Testing Nivolumab With or Without Ipilimumab in Deficient Mismatch Repair System (dMMR) Recurrent Endometrial Carcinoma
A Randomized Phase II Trial of Nivolumab and Ipilimumab Compared to Nivolumab Monotherapy in Patients With Deficient Mismatch Repair System Recurrent Endometrial Carcinoma
3 other identifiers
interventional
81
1 country
137
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_2
Started Jun 2022
Longer than P75 for phase_2
137 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 6, 2021
CompletedFirst Posted
Study publicly available on registry
November 9, 2021
CompletedStudy Start
First participant enrolled
June 2, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
July 30, 2032
ExpectedStudy Completion
Last participant's last visit for all outcomes
July 30, 2032
June 12, 2026
June 1, 2026
10.2 years
November 6, 2021
June 11, 2026
Conditions
Outcome Measures
Primary Outcomes (1)
Progression-free survival (PFS)
The statistical test used for decision making is the stratified, standardized log-rank test (Z) based on PFS. For the safety lead-in analysis, the primary endpoint is the observation of at least one dose-limiting toxicity (DLT) in the first 3 cycles of treatment. Patients are classified as having a DLT in 3 cycles or receiving adequate treatment.
From study entry to time of progression or death, whichever occurs first, or date of last contact if neither progression nor death has occurred, assessed up to 5 years after randomization
Secondary Outcomes (4)
Overall survival (OS)
Up to 5 years after randomization
Objective tumor response (ORR)
Up to 5 years after randomization
Progression-free survival (PFS) at 6 months
From study entry to time of progression or death, whichever occurs first, or date of last contact if neither progression nor death has occurred, assessed at 6 months after randomization
Incidence of adverse events
Up to 5 years after randomization
Study Arms (2)
Arm I (nivolumab and ipilimumab)
EXPERIMENTALPatients receive nivolumab IV over 30 minutes on day 1 of each cycle and ipilimumab IV over 90 minutes on day 1 of every other cycle. Cycles repeat every three weeks. Treatment with nivolumab and ipilimumab repeats for up to 8 cycles in the absence of disease progression, unacceptable toxicity, or CR. Patients then receive nivolumab alone on day 1 of each cycle. Cycles repeat every 4 weeks in the absence of disease progression, unacceptable toxicity, or CR. MAINTENANCE THERAPY: Patients achieving CR receive nivolumab for an additional 12 months in the absence of disease progression or unacceptable toxicity. Additionally, patients may optionally undergo collection of tissue samples on study as well as blood samples throughout the trial. Patients also undergo CT scan and/or MRI throughout the trial.
Arm II (nivolumab)
ACTIVE COMPARATORPatients receive nivolumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 3 weeks for up to 8 cycles, then every 4 weeks thereafter in the absence of disease progression, unacceptable toxicity, or CR. MAINTENANCE THERAPY: Patients achieving CR receive nivolumab for an additional 12 months in the absence of disease progression or unacceptable toxicity. Additionally, patients may optionally undergo collection of tissue samples on study as well as blood samples throughout the trial. Patients also undergo CT scan and/or MRI throughout the trial.
Interventions
Undergo collection of tissue and/or blood samples
Undergo CT
Given IV
Undergo MRI
Given IV
Eligibility Criteria
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
- +20 more criteria
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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- National Cancer Institute (NCI)lead
- NRG Oncologycollaborator
Study Sites (137)
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, 35233, United States
University Cancer and Blood Center LLC
Athens, Georgia, 30607, United States
Augusta University Medical Center
Augusta, Georgia, 30912, United States
Saint Alphonsus Cancer Care Center-Boise
Boise, Idaho, 83706, United States
Saint Luke's Cancer Institute - Boise
Boise, Idaho, 83712, United States
Saint Alphonsus Cancer Care Center-Caldwell
Caldwell, Idaho, 83605, United States
Kootenai Health - Coeur d'Alene
Coeur d'Alene, Idaho, 83814, United States
Saint Luke's Cancer Institute - Fruitland
Fruitland, Idaho, 83619, United States
Saint Luke's Cancer Institute - Meridian
Meridian, Idaho, 83642, United States
Saint Alphonsus Cancer Care Center-Nampa
Nampa, Idaho, 83687, United States
Saint Luke's Cancer Institute - Nampa
Nampa, Idaho, 83687, United States
Kootenai Clinic Cancer Services - Post Falls
Post Falls, Idaho, 83854, United States
Kootenai Clinic Cancer Services - Sandpoint
Sandpoint, Idaho, 83864, United States
University of Illinois
Chicago, Illinois, 60612, United States
Carle at The Riverfront
Danville, Illinois, 61832, United States
Carle Physician Group-Effingham
