immunotherapy agent(s) prior to first dose of tazemetostat)

- Radiotherapy (RT) (At least 14 days from last local site RT prior to first dose
of tazemetostat/At least 21 days from stereostatic radiosurgery prior to first
dose of tazemetostat/At least 12 weeks from craniospinal, ≥50% radiation of
pelvis, or total body irradiation prior to first dose of tazemetostat)

- High dose therapy with autologous hematopoietic cell infusion (At least 60 days
from last infusion prior to first dose of tazemetostat)

- Hematopoietic growth factor (At least 14 days from last dose of hematopoietic
growth factor prior to first dose of tazemetostat)

13. Has sufficient tumor tissue (slides or blocks) available for central confirmatory
testing

14. Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS
tumors

15. Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic
function.

16. For subjects with CNS Tumors 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

17. 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

18. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec

19. 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 and

- Agree to use effective contraception from a minimum of 7 days prior to first dose
until 6 months following the last dose of tazemetostat and have a male partner
who uses a condom, or

- Practice true abstinence or have a male partner who is vasectomized

20. Male subjects with a female partner of childbearing potential must:

- Be vasectomized, or

- Agree to use condoms as defined in Section 8.6.2, from first dose of tazemetostat
until 3 months following the last dose of tazemetostat, or

- Have a female partner who is NOT of childbearing potential

Exclusion Criteria:

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.

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

6. Has Thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) or
any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN
(e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing.

7. Has a prior history of T-LBL /T-ALL

8. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet

9. Has cardiovascular impairment, history of congestive heart failure greater than NYHA
Class II, 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

10. Is currently taking any prohibited medication(s)

11. Has an active infection requiring systemic treatment

12. Is immunocompromised (i.e. has congenital immunodeficiency), including subjects known
history of infection with human immunodeficiency virus (HIV)

13. Has known active infection with hepatitis B virus or hepatitis C virus

14. Has had a symptomatic venous thrombosis within 2 weeks prior to study enrollment -

15. For subjects with CNS involvement (primary tumor or metastatic disease), have any
active bleeding or new intratumoral hemorrhage of more than punctuate size of
screening MRI obtained within 14 days of starting study drug or known bleeding
diathesis or treatment with anti-platelet or anti-thrombotic agents

16. Has known hypersensitivity to any of the component of tazemetostat or other
inhibitor(s)of EZH2

17. Is unable to take oral medications, or has a malabsorption syndrome or any
uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that
would limit compliance with study requirements.

18. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled
infection, or psychiatric illness/social situations that would limit compliance with
study requirements.

19. For female subjects of childbearing potential: Is pregnant or nursing

20. For male subjects: Is unwilling to adhere to contraception criteria from time of
enrollment in the study to at least 3 months after last dose of tazemetostat.