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

NCT05112601 · National Cancer Institute (NCI)
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Official title
A Randomized Phase II Trial of Nivolumab and Ipilimumab Compared to Nivolumab Monotherapy in Patients With Deficient Mismatch Repair System Recurrent Endometrial Carcinoma
About this study
PRIMARY OBJECTIVE: I. To assess efficacy in terms of progression-free survival (PFS) for immunotherapy with dual immune checkpoint blockade (nivolumab/ipilimumab) versus (vs.) monotherapy (nivolumab) in patients with recurrent mismatch repair (MMR) deficient endometrial carcinoma with measurable or non-measurable (detectable) disease. SECONDARY OBJECTIVES: I. To evaluate the overall survival (OS) as estimated from time of enrollment to last follow-up or death. II. To evaluate the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in those with measurable disease at start of treatment. III. To evaluate progression-free survival at 6 months. IV. To evaluate the nature, frequency and degree of toxicity as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. V. To evaluate PFS and objective response rate in patients with prior anti-PD1/PDL1 therapy and compare efficacy of dual immune checkpoint inhibition vs. anti-PD1 monotherapy. OUTLINE: Patients are randomized into 1 of 2 arms. ARM I: Patients receive nivolumab intravenously (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 complete response (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. ARM II: Patients 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 on Arm I or II receive nivolumab for an additional 12 months in the absence of disease progression or unacceptable toxicity. Additionally, all patients may optionally undergo collection of tissue samples on study as well as blood samples throughout the trial. All patients also undergo computed tomography (CT) scan and/or magnetic resonance imaging (MRI) throughout the trial. Patients are followed every 3 months for 2 years, and then, every 6 months for 3 years.
Eligibility criteria
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 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 * 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 and for 5 months after the last dose of investigational drug. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) within 24 hours prior to the start of nivolumab. Women must not be breastfeeding. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) do not require contraception * WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial * Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression and the patient is stable off steroids for at least one month * The patient or a legally authorized representative must provide study-specific informed 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 with replacement hormones including physiologic corticosteroids are eligible * Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment 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 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
Study design
Enrollment target: 81 participants
Allocation: randomized
Masking: none
Age groups: adult, older_adult
Timeline
Starts: 2022-06-02
Estimated completion: 2026-04-30
Last updated: 2026-04-15
Interventions
Procedure: Biospecimen CollectionProcedure: Computed TomographyBiological: IpilimumabProcedure: Magnetic Resonance ImagingBiological: Nivolumab
Primary outcomes
  • Progression-free survival (PFS) (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)
Sponsor
National Cancer Institute (NCI) · nih
With: NRG Oncology
Contacts & investigators
InvestigatorHaider S Mahdi · principal_investigator, NRG Oncology
All locations (137)
University of Alabama at Birmingham Cancer CenterRecruiting
Birmingham, Alabama, United States
University Cancer and Blood Center LLCRecruiting
Athens, Georgia, United States
Augusta University Medical CenterRecruiting
Augusta, Georgia, United States
Saint Alphonsus Cancer Care Center-BoiseSuspended
Boise, Idaho, United States
Saint Luke's Cancer Institute - BoiseRecruiting
Boise, Idaho, United States
Saint Alphonsus Cancer Care Center-CaldwellSuspended
Caldwell, Idaho, United States
Kootenai Health - Coeur d'AleneRecruiting
Coeur d'Alene, Idaho, United States
Saint Luke's Cancer Institute - FruitlandRecruiting
Fruitland, Idaho, United States
Saint Luke's Cancer Institute - MeridianRecruiting
Meridian, Idaho, United States
Saint Alphonsus Cancer Care Center-NampaSuspended
Nampa, Idaho, United States
Saint Luke's Cancer Institute - NampaRecruiting
Nampa, Idaho, United States
Kootenai Clinic Cancer Services - Post FallsRecruiting
Post Falls, Idaho, United States
Kootenai Clinic Cancer Services - SandpointRecruiting
Sandpoint, Idaho, United States
University of IllinoisSuspended
Chicago, Illinois, United States
Carle at The RiverfrontRecruiting
Danville, Illinois, United States
Carle Physician Group-EffinghamRecruiting
Effingham, Illinois, United States