Effingham, Illinois, 62401, United States
Carle Physician Group-Mattoon/Charleston
Mattoon, Illinois, 61938, United States
Carle BroMenn Medical Center
Normal, Illinois, 61761, United States
Carle Cancer Institute Normal
Normal, Illinois, 61761, United States
Carle Cancer Center
Urbana, Illinois, 61801, United States
IU Health North Hospital
Carmel, Indiana, 46032, United States
Northwest Cancer Center - Crown Point
Crown Point, Indiana, 46307, United States
Northwest Oncology LLC
Dyer, Indiana, 46311, United States
Northwest Cancer Center - Hobart
Hobart, Indiana, 46342, United States
Saint Mary Medical Center
Hobart, Indiana, 46342, United States
Indiana University/Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, 46202, United States
Saint Catherine Hospital
Indianapolis, Indiana, 46312, United States
The Community Hospital
Munster, Indiana, 46321, United States
Women's Diagnostic Center - Munster
Munster, Indiana, 46321, United States
Northwest Cancer Center - Valparaiso
Valparaiso, Indiana, 46383, United States
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242, United States
The James Graham Brown Cancer Center at University of Louisville
Louisville, Kentucky, 40202, United States
UofL Health Medical Center Northeast
Louisville, Kentucky, 40245, United States
MaineHealth Maine Medical Center- Scarborough
Scarborough, Maine, 04074, United States
Bronson Battle Creek
Battle Creek, Michigan, 49017, United States
Corewell Health Grand Rapids Hospitals - Butterworth Hospital
Grand Rapids, Michigan, 49503, United States
Trinity Health Grand Rapids Hospital
Grand Rapids, Michigan, 49503, United States
Bronson Methodist Hospital
Kalamazoo, Michigan, 49007, United States
West Michigan Cancer Center
Kalamazoo, Michigan, 49007, United States
Beacon Kalamazoo Cancer Center
Kalamazoo, Michigan, 49009, United States
Trinity Health Muskegon Hospital
Muskegon, Michigan, 49444, United States
Corewell Health Lakeland Hospitals - Niles Hospital
Niles, Michigan, 49120, United States
Cancer and Hematology Centers of Western Michigan - Norton Shores
Norton Shores, Michigan, 49444, United States
Corewell Health Reed City Hospital
Reed City, Michigan, 49677, United States
Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center
Saint Joseph, Michigan, 49085, United States
Corewell Health Lakeland Hospitals - Saint Joseph Hospital
Saint Joseph, Michigan, 49085, United States
Munson Medical Center
Traverse City, Michigan, 49684, United States
University of Michigan Health - West
Wyoming, Michigan, 49519, United States
Mercy Hospital
Coon Rapids, Minnesota, 55433, United States
Essentia Health - Deer River Clinic
Deer River, Minnesota, 56636, United States
Essentia Health Cancer Center
Duluth, Minnesota, 55805, United States
Miller-Dwan Hospital
Duluth, Minnesota, 55805, United States
Fairview Southdale Hospital
Edina, Minnesota, 55435, United States
Essentia Health Hibbing Clinic
Hibbing, Minnesota, 55746, United States
Abbott-Northwestern Hospital
Minneapolis, Minnesota, 55407, United States
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota, 55416, United States
Regions Hospital
Saint Paul, Minnesota, 55101, United States
United Hospital
Saint Paul, Minnesota, 55102, United States
Essentia Health Sandstone
Sandstone, Minnesota, 55072, United States
Saint Francis Regional Medical Center
Shakopee, Minnesota, 55379, United States
Essentia Health Virginia Clinic
Virginia, Minnesota, 55792, United States
MU Health - University Hospital/Ellis Fischel Cancer Center
Columbia, Missouri, 65212, United States
Washington University School of Medicine
St Louis, Missouri, 63110, United States
Community Hospital of Anaconda
Anaconda, Montana, 59711, United States
Billings Clinic Cancer Center
Billings, Montana, 59101, United States
Saint Vincent Frontier Cancer Center
Billings, Montana, 59102, United States
Intermountain Health West End Clinic
Billings, Montana, 59106, United States
Bozeman Health Deaconess Hospital
Bozeman, Montana, 59715, United States
Benefis Sletten Cancer Institute
Great Falls, Montana, 59405, United States
Logan Health Medical Center
Kalispell, Montana, 59901, United States
Community Medical Center
Missoula, Montana, 59804, United States
Nebraska Methodist Hospital
Omaha, Nebraska, 68114, United States
Women's Cancer Center of Nevada
Las Vegas, Nevada, 89106, United States
University of New Mexico Cancer Center
Albuquerque, New Mexico, 87106, United States
Roswell Park Cancer Institute
Buffalo, New York, 14263, United States
University of Rochester
Rochester, New York, 14642, United States
State University of New York Upstate Medical University
Syracuse, New York, 13210, United States
Wilmot Cancer Institute at Webster
Webster, New York, 14580, United States
Duke University Medical Center
Durham, North Carolina, 27710, United States
Duke Women's Cancer Care Raleigh
Raleigh, North Carolina, 27607, United States
