Nivolumab + Ipilimumab for Childhood Cancers

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

45 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is evaluating whether two immunotherapy drugs may be effective for treating certain types of cancer.

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.

What data supports the effectiveness of the drug combination Nivolumab and Ipilimumab for childhood cancers?

The combination of Nivolumab and Ipilimumab has shown improved response rates in many adult cancers compared to using either drug alone, and in adults with advanced non-small cell lung cancer, it has demonstrated long-term effectiveness. However, while early studies in children have shown some activity in specific types of tumors, the effectiveness in more common childhood cancers remains limited. ^{1 2 3 4 5}

What safety information is available for the combination of nivolumab and ipilimumab in humans?

The combination of nivolumab and ipilimumab has been associated with a higher risk of immune-related side effects, which can be severe in some cases. In studies with melanoma patients, about 50% experienced serious side effects, and many required hospital care. Most side effects are reversible with early diagnosis and proper management. ^{6 7 8 9 10}

How is the drug combination of Nivolumab and Ipilimumab unique for treating childhood cancers?

The combination of Nivolumab and Ipilimumab is unique for treating childhood cancers because it uses two immune checkpoint inhibitors to enhance the body's immune response against cancer cells, a strategy that has shown improved outcomes in adults with other types of cancer but is now being explored in children with relapsed or hard-to-treat solid tumors. ^{1 2 11 12 13}

Research Team

Suzanne Forrest, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

References

1. United States 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. [2023]

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

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

3. England 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. [2021]

4. Germany 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. [2022]

5. England 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. [2020]

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

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

7. United States 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. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

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

9. England pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. [2022]

10. United States 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. [2023]

11. England 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. [2021]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Treatment of Refractory Squamous Cell Cancer of the Head and Neck with Nivolumab and Ipilimumab. [2022]

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

Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors. [2022]