Nivolumab +/− Ipilimumab for Endometrial Cancer
Recruiting in Palo Alto (17 mi)
+41 other locations
Age: 18+
Sex: Female
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Chronic steroids, Immunosuppressives
Disqualifiers: Endometrial serous carcinoma, Carcinosarcoma, Active autoimmune, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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.
Will I have to stop taking my current medications?
The trial requires that any prior therapy directed at the tumor, including chemotherapy, targeted agents, biologic agents, immunologic agents, and investigational agents, must be stopped at least 4 weeks before joining the study. Hormonal therapy must be stopped at least 3 weeks before joining. If you are on chronic steroid therapy, you may need to adjust your dose to 10mg or less of prednisone or equivalent.
What data supports the effectiveness of the drug Nivolumab +/− Ipilimumab for Endometrial Cancer?
Research shows that drugs targeting the PD-1/PD-L1 pathway, like Nivolumab, have shown activity in endometrial cancer, especially in cases with specific genetic markers (mismatch repair deficiency). This suggests potential effectiveness for Nivolumab in treating endometrial cancer.
12345What safety information is available for the combination of Nivolumab and Ipilimumab?
The combination of Nivolumab and Ipilimumab can cause immune-related side effects in about half of the patients, such as diarrhea, liver inflammation, and lung issues. These side effects can be serious but are often reversible with proper management, including the use of steroids. Close monitoring by healthcare professionals is important to manage these side effects effectively.
678910How is the drug combination of Nivolumab and Ipilimumab unique for treating endometrial cancer?
The combination of Nivolumab and Ipilimumab is unique because it uses two immune checkpoint inhibitors that help the body's immune system recognize and attack cancer cells, which is different from traditional chemotherapy that directly targets and kills cancer cells.
1112131415Eligibility Criteria
This trial is for adults over 18 with recurrent endometrial cancer that has a deficient mismatch repair system. Eligible participants may have had prior treatments but must be in good health with stable vital signs and organ function. Those with certain autoimmune diseases, severe allergies to the drugs being tested, or who are pregnant are excluded.Inclusion Criteria
If you have rheumatoid arthritis, Sjogren's syndrome, or psoriasis, it should be controlled with topical medication. If you have certain antibodies in your blood, your doctor will check if your organs are affected before you can join the trial.
I have had 1 or 2 treatments for my condition before.
I have chronic hepatitis B but it's under control with treatment.
+19 more
Exclusion Criteria
I am allergic to certain drugs similar to nivolumab or ipilimumab.
I have not had treatments targeting immune system checkpoints.
I stopped immunotherapy due to severe side effects.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Patients receive nivolumab and ipilimumab or nivolumab alone, with cycles repeating every 3 weeks for up to 8 cycles, then every 4 weeks thereafter
24 weeks
8 visits (in-person) every 3 weeks, then monthly visits
Maintenance Therapy
Patients achieving complete response receive nivolumab for an additional 12 months
12 months
Monthly visits
Follow-up
Participants are monitored for safety and effectiveness after treatment
5 years
Every 3 months for 2 years, then every 6 months for 3 years
Participant Groups
The study is testing if combining two immune system-boosting drugs, nivolumab and ipilimumab, can better shrink tumors compared to nivolumab alone in patients whose endometrial cancer has returned and shows DNA repair deficiencies.
2Treatment groups
Experimental Treatment
Active Control
Group I: Arm I (nivolumab and ipilimumab)Experimental Treatment5 Interventions
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.
Group II: Arm II (nivolumab)Active Control4 Interventions
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.
Ipilimumab is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Yervoy for:
- Advanced melanoma
- Stage III unresectable melanoma
- Stage IV metastatic melanoma
🇪🇺 Approved in European Union as Yervoy for:
- Advanced melanoma
- Stage III unresectable melanoma
- Stage IV metastatic melanoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
IU Health North HospitalCarmel, IN
Indiana University/Melvin and Bren Simon Cancer CenterIndianapolis, IN
Carle at The RiverfrontDanville, IL
Carle Physician Group-EffinghamEffingham, IL
More Trial Locations
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
NRG OncologyCollaborator
References
Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. [2022]Pembrolizumab demonstrated a clinically meaningful objective response rate in patients with previously treated, advanced MSI-H/dMMR endometrial cancer in the multicohort phase 2 KEYNOTE-158 study (ClinicalTrials.gov, NCT02628067). We present health-related quality of life (HRQoL) results for these patients.
