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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
81
Undergo collection of tissue and/or blood samples
Undergo CT
Given IV
Undergo MRI
Given IV
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
RECRUITINGUniversity Cancer and Blood Center LLC
Athens, Georgia, United States
RECRUITINGAugusta University Medical Center
Augusta, Georgia, United States
RECRUITINGSaint Alphonsus Cancer Care Center-Boise
Boise, Idaho, United States
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.
Time frame: 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
Overall survival (OS)
Will be assessed when the PFS data are mature. The null hypothesis will be that the hazard of death in regimen 1 is equal to the hazard of death in regimen 2. That is, Ho: HR = 1.00. The alternative will be that Ha: HR \< 1.00 (regimen 1 to 2). The number of deaths is unknown.
Time frame: Up to 5 years after randomization
Objective tumor response (ORR)
Defined as the frequency of patients who have either a partial or complete response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The number of patients with responses will be tabulated by the treatment they were randomized to. Fisher's Exact Test will be used to test the hypothesis that the probabilities of response in each arm is the same. ORR will be evaluated only in patients who had measurable disease per RECIST 1.1 before starting treatment.
Time frame: Up to 5 years after randomization
Progression-free survival (PFS) at 6 months
A patient who survives at least 6 months progression-free will be considered to have had a successful outcome. Those who progress or die within 6 months are considered treatment failures, and those who survive progression-free for less than 6 months will be considered to have an unknown outcome or indeterminate. If the patient's status cannot be determined, she will be moved to the "failure" status for analysis. Like tumor response, the hypothesis of equivalent probabilities will be assessed with Fisher's Exact Test.
Time frame: 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
Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE). Will be tabulated by frequency and severity by treatment regimen. The treatment regimens will be compared by classifying the toxicities as severe or not and tested for equivalent probabilities by Fisher's Exact Test or whether the estimated probabilities of severe toxicities diverge by more than 10%.
Time frame: Up to 5 years after randomization
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Saint Luke's Cancer Institute - Boise
Boise, Idaho, United States
RECRUITINGSaint Alphonsus Cancer Care Center-Caldwell
Caldwell, Idaho, United States
SUSPENDEDKootenai Health - Coeur d'Alene
Coeur d'Alene, Idaho, United States
RECRUITINGSaint Luke's Cancer Institute - Fruitland
Fruitland, Idaho, United States
RECRUITINGSaint Luke's Cancer Institute - Meridian
Meridian, Idaho, United States
RECRUITINGSaint Alphonsus Cancer Care Center-Nampa
Nampa, Idaho, United States
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