A Phase II Study of MK-3475 (Pembrolizumab) (NSC #776864) + Epacadostat (NSC #766086) in Recurrent Clear Cell Carcinoma of the Ovary

• Primary tumors must be at least 50% clear cell histomorphology in order to be eligible or have a histologically documented recurrence with at least 50% clear cell histomorphology. Recurrence should be biopsy proven as per standard of care unless the tumor is located in an area deemed unsafe to biopsy. Histologic confirmation of the original primary tumor is required via the pathology report. The percentage of clear cell histomorphology must be documented in the pathology report or in an addendum to the original report. If slides of the primary tumor are not available for review due to disposal of slides by the histology laboratory (typically 10 years after diagnosis), a biopsy of the recurrent or persistent tumor is required to confirm at least 50% clear cell histomorphology, as long as tumor is located in an area deemed safe to biopsy. The percentage of clear cell involvement must be documented in the pathology report or in an addendum to the original report

• All patents must have measurable disease, and at least one target lesion to be used to assess response as defined by RECIST 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

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

‣ History/physical examination within 28 days prior to registration

⁃ Imaging of target lesions within 28 days prior to registration

⁃ Further protocol-specific assessments

• Recovery from adverse effects of recent surgery, radiotherapy or chemotherapy (residual grade 1 toxicity is considered recovered)

∙ Any other prior therapy directed at the malignant tumor including chemotherapy, and biologic/targeted agents must be discontinued at least 4 weeks prior to registration. Any hormonal therapy directed at the malignant tumor must be discontinued at least 2 weeks prior to registration

∙ Any prior radiation therapy must be completed at least 4 weeks prior to registration, and progression must be outside the radiation field

∙ At least 4 weeks must have elapsed since any major surgery prior to registration

• The trial is open only to women with recurrent or progressive clear cell carcinoma of the ovary

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 28 days prior to registration

• Patients must have had one prior platinum-based chemotherapy for management of primary disease. Patients are allowed to receive, but are not required to receive, up to two additional cytotoxic regimens for management of recurrent or persistent disease

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

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

• Hemoglobin (Hgb) \>= 8.0 g/dL within 14 days prior to registration (Note: the use of transfusion of other intervention to achieve a Hgb \>= 8.0 g/dL is acceptable)

• Creatinine =\< 1.5 x institutional upper limit of normal (ULN) or creatinine clearance (CrCl) \>= 60 mL/min using Cockcroft-Gault formula (within 14 days prior to registration)

• Bilirubin =\< 2.5 x ULN (within 14 days prior to registration)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x ULN (within 14 days prior to registration)

• Normal thyroid function testing (thyroid-stimulating hormone \[TSH\]) (within 14 days prior to registration)

• Negative pregnancy test in women of childbearing potential

• Women of childbearing potential who are sexually active should be willing and able to use medically acceptable forms of contraception for the course of the study through 120 days after the last dose of MK-3475 (pembrolizumab). Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile, who have had a hysterectomy and/or bilateral oophorectomy) do not require contraception

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry