Triple Immunotherapy for Advanced Cancers

Overseen By Adi Diab, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Active autoimmune disease, Organ transplant, HIV/AIDS, 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: Unknown

Duration: 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—tocilizumab, ipilimumab, and nivolumab—to treat advanced cancers such as melanoma, non-small cell lung cancer, and urothelial carcinoma. The goal is to evaluate how effectively these drugs work together, particularly in aiding the immune system to combat cancer while managing side effects. This trial suits individuals with locally advanced forms of these cancers who have not received certain prior treatments. Participants must attend regular doctor visits and undergo tests, including biopsies. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant cancer research.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that participants should not have used certain investigational agents, live vaccines, or specific immune therapies recently. It's best to discuss your current medications with the study team to determine if any adjustments are needed.

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

Research has shown that combining ipilimumab and nivolumab can cause significant side effects. Up to 60% of patients may experience serious immune-related problems, including inflammation in various parts of the body.

Tocilizumab helps reduce these immune-related side effects by affecting the immune system to lessen these reactions, though its effectiveness remains under study.

While this combination aims to enhance the body's ability to fight cancer, it also carries notable risks. Patients considering this treatment should weigh these factors carefully. It is essential to consult a healthcare provider about potential side effects before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple immunotherapy treatment because it combines ipilimumab, nivolumab, and tocilizumab to tackle advanced cancers like melanoma, urothelial cancer, and non-small cell lung cancer (NSCLC). Unlike traditional options that often focus on chemotherapy or single-agent immunotherapies, this combination boosts the immune system's ability to fight cancer more effectively. Ipilimumab and nivolumab are both immune checkpoint inhibitors that help the immune system recognize and attack cancer cells, while tocilizumab is typically used to manage inflammation and may reduce treatment side effects. By integrating these mechanisms, researchers hope this approach will improve patient outcomes by enhancing effectiveness while managing toxicity better than existing treatments.

What evidence suggests that this trial's treatments could be effective for advanced cancers?

Research shows that using the drugs ipilimumab and nivolumab together can be effective for some advanced cancers. Studies have found that these drugs can shrink tumors in 45-55% of patients with advanced cancers like melanoma and non-small cell lung cancer. However, about half of the patients may experience serious immune-related side effects. In this trial, participants will receive a combination of ipilimumab, nivolumab, and tocilizumab. Tocilizumab is added to help reduce these side effects. While still under study, the combination of these three drugs appears promising for improving treatment by attacking the cancer and better managing side effects. ^{1 2 4 6}

Who Is on the Research Team?

Rodabe Amaria, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma, non-small cell lung cancer (NSCLC), or urothelial carcinoma. Participants must consent to specific testing and comply with study requirements. Exclusions include autoimmune diseases, certain heart conditions, active infections, recent use of immunosuppressants or live vaccines, and some other health issues.

Inclusion Criteria

I have NSCLC with a specific EGFR mutation and have had one prior EGFR TKI treatment.

I have advanced urothelial carcinoma and cannot receive cisplatin.

I have stage III or IV melanoma and know my BRAF status.

Exclusion Criteria

Prisoners or participants who are involuntarily incarcerated.

I haven't taken high-dose steroids or other immune-weakening drugs in the last 14 days.

I have had serious heart problems in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive ipilimumab and nivolumab with varying schedules based on cancer type, and tocilizumab for up to 12 weeks

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Tocilizumab

Trial Overview The trial tests tocilizumab combined with ipilimumab and nivolumab in treating locally advanced cancers. It aims to see if this combination can enhance the immune system's ability to fight cancer while managing side effects better than current treatments.

How Is the Trial Designed?

Group I: Cohort 3 (ipilimumab,, nivolumab, tocilizumab) Experimental Treatment 3 Interventions

Patients with NSCLC receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 2 weeks for up to 2 years. Patients also receive tocilizumab SC every 2 weeks for up to 12 weeks (6 doses). Treatment continues in the absence of disease progression or unacceptable toxicity.

Group II: Cohort 2 (ipilimumab, nivolumab, tocilizumab) Experimental Treatment 3 Interventions

Patients with urothelial cancer will receive ipilimumab IV over 90 minutes and nivolumab IV over 30 minutes on day 1. Treatment with ipilimumab and nivolumab repeats every 3 weeks for 4 doses, then treatment with nivolumab repeats every 4 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Starting on week 1, patients also receive tocilizumab SC every 2 weeks for up to 12 weeks (6 doses) in the absence of disease progression or unacceptable toxicity.

