Testing the Addition of the Immunotherapy Drug Pembrolizumab to the Usual Chemotherapy Treatment (Paclitaxel and Carboplatin) in Stage III-IV or Recurrent Endometrial Cancer

Inclusion Criteria:

• Measurable stage III, measurable stage IVA, stage IVB (with or without measurabledisease) or recurrent (with or without measurable disease) endometrial cancer.

• Pathology report showing results of institutional MMR IHC testing.

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

• Submission of tumor specimens for centralized MMR IHC testing is required after Step 1 and before Step 2 registration.

• In patients with measurable disease, lesions will be defined and monitored by RECISTversion (v) 1.1. Measurable disease is defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded).Each lesion must be >= 10 mm when measured by computed tomography (CT) or magneticresonance imaging (MRI). Lymph nodes must be >= 15 mm in short axis when measured byCT or MRI.

• Patients may have received

• NO prior chemotherapy for treatment of endometrial cancer OR

• Prior adjuvant chemotherapy (e.g., paclitaxel/carboplatin alone or as acomponent of concurrent chemotherapy and radiation therapy [with or withoutcisplatin]) provided adjuvant chemotherapy was completed >= 12 months prior toSTEP 2 registration.

• 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 STEP 2 registration.

• Patients may have received prior hormonal therapy for treatment of endometrialcancer. All hormonal therapy must be discontinued at least three weeks prior to STEP 2 registration.

• Interval or cytoreductive surgery, after start of treatment on this trial, and priorto documentation of disease progression, is NOT permitted.

• Age >= 18

• 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 upper limit of normal (ULN) (patients withknown Gilbert's disease who have bilirubin level =< 3 x ULN may be enrolled).

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

• Thyroid stimulating hormone (TSH) within normal limits. If TSH is not within normalrange despite no symptoms of thyroid dysfunction, normal Free T4 level is required.

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months of Step 2 registration areeligible for this trial.

• For patients of child bearing potential: negative urine or serum pregnancy test. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest is required.

• Administration of study drugs (pembrolizumab [MK-3475], paclitaxel, carboplatin) mayhave an adverse effect on pregnancy and poses a risk to the human fetus, includingembryo-lethality. Women of childbearing potential (WOCBP) must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) from atleast 14 days prior to Step 2 registration (for oral contraceptives), duringtreatment, and for 120 days after the last dose of study medication. Should a womanbecome pregnant or suspect she is pregnant while she is participating in this study,she should inform her treating physician immediately. Patients will be considered ofnonreproductive potential if they are either:

• Postmenopausal (defined as at least 12 months with no menses without analternative medical cause; in women < 45 years of age, a high folliclestimulating hormone (FSH) level in the postmenopausal range may be used toconfirm a postmenopausal state in women not using hormonal contraception orhormonal replacement therapy. In the absence of 12 months of amenorrhea, asingle FSH measurement is insufficient); OR

• Have a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy orbilateral tubal ligation/occlusion, at least 6 weeks prior to Step 2registration; OR

• Have a congenital or acquired condition that prevents childbearing.

• 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.

• 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.

Exclusion Criteria:

• Patients with prior treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4 therapeuticantibody or other similar agents.

• Patients who have a history of a severe hypersensitivity reaction to monoclonalantibody or pembrolizumab (MK-3475) and/or its excipients; and/or a severehypersensitivity reaction to paclitaxel and/or carboplatin

• Patients who are currently participating and receiving cancer-directed study therapyor have participated in a study of an investigational agent and receivedcancer-directed study therapy within 4 weeks prior to Step 2 registration.

• Patients who have a diagnosis of immunodeficiency or are receiving systemic steroidtherapy or any other form of immunosuppressive therapy within 7 days prior to Step 2registration.

• Patients who have received steroids as CT scan contrast premedication may beenrolled.

• The use of inhaled or topical corticosteroids is allowed.

• The use of mineralocorticoids (e.g., fludrocortisone) for patients withorthostatic hypotension or adrenocortical insufficiency is allowed.

• The use of physiologic doses of corticosteroids may be approved afterconsultation with the study chair.

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression, andthey have been off steroids for at least 4 weeks prior to Step 2 registration andremain clinically stable.

• 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. This includes, but is not limited to, patientswith a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemicautoimmune disease such as systemic lupus erythematosus (SLE), connective tissuediseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerativecolitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN),Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrenceor exacerbation of disease.

• Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus,thyroiditis managed with replacement hormones including physiologic corticosteroidsare 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.

• Patients who have a history of (non-infectious) pneumonitis that required steroids,or current pneumonitis.

• Uncontrolled intercurrent illness including, but not limited to: ongoing or activeinfection (except for uncomplicated urinary tract infection), interstitial lungdisease or active, non-infectious pneumonitis, symptomatic congestive heart failure,unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/socialsituations that would limit compliance with study requirements.

• Known clinically significant liver disease, including active viral, alcoholic, orother hepatitis; and cirrhosis.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, theHBV viral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For patients with HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load.

• Pregnant or lactating patients.