Carle Physician Group-Mattoon/CharlestonRecruiting
Mattoon, Illinois, United States
Carle BroMenn Medical CenterRecruiting
Normal, Illinois, United States
Carle Cancer Institute NormalRecruiting
Normal, Illinois, United States
Carle Cancer CenterRecruiting
Urbana, Illinois, United States
IU Health North HospitalRecruiting
Carmel, Indiana, United States
Northwest Cancer Center - Main CampusRecruiting
Crown Point, Indiana, United States
Northwest Oncology LLCRecruiting
Dyer, Indiana, United States
Northwest Cancer Center - HobartRecruiting
Hobart, Indiana, United States
Saint Mary Medical CenterRecruiting
Hobart, Indiana, United States
Indiana University/Melvin and Bren Simon Cancer CenterRecruiting
Indianapolis, Indiana, United States
Saint Catherine HospitalRecruiting
Indianapolis, Indiana, United States
The Community HospitalRecruiting
Munster, Indiana, United States
Women's Diagnostic Center - MunsterRecruiting
Munster, Indiana, United States
Northwest Cancer Center - ValparaisoRecruiting
Valparaiso, Indiana, United States
University of Iowa/Holden Comprehensive Cancer CenterRecruiting
Iowa City, Iowa, United States
The James Graham Brown Cancer Center at University of LouisvilleRecruiting
Louisville, Kentucky, United States
UofL Health Medical Center NortheastRecruiting
Louisville, Kentucky, United States
MaineHealth Maine Medical Center- ScarboroughRecruiting
Scarborough, Maine, United States
Bronson Battle CreekRecruiting
Battle Creek, Michigan, United States
Corewell Health Grand Rapids Hospitals - Butterworth HospitalRecruiting
Grand Rapids, Michigan, United States
Trinity Health Grand Rapids HospitalRecruiting
Grand Rapids, Michigan, United States
Bronson Methodist HospitalRecruiting
Kalamazoo, Michigan, United States
West Michigan Cancer CenterRecruiting
Kalamazoo, Michigan, United States
Beacon Kalamazoo Cancer CenterRecruiting
Kalamazoo, Michigan, United States
Trinity Health Muskegon HospitalRecruiting
Muskegon, Michigan, United States
Corewell Health Lakeland Hospitals - Niles HospitalRecruiting
Niles, Michigan, United States
Cancer and Hematology Centers of Western Michigan - Norton ShoresRecruiting
Norton Shores, Michigan, United States
Corewell Health Reed City HospitalRecruiting
Reed City, Michigan, United States
Corewell Health Lakeland Hospitals - Marie Yeager Cancer CenterRecruiting
Saint Joseph, Michigan, United States
Corewell Health Lakeland Hospitals - Saint Joseph HospitalRecruiting
Saint Joseph, Michigan, United States
Munson Medical CenterRecruiting
Traverse City, Michigan, United States
University of Michigan Health - WestRecruiting
Wyoming, Michigan, United States
Mercy HospitalRecruiting
Coon Rapids, Minnesota, United States
Essentia Health - Deer River ClinicRecruiting
Deer River, Minnesota, United States
Essentia Health Cancer CenterRecruiting
Duluth, Minnesota, United States
Miller-Dwan HospitalRecruiting
Duluth, Minnesota, United States
Fairview Southdale HospitalRecruiting
Edina, Minnesota, United States
Essentia Health Hibbing ClinicRecruiting
Hibbing, Minnesota, United States
Abbott-Northwestern HospitalRecruiting
Minneapolis, Minnesota, United States
Park Nicollet Clinic - Saint Louis ParkRecruiting
Saint Louis Park, Minnesota, United States
Regions HospitalRecruiting
Saint Paul, Minnesota, United States
United HospitalRecruiting
Saint Paul, Minnesota, United States
Essentia Health SandstoneRecruiting
Sandstone, Minnesota, United States
Saint Francis Regional Medical CenterRecruiting
Shakopee, Minnesota, United States
Essentia Health Virginia ClinicRecruiting
Virginia, Minnesota, United States
MU Health - University Hospital/Ellis Fischel Cancer CenterRecruiting
Columbia, Missouri, United States
Washington University School of MedicineRecruiting
St Louis, Missouri, United States
Community Hospital of AnacondaRecruiting
Anaconda, Montana, United States
Billings Clinic Cancer CenterRecruiting
Billings, Montana, United States
Saint Vincent Frontier Cancer CenterRecruiting
Billings, Montana, United States
Intermountain Health West End ClinicRecruiting
Billings, Montana, United States
Bozeman Health Deaconess HospitalRecruiting
Bozeman, Montana, United States
Benefis Sletten Cancer InstituteRecruiting
Great Falls, Montana, United States
Logan Health Medical CenterRecruiting
Kalispell, Montana, United States
Community Medical CenterRecruiting
Missoula, Montana, United States
Nebraska Methodist HospitalRecruiting
Omaha, Nebraska, United States
Women's Cancer Center of NevadaRecruiting
Las Vegas, Nevada, United States
University of New Mexico Cancer CenterRecruiting
Albuquerque, New Mexico, United States
Roswell Park Cancer InstituteActive Not Recruiting
Buffalo, New York, United States
University of RochesterRecruiting
Rochester, New York, United States
State University of New York Upstate Medical UniversityRecruiting
Syracuse, New York, United States
Wilmot Cancer Institute at WebsterRecruiting
Webster, New York, United States
Duke University Medical CenterRecruiting
Durham, North Carolina, United States
