A Randomized Phase II Trial of Nivolumab and Ipilimumab Compared to Nivolumab Monotherapy in Patients With Deficient Mismatch Repair System Recurrent Endometrial Carcinoma
Overview
- Phase
- Phase 2
- Intervention
- Biospecimen Collection
- Conditions
- Endometrial Adenocarcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 81
- Locations
- 249
- Primary Endpoint
- Progression-free survival (PFS)
- Status
- Recruiting
- Last Updated
- 11 days ago
Overview
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.
Detailed Description
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.
Investigators
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.
- •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.)
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
Arms & Interventions
Arm II (nivolumab)
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 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.
Intervention: Biospecimen Collection
Arm II (nivolumab)
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 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.
Intervention: Computed Tomography
Arm II (nivolumab)
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 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.
Intervention: Magnetic Resonance Imaging
Arm I (nivolumab and ipilimumab)
Patients 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.
Intervention: Nivolumab
Arm I (nivolumab and ipilimumab)
Patients 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.
Intervention: Biospecimen Collection
Arm II (nivolumab)
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 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.
Intervention: Nivolumab
Arm I (nivolumab and ipilimumab)
Patients 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.
Intervention: Ipilimumab
Arm I (nivolumab and ipilimumab)
Patients 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.
Intervention: Computed Tomography
Arm I (nivolumab and ipilimumab)
Patients 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.
Intervention: Magnetic Resonance Imaging
Outcomes
Primary Outcomes
Progression-free survival (PFS)
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
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.
Secondary Outcomes
- 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)