Nivolumab +/− Ipilimumab for Endometrial Cancer

Recruiting at 120 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Chronic steroids, Immunosuppressives

Disqualifiers: Endometrial serous carcinoma, Carcinosarcoma, Active autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 11

Duration: 24 weeks

81 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether combining two drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), is more effective than using nivolumab alone in shrinking tumors in individuals with recurrent endometrial cancer. Endometrial cancer with a faulty DNA repair system, known as deficient mismatch repair (dMMR), may respond well to these drugs, which enhance the immune system's ability to fight cancer. Individuals whose endometrial cancer has returned after treatment and who have this specific DNA repair issue are suitable candidates for the trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that patients generally tolerate the combination of nivolumab and ipilimumab well. In other types of cancer, studies have found that this combination offers significant benefits and is safe for most people. Most patients can undergo these treatments without serious problems.

Studies indicate that nivolumab alone is effective and safe for endometrial cancer patients with a specific genetic feature called a deficient mismatch repair system (dMMR). Some reports show that 80% of these patients experienced a major reduction or even disappearance of their cancer. Additionally, about 77% of patients had their cancer controlled, meaning it did not worsen.

In summary, both treatments—nivolumab alone and the nivolumab-ipilimumab combination—are considered safe based on past research. These treatments have shown positive results without major safety concerns for patients with similar conditions. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for endometrial cancer because they utilize the body's immune system in a novel way. Nivolumab and ipilimumab are immunotherapy drugs that work by blocking proteins that prevent the immune system from attacking cancer cells. This is different from traditional chemotherapy, which directly targets and kills cancer cells but can harm healthy cells as well. In particular, the combination of nivolumab and ipilimumab in one arm of the trial may offer a synergistic effect, potentially enhancing the immune response against the cancer compared to using nivolumab alone. This approach is promising because it could lead to more effective and possibly longer-lasting responses in patients with endometrial cancer.

What evidence suggests that this trial's treatments could be effective for recurrent endometrial cancer?

Research has shown that using nivolumab and ipilimumab together is very promising. In this trial, some participants will receive this combination, which studies have found to be more effective than other treatments. One study showed that 36% of patients experienced tumor shrinkage. Other participants in this trial will receive nivolumab alone, which also effectively controls the disease in 76.9% of patients with advanced endometrial cancer. In some cases, nivolumab alone made the cancer completely disappear in 80% of patients. Both treatments help the immune system fight cancer cells and may stop tumors from growing, especially in cancers with certain genetic issues. ^{1 2 3 4 6}

Who Is on the Research Team?

Haider Mahdi, MD

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab

Trial Overview

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.

How Is the Trial Designed?

Group I: Arm I (nivolumab and ipilimumab) Experimental Treatment 5 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 Control 4 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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Published Research Related to This Trial

In a real-world analysis of adverse events from two combination therapies for advanced renal cell carcinoma, cabozantinib (CAB) plus nivolumab (NIVO) showed higher incidence rates of seven types of toxicities compared to ipilimumab (IPI) plus NIVO.

Conversely, IPI + NIVO was associated with higher rates of three types of toxicities and had a greater incidence of serious adverse events, suggesting that both therapies have distinct safety profiles that can guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. Blas, L., Shiota, M., Tsukahara, S., et al.[2023]

Combined immune checkpoint blockade (ICB) using nivolumab and ipilimumab shows significant efficacy in treating advanced melanoma, but it also leads to a higher frequency and severity of adverse drug reactions (ADRs) compared to single-agent therapies, based on pooled safety data from 1551 patients.

Most immune-related ADRs are reversible with glucocorticoids, but due to the increased risk and rapid onset of these toxicities, clinicians must be well-trained to monitor and manage these side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Hassel, JC., Heinzerling, L., Aberle, J., et al.[2022]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

In the KEYNOTE-158 study, pembrolizumab showed a clinically meaningful objective response rate in patients with advanced MSI-H/dMMR endometrial cancer, with 84 out of 90 patients completing health-related quality of life (HRQoL) assessments.

Patients receiving pembrolizumab experienced significant improvements in their quality of life, with mean scores on the QLQ-C30 and EQ-5D-3L questionnaires increasing notably, especially among those who achieved a complete or partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. O'Malley, DM., Bariani, GM., Cassier, PA., et al.[2022]

PD-1 and PD-L1 inhibitors have shown effectiveness in treating ovarian, endometrial, and cervical cancers, particularly in cases of mismatch repair-deficient endometrial cancers, which exhibit the highest response rates.

Testing for mismatch repair deficiency or high microsatellite instability is recommended for all women with progressive gynecologic cancers to determine eligibility for treatment with pembrolizumab, a PD-1 inhibitor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of PD-1 Checkpoint Inhibition in Gynecologic Malignancies. Garcia, C., Ring, KL.[2022]

Pembrolizumab and dostarlimab, immune checkpoint inhibitors, have been approved for treating advanced recurrent endometrial cancer in patients with specific molecular subgroups, particularly those with mismatch repair deficiency (MMRd) or microsatellite instability-high (MSI-H) status, based on data from 15 studies involving 1609 patients.

The combination of pembrolizumab or dostarlimab with lenvatinib has shown efficacy in patients with mismatch repair proficient/microsatellite stable (MMRp/MSS) endometrial cancer, highlighting the importance of biomarker assessment to optimize treatment strategies for different molecular phenotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 Pathway in Advanced, Recurrent Endometrial Cancer: A Scoping Review with SWOT Analysis. Johnson, RL., Ganesan, S., Thangavelu, A., et al.[2023]

Nivolumab (Opdivo) combined with ipilimumab (Yervoy) has been approved by the FDA as a first-line treatment for adults with unresectable malignant pleural mesothelioma, based on promising results from the CHECKMATE 743 trial.

