A Phase I Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects
with Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

1. Age (at time of consent/assent): *6 months to *18 years
Cohort 4 only: *10 years to *18 years
2. Performance Status:
If <12 years of age: Lansky Performance Status >50%
If *12 years of age: Karnofsky Performance Status >50%
3. Has provided signed written informed consent/assent
4. Has a life expectancy of >3 months
5. Has relapsed or refractory disease and no standard treatment options
6. Is ineligible or inappropriate for other treatment regimens known to have
effective potential
7. Has a documented local diagnostic pathology of original biopsy
8. Has all prior treatment related clinically significant toxicities resolve
to * Grade 1 per CTCAE, version 4.03 or are clinically stable and not
clinically significant, at time of enrollment
9. Prior therapy(ies), must be completed according to the protocol
10. Has adequate hematologic BM & coagulation factors), renal & hepatic
function as defined by criteria in the protocol
11. Specific requirements for subjects with CNS involvement eg: stable deficits
within certain timeframe, stable seizure, treated brain metastases without
evidence of progression.
12. Has a LV fractional shortening of >27% or an LV ejection fraction of *50%
by ECHO or MUGA scan & NYHA *2
13. Has a QT interval corrected by Fridericia's formula (QTcF) *450 msec
14. Is able to swallow and retain orally administered medication and does not
have any uncontrolled GI condition that may alter absorption
15. Has sufficient tumor tissue available for central confirmatory testing of
IHC and/or cytogenetics/FISH and/or DNA mutation analysis
16. Is willing and able to comply with all aspects of the protocol as judged by
Investigator
17. 18. For female subjects of childbearing potential and for male subjects
with a female partner of childbearing potential Subject must adhere to
contraception methods described in the protocol
For Dose Escalation Only:
All criteria above and the following:
1. Has evaluable disease as defined as lesions that can be accurately measured
at least in one dimension by radiographic examination or physical examination
or/and other lesions such as bone lesions, leptomeningeal disease, ascites,
pleural/pericardial effusions, lymphangitis cutis/pulmonitis or
hepatosplenomegaly from disease.
2. Has one of the following histologically confirmed tumors: Rhabdoid tumor:
ATRT, MRT, RTK, selected tumors with rhabdoid features, INI1-negative tumor
(Epithelioid sarcoma, Epithelioid malignant peripheral nerve sheath tumor, EMC,
Myoepithelial carcinoma, Renal medullary carcinoma), other INI1-negative
malignant tumors, Synovial sarcoma with SS18-SSX rearrangement.
3. For subjects with ATRT, MRT, or RTK, or tumors with rhabdoid features only:
the following test results must be available:
*Morphology and immunophenotypic panel consistent with rhabdoid tumor, 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
4. For subjects with INI1 negative tumor only:
the following test results must be available:
*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
5. For subjects with synovial sarcoma only:
the following test results must be available:
*Morphology consistent with synovial sarcoma, and
*Cytogenetics or FISH and/or molecular confirmation (e.g.DNA sequencing) of
SS18 rearrangement t(X;18)(p11;q11)
For Dose Expansion Only:
All listed above and in addition:
1. Has measurable disease
2. Has one of the following tumors: Cohort 1: ATRT, Cohort 2: MRT, RTK,
selected tumors with rhabdoid features, Cohort 3: INI1-negative tumors or
synovial sarcoma: ES,Epithelioid malignant peripheral nerve sheath tumor, EMC,
Myoepithelial carcinoma, Renal medullary carcinoma, Chordoma (poorly
differentiated or de-differentiated), other INI1-negative malignant tumors,
Cohort 4: one of the tumor types defined in Cohorts 1 through 3 or synovial
sarcoma with SS18-SSX rearrangement.
3. For subjects with ATRT/MRT/RTK only-have test results available:
*Morphology and immunophenotypic panel consistent with rhabdoid tumor, and,
*Loss of INI1 or SMARCA4 confirmed by IHC, or *Molecular confirmation of tumor
bi-allelic INI1 or SMARCA4 loss/mutation
4. For subjects with INI1-negative tumors only: - Have test results available:
*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/mutation
5. For subjects with synovial sarcoma with SS18-SSX rearrangement (In Cohort 4
only): morphology consistent with synovial sarcoma & Cytogenetics or FISH &/or
molecular confirmation of SS18 rearrangement t (X;18)(p11;q11)
6. For subjects Cohort 4: Able to swallow and retain orally administered
tablets

1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of
zeste homolog2 (EZH2)
2. Is being actively treated for another concurrent malignancy or is less than
five years from completion of treatment for another malignancy
3. Has participated in another interventional clinical study and received
investigational drug within 30 days or five half-lives, whichever is longer,
prior to the planned first dose of tazemetostat
4. Has had major surgery within 2 weeks prior to enrollment
5. Has clinically active heart disease including prolonged QTcF (>450 msec)
6. Is currently taking any prohibited medication(s) as described in section 7.3
7. 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
8. Has an active infection requiring systemic treatment
9. Is immunocompromised (ie congenital immunodeficiency), including subjects
with known history of infection with human immunodeficiency virus (HIV)
10. Has known history of chronic infection with hepatitis B virus (hepatitis B
surface antigen positive) or hepatitis C virus (detectable HCV RNA)
11. Has had a symptomatic venous thrombosis within 14 days prior to study
enrollment
12. 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
13. Has known hypersensitivity to any of the components of tazemetostat or
other inhibitor(s) of EZH2, or hypersensitivity to Ora-sweet or methylparaben
14. Has an uncontrolled intercurrent illness including, but not limited to,
uncontrolled infection, or psychiatric illness/social situations that would
limit compliance with study requirements
15. For female subjects of childbearing potential: Is pregnant or nursing
16. For male subjects: Is unwilling to adhere to contraception criteria from
time of enrollment in study to at least 3 months after last dose of
tazemetostat.