Nivolumab +/− Ipilimumab for Endometrial Cancer

Recruiting at 88 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

90 Participants Needed

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. ^{1 2 3 4 5}

What 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. ^{6 7 8 9 10}

How 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. ^{11 12 13 14 15}

Research Team

Haider Mahdi, MD

Principal Investigator

NRG Oncology

Eligibility 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.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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, 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]

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]

References

1. United States 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. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

The Role of PD-1 Checkpoint Inhibition in Gynecologic Malignancies. [2022]

3. Switzerland 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. [2023]

4. United States 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. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Emerging options for the treatment of melanoma - focus on ipilimumab. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

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

12. England pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. [2023]

13. Japan pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nivolumab with ipilimumab for recurrent malignant pleural mesothelioma after primary surgical intervention. [2023]

14. United States 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. [2022]

15. New Zealand pubmed.ncbi.nlm.nih.gov

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