The approval was supported by an interim analysis comparing the combination therapy to standard chemotherapy, indicating that this new treatment option may offer better outcomes for patients with this challenging cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves Nivolumab Plus Ipilimumab for Previously Untreated Unresectable Malignant Pleural Mesothelioma. Wright, K.[2021]

Nivolumab (Opdivo) significantly improves overall survival and response rates in previously-treated patients with advanced nonsquamous non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CheckMate 057 trial.

Nivolumab has a manageable adverse event profile and is better tolerated than docetaxel, making it a valuable treatment option for patients who have progressed after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. Keating, GM.[2018]

In a phase II trial involving women with recurrent endometrial cancer, the combination of nivolumab and cabozantinib significantly improved progression-free survival (PFS) to a median of 5.3 months compared to 1.9 months for nivolumab alone, indicating enhanced efficacy of the combination therapy.

The study identified specific immune cell profiles that may predict treatment response, particularly in patients previously treated with immunotherapy, suggesting that immune profiling could help tailor future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer. Lheureux, S., Matei, DE., Konstantinopoulos, PA., et al.[2023]

In a review of 129 oncology patients treated with immune checkpoint inhibitors, 51.9% experienced at least one immune-related adverse event (irAE), highlighting the common occurrence of these side effects.

Nearly half of the irAEs were managed according to established guidelines, but there was significant variability in documentation and management practices, indicating a need for improved adherence as immunotherapy use increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. Teimouri, A., Minard, LV., Scott, SN., et al.[2022]

Ipilimumab is an FDA-approved monoclonal antibody that activates T-cells to treat advanced melanoma, showing a clear survival benefit in Phase III studies with ongoing investigations for other solid tumors.

While ipilimumab can cause immune-related adverse events (irAEs) in 60% of patients, most of these side effects are reversible with proper management, highlighting the importance of monitoring and early intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging options for the treatment of melanoma - focus on ipilimumab. Roddie, C., Peggs, KS.[2020]

In a phase II study involving 46 patients with advanced endometrial cancer, the combination of pembrolizumab with carboplatin and paclitaxel resulted in a high objective response rate (ORR) of 74.4%, significantly exceeding the historical control rate of 50%.

The treatment was generally well-tolerated, with common mild side effects like anemia and fatigue, while immune profiling indicated that responders had enriched CD8+ and CD4+ T cell populations, suggesting a potential mechanism of action related to immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium. Barber, EL., Chen, S., Pineda, MJ., et al.[2023]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

In a study of 41 patients with recurrent malignant pleural mesothelioma (MPM), the combination of nivolumab and ipilimumab showed a promising overall response rate (ORR) of 43.9% and a disease control rate (DCR) of 75.6%, indicating potential efficacy after primary surgical treatment.

While the treatment demonstrated clinical efficacy, it was associated with a high incidence of adverse events (AEs), with 70.7% of patients experiencing AEs, including serious grade 3-4 events in 34.1% of patients, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nivolumab with ipilimumab for recurrent malignant pleural mesothelioma after primary surgical intervention. Nakamura, A., Hashimoto, M., Kondo, N., et al.[2023]

In a phase 3 clinical trial involving 252 patients with advanced squamous non-small cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone, with median survival times of 10 months and 11 months respectively.

While the combination treatment showed a slightly better progression-free survival (IA-PFS) of 3.8 months compared to 2.9 months for nivolumab alone, the difference was not statistically significant, and both treatments had similar response rates and adverse event profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Gettinger, SN., Redman, MW., Bazhenova, L., et al.[2022]

Citations

1.

onclive.com

onclive.com/view/nivolumab-yields-high-clinical-cr-rates-allowing-for-surgery-omission-in-dmmr-msi-h-endometrial-cancer

Nivolumab Yields High Clinical CR Rates Allowing for ...

Nivolumab achieved an 80% clinical complete response rate in resectable dMMR/MSI-H endometrial cancer, with many patients avoiding surgery. No ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10773226/

A comprehensive analysis of immunotherapy in advanced ...

The 22 patients in this study with advanced/recurrent uterine cancer received 240 mg nivolumab every 2 weeks. The primary endpoint was the ORR and the ...

3.

sciencedirect.com

sciencedirect.com/science/article/pii/S0936655525001542

Real World Multi-centre UK Review of Nivolumab ...

Checkpoint inhibitor monotherapy with nivolumab brought disease control rates of 76.9% in this multi-centre UK metastatic endometrial cancer MMR-deficient ...

4.

esmo.org

esmo.org/oncology-news/nivolumab-achieves-high-orr-and-durable-pfs-in-patients-with-dmmr-msi-h-recurrent-endometrial-or-ovarian-cancer

Nivolumab Achieves High ORR and Durable PFS in ...

The use of nivolumab for dMMR/MSI-H endometrial or ovarian cancer met the pre-specified endpoint for clinical efficacy, with an objective response rate (ORR) ...

5.

clinicaloncologyonline.net

clinicaloncologyonline.net/article/S0936-6555(25)00154-2/fulltext

Real World Multi-centre UK Review of Nivolumab ...

Checkpoint inhibitor monotherapy with nivolumab brought disease control rates of 76.9% in this multi-centre UK metastatic endometrial cancer ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12099038/

A phase II study of induction PD-1 blockade (nivolumab) in ...

Fifteen patients with MMRd endometrial cancers showed 53% of ORR and a 74% disease control rate. In 49 MSI-H endometrial cancer patients enrolled on the KEYNOTE ...