Testing Nivolumab With or Without Ipilimumab in Deficient Mismatch Repair System (dMMR) Recurrent Endometrial Carcinoma

Inclusion Criteria:

• Patients with measurable or non-measurable (detectable) recurrent endometrial cancer

• Measurable disease will be defined and monitored by RECIST v 1.1. Measurable diseaseis defined per RECIST 1.1 criteria as at least one lesion that can be accuratelymeasured in at least one dimension (longest diameter to be recorded). Each lesionmust be >= 10 mm when measured by computed tomography (CT) or magnetic resonanceimaging (MRI). Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI

• Non-measurable (detectable) disease in a patient is defined in this protocol perRECIST 1.1 criteria as one who does not have measurable disease but has at least oneof the following conditions:

• All other lesions (or sites of disease), including small lesions (longestdiameter <10 mm or pathological lymph nodes with >= 10 to < 15 mm short axis),are considered non-measurable disease

• Ascites and/or pleural effusion attributed to tumor

• Solid and/or cystic abnormalities on radiographic imaging that do not meetRECIST 1.1 definitions for target lesions

• Patients must have endometrial cancer with deficient mismatch repair system. Allpatients must have institutional immunohistochemistry (IHC) and/or microsatelliteinstability (MSI) testing to determine mismatch repair (MMR) status. MMR deficiencyis defined as lack of expression of one or more mismatch repair proteins (MLH1,PMS2, MSH2, MSH6, EPCAM) by immunohistochemistry and/or presence of microsatelliteinstability high using the National Cancer Institute (NCI)-5plex and Promega v1.2assays, or institutional standards (e.g. next-generation sequencing [NGS] panel)

• Method(s) of detection of MMR deficiency will be recorded for each patient. Aninstitutional pathology report, and additional reports if available,documenting these results must be submitted. Patients with "equivocal" resultson MMR testing by immunohistochemistry may be eligible if they have documentedevidence of microsatellite instability by MSI testing or by next generationsequencing assays. MMR testing by IHC may be used to resolveequivocal/indeterminate MSI results

• Histologic confirmation of the original primary tumor is required (submission ofpathology report(s) is required). Patients with the following histologic types areeligible: Endometrioid adenocarcinoma, mucinous adenocarcinoma,dedifferentiated/undifferentiated carcinoma, clear cell adenocarcinoma, mixedepithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.)

• Patients may have received 1-2 prior lines of systemic therapy:

• Prior anti-PD1/PD-L1 therapy is allowed if given in combination withchemotherapy or radiation therapy in adjuvant or primary metastatic/recurrentsettings. Patients must have had a complete response and have diseaseprogression/relapse with treatment-free interval of 12 months or more from lastdose of therapy with immune check inhibition

• Patients may have received prior radiation therapy for treatment of endometrialcancer. Prior radiation therapy may have included pelvic radiation therapy, extendedfield pelvic/para aortic radiation therapy, intravaginal brachytherapy, and/orpalliative radiation therapy. All radiation therapy must be completed at least 4weeks prior to registration

• Patients may have received prior hormonal therapy for treatment of endometrialcancer. All hormonal therapy must be discontinued at least three weeks prior toregistration

• Any other prior therapy directed at the malignant tumor including chemotherapy,targeted agents, biologic agents, immunologic agents, and any investigationalagents, must be discontinued at least 4 weeks prior to registration (6 weeks fornitrosoureas or mitomycin C)

• Age >= 18

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2

• Platelets >= 100,000/mcl

• Absolute neutrophil count (ANC) >= 1,500/mcl

• Creatinine =< 1.5 x institutional/laboratory upper limit of normal (ULN)

• Total serum bilirubin level =< 1.5 x ULN (patients with known Gilbert's disease whohave bilirubin level =<3 x ULN may be enrolled)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN

• Adequate oxygen saturation via pulse oximeter (CTCAE v.5.0 hypoxia < grade 2 within 28 days prior to registration)

• Thyroid-stimulating hormone (TSH) within normal limits (TSH < ULN allowed ineuthyroid patients on thyroid replacement therapy). TSH testing is only required ifclinically indicated

• Patients must have recovered from effects of recent surgery, radiotherapy orchemotherapy. At least 4 weeks must have elapsed since major surgery

• As clinically indicated, patients with known history or current symptoms of cardiacdisease, or history of treatment with cardiotoxic agents, should have a clinicalrisk assessment of cardiac function using the New York Heart Association FunctionalClassification. To be eligible for this trial, patients should be class 2B or betterand have a corrected QT (QTc) interval < 450 msec

• The effects of nivolumab, and ipilimumab on the developing human fetus are unknown.For this reason and because nivolumab and ipilimumab are known to be teratogenic,women of child-bearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry andfor 5 months after the last dose of investigational drug. Women of childbearingpotential must have a negative serum or urine pregnancy test (minimum sensitivity 25IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hoursprior to the start of nivolumab. Women must not be breastfeeding. Women who are notof childbearing potential (i.e., who are postmenopausal or surgically sterile) donot require contraception

• WOCBP is defined as any female who has experienced menarche and who has notundergone surgical sterilization (hysterectomy or bilateral oophorectomy) orwho is not postmenopausal. Menopause is defined clinically as 12 months ofamenorrhea in a woman over 45 in the absence of other biological orphysiological causes. In addition, women under the age of 55 must have adocumented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months of registration are eligiblefor this trial

• Patients with evidence of chronic hepatitis B virus (HBV) infection must have anundetectable HBV viral load on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression andthe patient is stable off steroids for at least one month

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

• Patients with vitiligo, endocrine deficiencies including thyroiditis managed withreplacement hormones including physiologic corticosteroids are eligible

• Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome andpsoriasis controlled with topical medication and patients with positive serology,such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluatedfor the presence of target organ involvement and potential need for systemictreatment but should otherwise be eligible

Exclusion Criteria:

• Patients with a diagnosis of endometrial serous carcinoma or carcinosarcoma

• Patients who received prior anti-PD1/PD-L1 therapy and had grade 3-4 or recurringgrade 2 immune-related toxicities that led to dose delay or discontinuation ofimmunotherapy due to those toxicities

• Patients who received anti-CTLA-4 therapy or other immunotherapeutic agents

• Patients on chronic steroid therapy except those on replacement therapy at a dailydose of 10mg or less prednisone or equivalent

• Patients on immunosuppressive therapy, with the exception of:

• Intra-nasal, inhaled, topical or local steroid injections

• Premedication for hypersensitivity reaction

• Patients with active autoimmune disease or history of autoimmune disease that mightrecur, which may affect vital organ function or require immune suppressive treatmentincluding systemic corticosteroids, should be excluded. These include but are notlimited to patients with a history of immune related neurologic disease, multiplesclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome,myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD),Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxicepidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndromeshould be excluded because of the risk of recurrence or exacerbation of disease

• Patients with known immune impairment who may be unable to respond to anti-CTLA-4antibody

• Patients with uncontrolled intercurrent illness including, but not limited to:ongoing or active infection (except for uncomplicated urinary tract infection),interstitial lung disease or active, non-infectious pneumonitis, symptomaticcongestive heart failure, unstable angina pectoris, cardiac arrhythmia, orpsychiatric illness/social situations that would limit compliance with studyrequirements

• Women who are pregnant or unwilling to discontinue nursing

• Prior therapy with CTLA-4 inhibitors, or any other antibody or drug specificallytargeting T-cell co-stimulation or immune checkpoint pathways

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to nivolumab, and/or ipilimumab including severehypersensitivity reactions to any monoclonal antibody