Nivolumab + Ipilimumab for Childhood Cancers

Not currently recruiting at 8 trial locations

Overseen By Suzanne Forrest, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: HIV, Hepatitis B, Hepatitis C, 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: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two immunotherapy drugs, nivolumab and ipilimumab, to determine their effectiveness in treating certain childhood cancers. It specifically targets INI1-negative tumors, which lack a gene that normally controls cell growth. The trial includes two groups: one for children with extracranial solid tumors and another for those with central nervous system (CNS) tumors. Eligible participants have INI1-negative tumors that have recurred after treatment or have not responded to standard treatments, such as malignant rhabdoid tumors or atypical teratoid rhabdoid tumors. 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 a 'washout period' (time without taking certain medications) for previous cancer treatments before starting the study. You cannot be on other investigational drugs or systemic steroids, but some local steroid treatments are allowed. It's best to discuss your specific medications with the trial team.

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

In a previous study, researchers found that combining nivolumab and ipilimumab can be manageable for patients. This combination has been used to treat both adults and children aged 12 and older. However, some serious side effects have been reported, including heart problems, such as inflammation of the heart muscle, and issues with the nervous system.

Although this treatment is not currently recommended for brain cancers in children, it has been studied in various other childhood solid tumors. While some safety information is available, more research is needed to fully understand the risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about nivolumab and ipilimumab for childhood cancers because these treatments work by harnessing the body's immune system to fight cancer. Unlike traditional chemotherapy, which directly targets cancer cells but can also harm healthy cells, nivolumab and ipilimumab are immune checkpoint inhibitors. They block proteins that prevent the immune system from attacking cancer cells, potentially leading to more targeted and effective treatment. This approach is particularly promising for patients with INI1-negative relapsed or refractory tumors, which are often resistant to conventional therapies. By activating the immune system, these drugs offer a novel pathway for tackling tough-to-treat childhood cancers.

What evidence suggests that nivolumab and ipilimumab might be an effective treatment for INI1-negative tumors?

Research shows that using nivolumab and ipilimumab together can be promising for treating certain cancers. In this trial, participants with solid tumors (Stratum 1) will receive this combination, which studies have found significantly lowers the risk of disease progression or death compared to nivolumab alone. Participants with brain and spinal cord tumors (Stratum 2) will also receive the combination, which has shown some positive effects, although the overall improvement rate remains modest. Despite challenges, these immunotherapy drugs help the immune system find and attack cancer cells. Overall, early results are encouraging, but effectiveness can depend on the type of tumor. ^{2 3 6 7 8}

Who Is on the Research Team?

Suzanne Forrest, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for children and young adults with specific INI1-negative tumors, including kidney tumors and various sarcomas. Participants must have relapsed or refractory disease without standard treatment options, measurable disease, good performance status, recovered from prior treatments' effects, adequate organ function, and no recent vaccines.

Inclusion Criteria

You must have a specific amount of disease that can be measured by certain criteria.

My organs are functioning well.

My tumor has specific genetic and protein markers.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

Pregnancy or Breast-Feeding

I am on medication for an autoimmune disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Combination Therapy

Participants receive combination therapy with nivolumab and ipilimumab on day 1 of a 21-day cycle for 4 cycles

12 weeks

4 visits (in-person)

Monotherapy

Participants receive nivolumab monotherapy on day 1 and day 15 of a 28-day cycle starting with cycle 5

Ongoing

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab

Trial Overview

The study tests the combination of two immunotherapy drugs: Nivolumab and Ipilimumab. These are given together to see if they can effectively treat certain aggressive cancers that lack a protein called INI1.

How Is the Trial Designed?