Essentia Health Cancer Center-South University Clinic
Fargo, North Dakota, 58103, United States
UHHS-Chagrin Highlands Medical Center
Beachwood, Ohio, 44122, United States
Miami Valley Hospital South
Centerville, Ohio, 45459, United States
Geauga Hospital
Chardon, Ohio, 44024, United States
Good Samaritan Hospital - Cincinnati
Cincinnati, Ohio, 45220, United States
Case Western Reserve University
Cleveland, Ohio, 44106, United States
Cleveland Clinic Cancer Center/Fairview Hospital
Cleveland, Ohio, 44111, United States
Cleveland Clinic Foundation
Cleveland, Ohio, 44195, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210, United States
Hillcrest Hospital Cancer Center
Mayfield Heights, Ohio, 44124, United States
UH Seidman Cancer Center at Lake Health Mentor Campus
Mentor, Ohio, 44060, United States
University Hospitals Parma Medical Center
Parma, Ohio, 44129, United States
UH Seidman Cancer Center at Saint John Medical Center
Westlake, Ohio, 44145, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104, United States
Oklahoma Cancer Specialists and Research Institute-Tulsa
Tulsa, Oklahoma, 74146, United States
Saint Alphonsus Cancer Care Center-Ontario
Ontario, Oregon, 97914, United States
Providence Portland Medical Center
Portland, Oregon, 97213, United States
Providence Saint Vincent Medical Center
Portland, Oregon, 97225, United States
UPMC-Heritage Valley Health System Beaver
Beaver, Pennsylvania, 15009, United States
UPMC Hillman Cancer Center at Butler Health System
Butler, Pennsylvania, 16001, United States
UPMC Hillman Cancer Center - Passavant - Cranberry
Cranberry Township, Pennsylvania, 16066, United States
UPMC Hillman Cancer Center Erie
Erie, Pennsylvania, 16505, United States
UPMC Cancer Center at UPMC Horizon
Farrell, Pennsylvania, 16121, United States
UPMC Cancer Centers - Arnold Palmer Pavilion
Greensburg, Pennsylvania, 15601, United States
IRMC Cancer Center
Indiana, Pennsylvania, 15701, United States
UPMC-Johnstown/John P. Murtha Regional Cancer Center
Johnstown, Pennsylvania, 15901, United States
UPMC Cancer Center at UPMC McKeesport
McKeesport, Pennsylvania, 15132, United States
UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion
Mechanicsburg, Pennsylvania, 17050, United States
UPMC Hillman Cancer Center - Monroeville
Monroeville, Pennsylvania, 15146, United States
UPMC Hillman Cancer Center in Coraopolis
Moon Township, Pennsylvania, 15108, United States
UPMC Hillman Cancer Center - Part of Frick Hospital
Mount Pleasant, Pennsylvania, 15666, United States
Arnold Palmer Cancer Center Medical Oncology Norwin
N. Huntingdon, Pennsylvania, 15642, United States
UPMC Cancer Center-Natrona Heights
Natrona Heights, Pennsylvania, 15065, United States
UPMC Hillman Cancer Center - New Castle
New Castle, Pennsylvania, 16105, United States
UPMC-Magee Womens Hospital
Pittsburgh, Pennsylvania, 15213, United States
UPMC-Saint Margaret
Pittsburgh, Pennsylvania, 15215, United States
UPMC-Mercy Hospital
Pittsburgh, Pennsylvania, 15219, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232, United States
UPMC-Passavant Hospital
Pittsburgh, Pennsylvania, 15237, United States
UPMC-Saint Clair Hospital Cancer Center
Pittsburgh, Pennsylvania, 15243, United States
UPMC Cancer Center at UPMC Northwest
Seneca, Pennsylvania, 16346, United States
UPMC Cancer Center-Washington
Washington, Pennsylvania, 15301, United States
UPMC West Mifflin-Cancer Center Jefferson
West Mifflin, Pennsylvania, 15122, United States
Women and Infants Hospital
Providence, Rhode Island, 02905, United States
Parkland Memorial Hospital
Dallas, Texas, 75235, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390, United States
UT Southwestern/Simmons Cancer Center-Fort Worth
Fort Worth, Texas, 76104, United States
UT Southwestern Clinical Center at Richardson/Plano
Richardson, Texas, 75080, United States
University of Virginia Cancer Center
Charlottesville, Virginia, 22908, United States
Henrico Doctor's Hospital
Richmond, Virginia, 23229, United States
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298, United States
Swedish Cancer Institute-Edmonds
Edmonds, Washington, 98026, United States
Swedish Cancer Institute-Issaquah
Issaquah, Washington, 98029, United States
Fred Hutchinson Cancer Center
Seattle, Washington, 98109, United States
Swedish Medical Center-First Hill
Seattle, Washington, 98122, United States
Duluth Clinic Ashland
Ashland, Wisconsin, 54806, United States
Northwest Wisconsin Cancer Center
Ashland, Wisconsin, 54806, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Haider S Mahdi
NRG Oncology
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
November 6, 2021
First Posted
November 9, 2021
Study Start
June 2, 2022
Primary Completion (Estimated)
July 30, 2032
Study Completion (Estimated)
July 30, 2032
Last Updated
June 12, 2026
Record last verified: 2026-06
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.