Duke Women's Cancer Care RaleighRecruiting
Raleigh, North Carolina, United States
Essentia Health Cancer Center-South University ClinicRecruiting
Fargo, North Dakota, United States
UHHS-Chagrin Highlands Medical CenterRecruiting
Beachwood, Ohio, United States
Miami Valley Hospital SouthRecruiting
Centerville, Ohio, United States
Geauga HospitalRecruiting
Chardon, Ohio, United States
Good Samaritan Hospital - CincinnatiRecruiting
Cincinnati, Ohio, United States
Case Western Reserve UniversityRecruiting
Cleveland, Ohio, United States
Cleveland Clinic Cancer Center/Fairview HospitalRecruiting
Cleveland, Ohio, United States
Cleveland Clinic FoundationRecruiting
Cleveland, Ohio, United States
Ohio State University Comprehensive Cancer CenterRecruiting
Columbus, Ohio, United States
Hillcrest Hospital Cancer CenterRecruiting
Mayfield Heights, Ohio, United States
UH Seidman Cancer Center at Lake Health Mentor CampusRecruiting
Mentor, Ohio, United States
University Hospitals Parma Medical CenterRecruiting
Parma, Ohio, United States
UH Seidman Cancer Center at Saint John Medical CenterRecruiting
Westlake, Ohio, United States
University of Oklahoma Health Sciences CenterRecruiting
Oklahoma City, Oklahoma, United States
Oklahoma Cancer Specialists and Research Institute-TulsaRecruiting
Tulsa, Oklahoma, United States
Saint Alphonsus Cancer Care Center-OntarioSuspended
Ontario, Oregon, United States
Providence Portland Medical CenterRecruiting
Portland, Oregon, United States
Providence Saint Vincent Medical CenterRecruiting
Portland, Oregon, United States
UPMC-Heritage Valley Health System BeaverRecruiting
Beaver, Pennsylvania, United States
UPMC Hillman Cancer Center at Butler Health SystemRecruiting
Butler, Pennsylvania, United States
UPMC Hillman Cancer Center - Passavant - CranberryRecruiting
Cranberry Township, Pennsylvania, United States
UPMC Hillman Cancer Center ErieRecruiting
Erie, Pennsylvania, United States
UPMC Cancer Center at UPMC HorizonRecruiting
Farrell, Pennsylvania, United States
UPMC Cancer Centers - Arnold Palmer PavilionRecruiting
Greensburg, Pennsylvania, United States
IRMC Cancer CenterRecruiting
Indiana, Pennsylvania, United States
UPMC-Johnstown/John P. Murtha Regional Cancer CenterRecruiting
Johnstown, Pennsylvania, United States
UPMC Cancer Center at UPMC McKeesportRecruiting
McKeesport, Pennsylvania, United States
UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer PavilionRecruiting
Mechanicsburg, Pennsylvania, United States
UPMC Hillman Cancer Center - MonroevilleRecruiting
Monroeville, Pennsylvania, United States
UPMC Hillman Cancer Center in CoraopolisRecruiting
Moon Township, Pennsylvania, United States
UPMC Hillman Cancer Center - Part of Frick HospitalRecruiting
Mount Pleasant, Pennsylvania, United States
Arnold Palmer Cancer Center Medical Oncology NorwinRecruiting
N. Huntingdon, Pennsylvania, United States
UPMC Cancer Center-Natrona HeightsRecruiting
Natrona Heights, Pennsylvania, United States
UPMC Hillman Cancer Center - New CastleRecruiting
New Castle, Pennsylvania, United States
UPMC-Magee Womens HospitalRecruiting
Pittsburgh, Pennsylvania, United States
UPMC-Saint MargaretRecruiting
Pittsburgh, Pennsylvania, United States
UPMC-Mercy HospitalRecruiting
Pittsburgh, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)Recruiting
Pittsburgh, Pennsylvania, United States
UPMC-Passavant HospitalRecruiting
Pittsburgh, Pennsylvania, United States
UPMC-Saint Clair Hospital Cancer CenterRecruiting
Pittsburgh, Pennsylvania, United States
UPMC Cancer Center at UPMC NorthwestRecruiting
Seneca, Pennsylvania, United States
UPMC Cancer Center-WashingtonRecruiting
Washington, Pennsylvania, United States
UPMC West Mifflin-Cancer Center JeffersonRecruiting
West Mifflin, Pennsylvania, United States
Women and Infants HospitalRecruiting
Providence, Rhode Island, United States
Parkland Memorial HospitalRecruiting
Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-DallasRecruiting
Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Fort WorthRecruiting
Fort Worth, Texas, United States
UT Southwestern Clinical Center at Richardson/PlanoRecruiting
Richardson, Texas, United States
University of Virginia Cancer CenterRecruiting
Charlottesville, Virginia, United States
Henrico Doctor's HospitalRecruiting
Richmond, Virginia, United States
VCU Massey Comprehensive Cancer CenterRecruiting
Richmond, Virginia, United States
Swedish Cancer Institute-EdmondsRecruiting
Edmonds, Washington, United States
Swedish Cancer Institute-IssaquahRecruiting
Issaquah, Washington, United States
Fred Hutchinson Cancer CenterActive Not Recruiting
Seattle, Washington, United States
Swedish Medical Center-First HillRecruiting
Seattle, Washington, United States
Duluth Clinic AshlandRecruiting
Ashland, Wisconsin, United States
Northwest Wisconsin Cancer CenterRecruiting
Ashland, Wisconsin, United States
Testing Nivolumab With or Without Ipilimumab in Deficient Mismatch Repair System (dMMR) Recurrent Endometrial Carcinoma · TrialPath