A Phase II Study of Tazemetostat (EPZ-6438) in Recurrent or Persistent Endometrioid or Clear Cell Carcinoma of the Ovary, and Recurrent or Persistent Endometrioid Endometrial Adenocarcinoma

• Pathologically (histologically or cytologically) proven diagnosis of recurrent or persistent ovarian endometrioid or clear cell carcinoma, OR recurrent or persistent endometrioid endometrial adenocarcinoma; patients with recurrent endometrial cancer must have mismatch repair (MMR) immunohistochemistry completed; if they are found to be mismatch repair deficient, they should be offered treatment with immune checkpoint inhibition before consideration for treatment on trial; primary ovarian tumors must be at least 50% endometrioid or clear cell morphology, or have histologically documented recurrence with at least 50% endometrioid or clear cell morphology; institutional pathology reports must be provided indicating at least 50% endometrioid or clear cell morphology for ovarian tumors (primary or recurrent lesions)

‣ Only patients with recurrent or persistent ovarian clear cell carcinoma (OCCC) with ARID1A pathologic variant or likely pathologic variant mutations per next generation sequencing (NGS) are eligible for entry (20-OCT-2021)

⁃ Institutional pathology reports must be provided indicating at least 50% clear cell morphology for ovarian tumors (primary or recurrent lesions) and NGS report must be available for step 1 registration (20-OCT-2021) (09-DEC-2021)

⁃ All other eligibility criteria and ineligibility criteria must be met for step 2 registration (20-OCT-2021) (09-DEC-2021)

• 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, but no more than 3, prior cytotoxic regimens for management of primary disease; unlimited prior hormonal therapy, targeted therapy (including immunotherapy) or antiangiogenic therapy will be permitted

• Patients must have completed prior therapy:

‣ Chemotherapy: cytotoxic

• At least 28 days since last dose of chemotherapy prior to step 2 registration.

⁃ Chemotherapy: nitrosoureas

• At least 6 weeks since last dose of chemotherapy prior to step 2 registration.

⁃ Chemotherapy: non-cytotoxic (e.g. small molecule inhibitor)

• At least 28 days since last dose of chemotherapy prior to step 2 registration.

⁃ Monoclonal antibody(ies)

• At least 28 days since last dose of monoclonal antibody prior to step 2 registration.

⁃ Immunotherapy

• At least 28 days since last dose of immunotherapy prior to step 2 registration.

⁃ Radiotherapy (RT)

• At least 14 days from last local site RT prior to step 2 registration.

∙ At least 21 days from stereotactic radiosurgery prior to step 2 registration.

∙ At least 12 weeks from craniospinal, \>= 50% radiation of pelvis or total body irradiation prior to step 2 registration.

∙ Patients with central nervous system (CNS) disease should demonstrate evidence of stabilization after the 28-day time point after definitive treatment.

∙ Full recovery of radiation related side effects prior to step 2 registration.

∙ All subjects must have evidence of measurable disease outside of the radiation field at the time of step 2 registration

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

‣ History/physical examination within 14 days prior to step 2 registration

⁃ Imaging of the chest, abdomen and pelvis within 28 days prior to step 2 registration

• Age \>= 18

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 14 days prior to step 2 registration

• Platelets \>= 100,000/mcl (within 14 days prior to step 2 registration)

• Absolute neutrophil count (ANC) \>= 1,500/mcl (within 14 days prior to step 2 registration)

• Hemoglobin \>= 8 g/dL (within 14 days prior to step 2 registration)

• Differential with no clinically significant morphologic abnormalities on complete blood count (CBC) testing; manual differential is encouraged, if clinically indicated, and in cases where an automated differential is abnormal (within 14 days prior to step 2 registration)

• Creatinine =\< 1.5 x institutional/laboratory upper limit of normal (ULN) (within 14 days prior to step 2 registration)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3 x ULN (within 14 days prior to step 2 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) (within 14 days prior to step 2 registration)

• Patients must be able to swallow and retain oral medications and not have gastrointestinal illnesses that would preclude absorption of tazemetostat as judged by the treating physician (20-OCT-2021)

• Women of childbearing potential must be willing and able to use adequate contraception (hormonal and barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after the last dose of study agent; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately; theoretically, CYP3A induction with tazemetostat use may result in the loss of efficacy in hormonal contraceptives, thus a barrier method of contraception must be used in addition to hormonal contraceptives due to the potential drug-drug interaction with tazemetostat (20-OCT-2021)

• 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

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial (08/13/2019)