The Role of PD-1 Checkpoint Inhibition in Gynecologic Malignancies. [2022]Activity of PD-1 and PD-L1 inhibitors has been demonstrated in ovarian, endometrial, and cervical cancer, with a tolerable side effect profile and the highest response rate seen in mismatch repair-deficient endometrial cancers. Other biomarkers are under active investigation. Tumor testing for mismatch repair deficiency or high microsatellite instability for treatment with pembrolizumab should be considered an option for all women with progressive gynecologic malignancy.
Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 Pathway in Advanced, Recurrent Endometrial Cancer: A Scoping Review with SWOT Analysis. [2023]Results of recent clinical trials using the immune check point inhibitors (ICI) pembrolizumab or dostarlimab with/without lenvatinib has led to their approval for specific molecular subgroups of advanced recurrent endometrial cancer (EC). Herein, we summarise the clinical data leading to this first tissue-agnostic approval. As this novel therapy is not yet available in the United Kingdom standard care setting, we explore the strengths, weaknesses, opportunities, and threats (SWOT) of ICI treatment in EC. Major databases were searched focusing on clinical trials using programmed cell death protein 1 (PD-1) and its ligand (PD-L1) ICI which ultimately contributed to anti-PD-1 approval in EC. We performed a data quality assessment, reviewing survival and safety analysis. We included 15 studies involving 1609 EC patients: 458 with mismatch repair deficiency (MMRd)/microsatellite instability-high (MSI-H) status and 1084 with mismatch repair proficiency/microsatellite stable (MMRp/MSS) status. Pembrolizumab/dostarlimab have been approved for MMRd ECs, with the addition of lenvatinib for MMRp cases in the recurrent setting. Future efforts will focus on the pathological assessment of biomarkers to determine molecular phenotypes that correlate with response or resistance to ICI in order to identify patients most likely to benefit from this treatment.
Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium. [2023]The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC).
Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer. [2023]Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling.
Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. [2022]Immune checkpoint inhibitors (ICIs) affect immunologic homeostasis, leading to immune-related adverse events (irAEs). Early irAE detection and management can prevent significant morbidity and mortality. A retrospective chart review was performed to characterize irAEs associated with nivolumab, ipilimumab, and nivolumab plus ipilimumab in adult medical oncology patients in Nova Scotia Health-Central Zone from 2013-2020, and to describe adherence to toxicity management guidelines. Diarrhea/colitis, hepatitis, pneumonitis, nephrotoxicity, and cardiotoxicity were studied. Of 129 charts reviewed, 67 patients (51.9%) experienced at least one irAE for a total of 98 irAEs and a 1.5% fatality rate. Of these irAEs, 33.7% led to an emergency room visit. Patients were admitted to hospital and steroids were used in 24.5% and 35.7% of cases, respectively. In 17.3% of irAEs, ICIs were permanently discontinued. In 20.4% of irAEs, ICIs were held, and patients were monitored; while in 18.4%, ICIs were held until the irAE was Grade 0-1 (and until steroids were tapered). Almost 47% of irAEs were managed according to guidelines (14.3% were not), and 38.8% had no documented management. Patients receiving immunotherapy frequently experience irAEs with half of irAEs having documented management adhering to guidelines. As immunotherapy indications expand, it is important to ensure irAEs are documented and managed appropriately.
Emerging options for the treatment of melanoma - focus on ipilimumab. [2020]Ipilimumab is a fully human immunoglobulin subclass G1 anticytotoxic-T-lymphocyte-antigen-4 monoclonal antibody. It has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for use in advanced melanoma following clear evidence of survival benefit in randomized Phase III studies. It is also under investigation as a treatment for other solid tumors such as renal cell, lung, and prostate cancers. The purported mechanism of antitumor activity of ipilimumab is through T-cell activation, and the side effect profile reflects this. Immune-related adverse events (irAEs) affect 60% of treated patients and 15% are defined as severe. Fortunately, most irAEs are reversible with early diagnosis and correct management. FDA approval of ipilimumab is dependent on the careful execution of a risk evaluation and mitigation strategy, with the aim of increasing awareness amongst patients and clinicians of the immunological risks of treatment, and providing algorithms for management of irAEs as they develop. Ipilimumab is one of the first immunotherapies to become widely available in the setting of solid tumors, and ongoing research aims to elucidate optimal dosing, optimal scheduling, and expanded access to ipilimumab as an adjuvant or maintenance therapy where appropriate. The identification of clinical correlates or biomarkers to identify those likely to benefit from this high-cost therapy is a top priority.
Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]Recently, many agents and combinations for metastatic and advanced renal cell carcinoma have been approved. This study aims to highlight the comprehensive differences in adverse events (AEs) between cabozantinib (CAB) plus nivolumab (NIVO) and ipilimumab (IPI) plus NIVO based on a real-world big dataset.
Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. [2022]Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in diagnosis and management might result in symptom worsening and further complications, clinicians shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides a literature overview on published case reports for rare ADR with suspected potential underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically important side effects arising from combined ICB. Pooled safety data from 1551 patients with advanced melanoma, treated either with 3mg/kg ipilimumab plus 1mg/kg nivolumab (N=407), or nivolumab alone (N=787), or ipilimumab alone (N=357) demonstrate that immune-related ADR occur more frequently for the combination, with a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience in diagnosis and treatment of ADR is necessary.
Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]Recent studies suggest that combining nivolumab with ipilimumab is a more effective treatment for melanoma patients, compared to using ipilimumab or nivolumab alone. However, treatment with these immunotherapeutic agents is frequently associated with increased risk of toxicity, and (auto-) immune-related adverse events. The precise pathophysiologic mechanisms of these events are not yet clear, and evidence from clinical trials and translational studies remains limited. Our retrospective analysis of ~7700 metastatic melanoma patients treated with ipilimumab and/or nivolumab from the FDA Adverse Event Reporting System (FAERS) demonstrates that the identified immune-related reactions are specific to ipilimumab and/or nivolumab, and that when the two agents are administered together, their safety profile combines reactions from each drug alone. While more prospective studies are needed to characterize the safety of ipilimumab and nivolumab, the present work constitutes perhaps the first effort to examine the safety of these drugs and their combination based on computational evidence from real world post marketing data.
FDA Approves Nivolumab Plus Ipilimumab for Previously Untreated Unresectable Malignant Pleural Mesothelioma. [2021]The FDA approved nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma. The approval was based on efficacy results from a pre-specified interim analysis from the open-label, multi-center, randomized phase 3 CHECKMATE 743 (NCT02899299) trial, designed to evaluate nivolumab plus ipilimumab compared with chemotherapy (pemetrexed and cisplatin or carboplatin) in patients with histologically confirmed unresectable MPM and no prior systemic therapy or palliative radiotherapy within 14 days of initiation of therapy.
Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. [2023]Nivolumab (Opdivo™) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer.
Efficacy and safety of nivolumab with ipilimumab for recurrent malignant pleural mesothelioma after primary surgical intervention. [2023]Treatment of recurrent malignant pleural mesothelioma (MPM) remains challenging. Our study examined the efficacy, tolerability, and safety of nivolumab with ipilimumab treatment for recurrent MPM after primary curative-intent surgery.
Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer: The Lung-MAP S1400I Phase 3 Randomized Clinical Trial. [2022]Nivolumab plus ipilimumab is superior to platinum-based chemotherapy in treatment-naive advanced non-small cell lung cancer (NSCLC). Nivolumab is superior to docetaxel in advanced pretreated NSCLC.
Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. [2018]The programmed death (PD)-1 immune checkpoint inhibitor nivolumab (Opdivo(®)) is approved in the USA for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have progression on or after platinum-based chemotherapy and in the EU for the treatment of adults with locally advanced or metastatic NSCLC after prior chemotherapy. In previously-treated patients with advanced nonsquamous NSCLC, overall survival was significantly prolonged and the overall response rate was significantly higher in patients who received intravenous nivolumab 3 mg/kg every 2 weeks versus intravenous docetaxel in the pivotal CheckMate 057 trial. Progression-free survival did not significantly differ between patients receiving nivolumab and those receiving docetaxel. Intravenous nivolumab had a manageable adverse event profile (including immune-mediated adverse events) and was better tolerated than docetaxel in the CheckMate 057 trial. Thus, nivolumab is an important new option for use in previously-treated patients with advanced nonsquamous NSCLC.