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

Recruiting now · Phase 2

Conditions studied: Endometrial Adenocarcinoma, Endometrial Clear Cell Adenocarcinoma, Endometrial Dedifferentiated Carcinoma, Endometrial Endometrioid Adenocarcinoma, Endometrial Mixed Cell Adenocarcinoma, Endometrial Mucinous Adenocarcinoma, Endometrial Undifferentiated Carcinoma, Endometrioid Adenocarcinoma, Recurrent Endometrial Carcinoma

In brief

This phase II trial tests whether the combination of nivolumab and ipilimumab is better than nivolumab alone to shrink tumors in patients with deficient mismatch repair system (dMMR) endometrial carcinoma that has come back after a period of time during which the cancer could not be detected (recurrent). Deoxyribonucleic acid (DNA) mismatch repair (MMR) is a system for recognizing and repairing damaged DNA. In 2-3% of endometrial cancers this may be due to a hereditary condition resulted from gene mutation called Lynch Syndrome (previously called hereditary nonpolyposis colorectal cancer or HNPCC). MMR deficient cells usually have many DNA mutations. Tumors that have evidence of mismatch repair deficiency tend to be more sensitive to immunotherapy. There is some evidence that nivolumab with ipilimumab can shrink or stabilize cancers with deficient mismatch repair system. However, it is not known whether this will happen in endometrial cancer; therefore, this study is designed to answer that question. Monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with ipilimumab may be better than nivolumab alone in treating dMMR recurrent endometrial carcinoma.

Key facts

Study ID

NCT05112601

Run by

National Cancer Institute (NCI)

People needed

81

Starts

2022-06-02

Expected to finish

2032-07-30

Last updated by the study team

2026-08-07

Who can join

Age: 18 and older. Sex: female. Healthy volunteers: not accepted.

You may qualify if…

• Patients with measurable or non-measurable (detectable) recurrent endometrial cancer
• Measurable disease will be defined and monitored by RECIST v 1.1. Measurable disease is defined per RECIST 1.1 criteria 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) or magnetic resonance imaging (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 per RECIST 1.1 criteria as one who does not have measurable disease but has at least one of the following conditions:
• All other lesions (or sites of disease), including small lesions (longest diameter <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 meet RECIST 1.1 definitions for target lesions
• Patients must have endometrial cancer with deficient mismatch repair system. All patients must have institutional immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing to determine mismatch repair (MMR) status. MMR deficiency is defined as lack of expression of one or more mismatch repair proteins (MLH1, PMS2, MSH2, MSH6, EPCAM) by immunohistochemistry and/or presence of microsatellite instability high using the National Cancer Institute (NCI)-5plex and Promega v1.2 assays, or institutional standards (e.g. next-generation sequencing [NGS] panel)
• Method(s) of detection of MMR deficiency will be recorded for each patient. An institutional pathology report, and additional reports if available, documenting these results must be submitted. Patients with "equivocal" results on MMR testing by immunohistochemistry may be eligible if they have documented evidence of microsatellite instability by MSI testing or by next generation sequencing assays. MMR testing by IHC may be used to resolve equivocal/indeterminate MSI results
• Histologic confirmation of the original primary tumor is required (submission of pathology report(s) is required). Patients with the following histologic types are eligible: Endometrioid adenocarcinoma, mucinous adenocarcinoma, dedifferentiated/undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial 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 with chemotherapy or radiation therapy in adjuvant or primary metastatic/recurrent settings. Patients must have had a complete response and have disease progression/relapse with treatment-free interval of 12 months or more from last dose of therapy with immune check inhibition
• Patients may have received prior radiation therapy for treatment of endometrial cancer. Prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para aortic radiation therapy, intravaginal brachytherapy, and/or palliative radiation therapy. All radiation therapy must be completed at least 4 weeks prior to registration
• Patients may have received prior hormonal therapy for treatment of endometrial cancer. All hormonal therapy must be discontinued at least three weeks prior to registration
• Any other prior therapy directed at the malignant tumor including chemotherapy, targeted agents, biologic agents, immunologic agents, and any investigational agents, must be discontinued at least 4 weeks prior to registration (6 weeks for nitrosoureas 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 who have 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 in euthyroid patients on thyroid replacement therapy). TSH testing is only required if clinically indicated
• Patients must have recovered from effects of recent surgery, radiotherapy or chemotherapy. At least 4 weeks must have elapsed since major surgery
• As clinically indicated, patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better and have a corrected QT (QTc) interval < 450 msec

You may not qualify if…

• 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 recurring grade 2 immune-related toxicities that led to dose delay or discontinuation of immunotherapy 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 daily dose 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 might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, 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 toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should 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-4 antibody
• 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, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Women who are pregnant or unwilling to discontinue nursing
• Prior therapy with CTLA-4 inhibitors, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab, and/or ipilimumab including severe hypersensitivity reactions to any monoclonal antibody

Where it is running

• Saint Catherine Hospital — Indianapolis, Indiana, United States (enrolling)
• Northwest Cancer Center - Valparaiso — Valparaiso, Indiana, United States (enrolling)
• University of Alabama at Birmingham Cancer Center — Birmingham, Alabama, United States (enrolling)
• Indiana University/Melvin and Bren Simon Cancer Center — Indianapolis, Indiana, United States (enrolling)
• The Community Hospital — Munster, Indiana, United States (enrolling)
• Women's Diagnostic Center - Munster — Munster, Indiana, United States (enrolling)
• Saint Luke's Cancer Institute - Fruitland — Fruitland, Idaho, United States (enrolling)
• Saint Luke's Cancer Institute - Meridian — Meridian, Idaho, United States (enrolling)
• Saint Luke's Cancer Institute - Boise — Boise, Idaho, United States (enrolling)
• Saint Luke's Cancer Institute - Nampa — Nampa, Idaho, United States (enrolling)
• Kootenai Clinic Cancer Services - Post Falls — Post Falls, Idaho, United States (enrolling)
• Kootenai Clinic Cancer Services - Sandpoint — Sandpoint, Idaho, United States (enrolling)
• Kootenai Health - Coeur d'Alene — Coeur d'Alene, Idaho, United States (enrolling)
• Carle at The Riverfront — Danville, Illinois, United States (enrolling)
• Carle Physician Group-Effingham — Effingham, Illinois, United States (enrolling)
• Carle Physician Group-Mattoon/Charleston — Mattoon, Illinois, United States (enrolling)
• Carle BroMenn Medical Center — Normal, Illinois, United States (enrolling)
• Carle Cancer Institute Normal — Normal, Illinois, United States (enrolling)
• Carle Cancer Center — Urbana, Illinois, United States (enrolling)
• IU Health North Hospital — Carmel, Indiana, United States (enrolling)
• Northwest Cancer Center - Crown Point — Crown Point, Indiana, United States (enrolling)
• Northwest Oncology LLC — Dyer, Indiana, United States (enrolling)
• Northwest Cancer Center - Hobart — Hobart, Indiana, United States (enrolling)
• Saint Mary Medical Center — Hobart, Indiana, United States (enrolling)
• University of Iowa/Holden Comprehensive Cancer Center — Iowa City, Iowa, United States (enrolling)

Full record on ClinicalTrials.gov

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