Tazemetostat in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Endometrial Cancer

PRIMARY OBJECTIVES:

I. To assess the clinical activity (overall response rate) of tazemetostat in patients with
recurrent or persistent endometrioid or clear cell ovarian or primary peritoneal cancer, and
low grade endometrioid endometrial adenocarcinoma.

SECONDARY OBJECTIVES:

I. To examine the nature and degree of toxicity in this patient population treated with this
regimen.

II. To examine the progression free survival and overall survival for this patient population
receiving tazemetostat.

TERTIARY OBJECTIVES:

I. To evaluate BAF250a expression in patient samples as an indicator of ARID1A mutation
status and correlation with clinical response to study drug.

II. To examine the correlation between ARID1A mutation and BAF250a expression and to identify
potential mutations predictive of response in patients with preserved BAF250a expression.

OUTLINE:

Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-28. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Pathologically (histologically or cytologically) proven diagnosis of
recurrent/persistent ovarian, or peritoneal endometrioid/clear cell carcinoma, OR
recurrent/persistent low grade (grade 1 or 2) endometrioid endometrial adenocarcinoma;
primary ovarian tumors must be at least 50% endometrioid/clear cell morphology, or
have histologically documented recurrence with at least 50% endometrioid/clear cell
morphology; appropriate tissue sections must be available for histologic evaluation
for central pathology review by National Research Group (NRG) Oncology

- All patients must have measurable disease as defined by Response Evaluation Criteria
in Solid Tumors (RECIST) version (v) 1.1; measurable disease is defined as at least
one lesion that can be accurately measured in at least one dimension (longest diameter
to be recorded); each lesion must be >= 10 mm when measured by computed tomography
(CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >=
20 mm when measured by chest x-ray; lymph nodes must be > 15 mm in short axis when
measured by CT or MRI

- Patients must have had at least one prior platinum-based chemotherapeutic regimen for
management of primary disease; unlimited prior hormonal therapy, targeted therapy or
antiangiogenic therapy will be permitted

- Patients must be 7 days to 6 weeks out from prior therapy:

- Chemotherapy cytotoxic: At least 21 days since last dose of chemotherapy prior to
first dose of tazemetostat

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

- Chemotherapy non-cytotoxic (e.g. small molecule inhibitor): At least 7 days or
five half-lives, whichever is shorter, since last dose of chemotherapy prior to
first dose of tazemetostat

- Monoclonal antibody(ies): At least 28 days since last dose of chemotherapy prior
to first dose of tazemetostat

- Immunotherapy: At least 21 days since last dose of chemotherapy prior to first
dose of tazemetostat

- Radiotherapy (RT): At least 28 days from last local site RT prior to first dose
of tazemetostat

- At least 21 days from stereotactic radiosurgery prior to first dose of
tazemetostat

- At least 28 days from craniospinal, > 50% radiation of pelvis or total body
irradiation prior to first dose of tazemetostat

- Appropriate stage for study entry based on the following diagnostic workup:

- History/physical examination within 28 days prior to registration

- Imaging of the chest, abdomen and pelvis within 30 days prior to registration

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 28
days prior to registration

- Within 14 days prior to registration: Absolute neutrophil count (ANC) >= 1,500/mcl

- Within 14 days prior to registration: Hemoglobin (Hgb) >= 9 g/dL

- Within 14 days prior to registration: Serum creatinine =< 1.5 x upper limit of normal
(ULN)

- Within 14 days prior to registration: Aspartate aminotransferase (AST)/alanine
aminotransferase (ALT) =< 3 x ULN

- Within 14 days prior to registration: Total serum bilirubin level =< 1.5 x ULN; direct
bilirubin =< ULN for subjects with total bilirubin > 1.5 x ULN (patients with isolated
indirect bilirubin elevations and a history of Gilbert's syndrome are eligible)

- The patient or a legally authorized representative must provide study-specific
informed consent and authorization permitting release of personal health information
prior to study entry

Exclusion Criteria:

- Prior treatment with an investigational EZH2 inhibitor

- Patients whose circumstances do not permit completion of the study or the required
follow-up

- Patients who are unable to swallow pills

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years, with the exception of those with a negligible risk of
metastases or death, such as carcinoma in situ of the breast or cervix

- Severe, active co-morbidity defined as follows:

- Life expectancy < 3 months

- Pregnant or lactating patients

- Human immunodeficiency virus (HIV) positive patients on combination antiretroviral
therapy are ineligible