Group I: Solid Tumor (Stratum 1) Experimental Treatment 2 Interventions

* Patients will receive combination therapy with nivolumab at a predetermined dose and ipilimumab at a predetermined dose day 1 of a 21-day cycle for 4 cycles * Starting with cycle 5, patients will receive nivolumab monotherapy at a predetermined dose on day 1 and day 15 of a 28-day cycle * Patients with INI1-negative relapsed or refractory extracranial solid tumors

Group II: CNS (Stratum 2) Experimental Treatment 2 Interventions

* Patients will receive combination therapy with nivolumab at a predetermined dose and ipilimumab at a predetermined dose day 1 of a 21-day cycle for 4 cycles * Starting with cycle 5, patients will receive nivolumab monotherapy at a predetermined dose on day 1 and day 15 of a 28-day cycle * Patients with INI1-negative relapsed or refractory CNS tumors

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?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

Published Research Related to This Trial

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 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]

In a study of 373 patients from 11 phase I clinical trials, ipilimumab-related grade 3/4 adverse events were more common in patients who responded to treatment, indicating a potential link between therapeutic response and toxicity.

The likelihood of experiencing severe adverse events increased with the number of additional agents used alongside ipilimumab, while longer treatment duration was associated with more low-grade toxicities but not high-grade ones.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic and predictive factors associated with ipilimumab-related adverse events: a retrospective analysis of 11 NCI-sponsored phase I clinical trials. Chauhan, A., Kabir, T., Wu, J., et al.[2023]

The combination of nivolumab and ipilimumab is well tolerated in children and young adults with recurrent solid tumors, with a recommended phase II dose (RP2D) established at 3 mg/kg nivolumab and 1 mg/kg ipilimumab, showing some clinical activity.

At the RP2D, two patients achieved sustained partial responses, while increasing the ipilimumab dose to 3 mg/kg resulted in higher toxicity without any observed clinical benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I/II Trial of Nivolumab plus Ipilimumab in Children and Young Adults with Relapsed/Refractory Solid Tumors: A Children's Oncology Group Study ADVL1412. Davis, KL., Fox, E., Isikwei, E., et al.[2023]

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, an immune checkpoint inhibitor, was safely administered to 33 pediatric patients with recurrent or progressive solid tumors, showing a similar spectrum of immune-related adverse events as seen in adults, although some toxicities appeared after just one dose.

While no objective tumor regressions were observed, patients experiencing immune-related toxicities had improved overall survival, suggesting that these adverse effects may correlate with a beneficial immune response against the tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors. Merchant, MS., Wright, M., Baird, K., 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]

Early clinical studies show that immune checkpoint inhibitors have high activity in specific pediatric cancers like Hodgkin lymphoma and hypermutant tumors, but limited effectiveness in more common childhood malignancies.

There is a consensus that enrolling children in new monotherapy trials for checkpoint inhibitors with the same mechanism of action as those already studied is not scientifically justified, suggesting a need to focus on combination therapies instead.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ACCELERATE and European Medicines Agency Paediatric Strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients. Pearson, ADJ., Rossig, C., Lesa, G., et al.[2020]

Nivolumab combined with ipilimumab significantly improves overall survival in adult patients with intermediate/poor-risk advanced renal cell carcinoma compared to sunitinib, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

In the study involving 1096 patients, the median overall survival was not reached for the nivolumab + ipilimumab group, while it was 25.95 months for the sunitinib group, highlighting the potential of this combination therapy for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. Ali, S., Camarero, J., Hennik, P., et al.[2021]

Nivolumab, a PD-1 inhibitor, has been FDA-approved for treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) after platinum-based therapy, but treatment options remain limited for these patients.

A case study of a 46-year-old male with refractory HNSCC showed successful treatment using a combination of nivolumab and ipilimumab, suggesting potential efficacy for this combination therapy in HNSCC, similar to its success in metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Refractory Squamous Cell Cancer of the Head and Neck with Nivolumab and Ipilimumab. Schwab, KS., Kristiansen, G., Schild, HH., et al.[2022]

Nivolumab, a PD-1 blocking antibody, was found to be safe and well tolerated in a study involving 85 children and young adults with recurrent or refractory non-CNS solid tumors or lymphoma, establishing a recommended phase 2 dose of 3 mg/kg without significant dose-limiting toxicities.