Group III: Cohort 1 (ipilimumab, nivolumab, tocilizumab) Experimental Treatment 3 Interventions

Patients with melanoma will receive ipilimumab IV over 90 minutes and nivolumab IV over 30 minutes on day 1. Treatment with ipilimumab and nivolumab repeats every 3 weeks for 4 doses, then treatment with nivolumab repeats every 4 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Cohort 1 will be divided into 2 sub-groups: sub-group 1 of 25 patients, and subgroup 2 of 10 patients that will consist of varying Tocilizumab administration doses. For sub-group 1, Tocilizumab 162mg will be administered subcutaneously every 2 weeks starting week 0, up to 12 weeks for a total of 6 doses. For sub-group 2 , Tocilizumab 162mg will be administered subcutaneously once every week starting at week 0 up to week 6 followed by Tocilizumab administered subcutaneously every 2 weeks starting at week 6 up to 12 weeks for a total of 9 doses.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

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 pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., 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]

Nivolumab (Opdivo) is an effective immune checkpoint inhibitor that enhances the immune system's ability to fight advanced cancers, showing impressive durability of response compared to traditional therapies.

It is well tolerated and approved for several types of cancer, including non-small cell lung cancer, melanoma, and renal cell carcinoma, with ongoing research to identify biomarkers for response and explore combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in advanced cancers. Rajan, A., Kim, C., Heery, CR., et al.[2023]

In a study of 1255 patients with metastatic non-small cell lung cancer (NSCLC), first-line treatment with nivolumab plus ipilimumab (NIVO+IPI) showed a high incidence of treatment-related adverse events (TRAEs), with 78% experiencing any-grade TRAEs and 34% experiencing severe (grade 3 or 4) TRAEs, but the treatment was generally well tolerated.

Patients who discontinued NIVO+IPI due to TRAEs still had a favorable long-term survival rate, with a 3-year overall survival of 50%, indicating that stopping treatment because of side effects did not negatively impact their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. Paz-Ares, LG., Ciuleanu, TE., Pluzanski, A., et al.[2023]

In a phase 3 trial with patients suffering from advanced melanoma, the combination of nivolumab and ipilimumab resulted in significantly longer overall survival rates (58% at 3 years) compared to ipilimumab alone (34%).

The safety profile of the combination therapy was consistent with previous reports, showing that 59% of patients experienced severe treatment-related adverse events, indicating that while effective, the combination therapy has a higher risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. Wolchok, JD., Chiarion-Sileni, V., Gonzalez, R., 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]

In the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

Ipilimumab showed a best overall response rate (BORR) of 5.8% and a disease control rate (DCR) of 27% in patients with advanced melanoma, indicating some level of efficacy in this challenging population.

The treatment resulted in promising long-term survival rates, with 1- and 2-year survival rates of 47.2% and 32.8%, respectively, and a median overall survival of 10.2 months, while adverse events were primarily immune-related but manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. O'Day, SJ., Maio, M., Chiarion-Sileni, V., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04940299

NCT04940299 | Tocilizumab, Ipilimumab, and Nivolumab ... This phase II trial investigates the side effects of tocilizumab, ipilimumab, and nivolumab in treating patients with melanoma, non-small cell lung cancer, ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.9553

Phase II trial of weekly or bi-weekly tocilizumab with ... Phase II trial of weekly or bi-weekly tocilizumab with ipilimumab and nivolumab in advanced melanoma: Clinical outcomes and biomarker analysis.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10766714/

Real-world outcomes of nivolumab plus ipilimumab and ... Real-world data suggests that NICT could be a favorable treatment option compared with PCT for patients with advanced NSCLC. Further follow-up ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(21)03654-1/fulltext

1040O Phase II trial of ipilimumab, nivolumab and ... Immunotherapy with ipilimumab and nivolumab has response rates of 45-55%, but 50% of patients (pts) suffer grade 3-5 immune-related adverse events.

5. opdivo.com opdivo.com/bladder-urinary-tract-cancer/clinical-trial-results/advanced-untreated-immunotherapy-chemo

Clinical trial results for advanced bladder or urinary tract ... See how OPDIVO® (nivolumab) plus chemotherapy performed in a clinical trial as a treatment for certain adults with advanced bladder or urinary tract cancer, ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa1910836

Five-Year Survival with Combined Nivolumab and ... Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group.