The treatment showed clinical activity specifically in lymphoma cases, with responses observed in patients with Hodgkin and non-Hodgkin lymphoma, but did not demonstrate significant effectiveness against other common pediatric solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Davis, KL., Fox, E., Merchant, MS., et al.[2021]

In a phase 1/2 trial involving 21 pediatric patients with refractory solid tumors, avelumab (administered at doses of 10 or 20 mg/kg) demonstrated a safety profile similar to that seen in adults, with significant treatment-related adverse events occurring in a minority of patients.

Despite the safety findings, avelumab did not lead to objective responses in the majority of patients, although some patients with CNS tumors experienced stable disease for extended periods, indicating limited but potential clinical benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab in paediatric patients with refractory or relapsed solid tumours: dose-escalation results from an open-label, single-arm, phase 1/2 trial. Loeb, DM., Lee, JW., Morgenstern, DA., et al.[2022]

In a real-world study of 709 patients with advanced melanoma treated with ipilimumab plus nivolumab, 50.7% experienced severe treatment-related adverse events, highlighting the need for careful monitoring during therapy.

Despite the high rate of adverse events, the combination therapy showed promising long-term survival outcomes, with a median overall survival of 28.7 months and a 4-year overall survival rate of 50% for patients similar to those in the CheckMate-067 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands. van Zeijl, MCT., van Breeschoten, J., de Wreede, LC., et al.[2023]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10398811/

Nivolumab with or without ipilimumab in pediatric patients with ...

Median PFS was 1.4 (80% CI, 1.4–2.6) months with NIVO3 and 4.6 (80% CI, 1.4–5.4) months with NIVO3 + IPI1; 6-month PFS rates were 27.3% (95% CI, ...

2.

fda.gov

fda.gov/media/168489/download

NDA/BLA Multi-disciplinary Review and Evaluation

Among the 43 efficacy evaluable pediatric patients who received nivolumab in combination with ipilimumab the ORR was 4.7% (95% CI: 0.6, 15.8) ...

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03130959

A Study to Evaluate the Safety and Efficacy of Nivolumab ...

Phase Ib /II Clinical Trial of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Pediatric Subjects With High Grade Primary CNS Malignancies.

4.

ajmc.com

ajmc.com/view/research-report-asco-2019

Research Report: ASCO 2019

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated significant clinical benefit in patients with solid pediatric tumors that progressed ...

5.

news.bms.com

news.bms.com/news/details/2021/Six-and-a-Half-Year-Outcomes-for-Opdivo-nivolumab-in-Combination-with-Yervoy-ipilimumab-Continue-to-Demonstrate-Durable-Long-Term-Survival-Benefits-in-Patients-with-Advanced-Melanoma/default.aspx

Six-and-a-Half-Year Outcomes for Opdivo (nivolumab) in ...

In addition, the Opdivo plus Yervoy combination demonstrated a 6.5-year progression-free survival (PFS) rate of 34% (median of 11.5 months) ...

6.

opdivohcp.com

opdivohcp.com/safety/nsclc/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Safety ...

Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: ...

7.

news.bms.com

news.bms.com/news/details/2025/U-S--Food-and-Drug-Administration-Approves-Opdivo-nivolumab-plus-Yervoy-ipilimumab-as-a-Treatment-for-Patients-with-Previously-Untreated-Microsatellite-Instability-High-or-Mismatch-Repair-Deficient-Unresectable-or-Metastatic-Colorectal-Cancer1/default.aspx

U.S. Food and Drug Administration Approves Opdivo ...

Based on the Phase 3 CheckMate-8HW trial, Opdivo plus Yervoy demonstrated reduction in the risk of disease progression or death by 79% vs.

8.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02304458

Nivolumab With or Without Ipilimumab in Treating Younger ...

Assess antitumor effects of nivolumab in combination with ipilimumab across selected childhood solid tumors in two dose combinations (Part D and Part E). VI.