Immunotherapy + Cryoablation for Pediatric Solid Cancers

Overseen By Ann Liew, MS

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's National Research Institute

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Autoimmune disorders, Organ transplant, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

5 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of freezing tumors and using two immune-boosting drugs in young patients with hard-to-treat tumors. The freezing method kills some cancer cells directly, while the drugs help the immune system attack others.

Will I have to stop taking my current medications?

The trial does not allow any concurrent chemotherapy or biologic therapy for cancer treatment. However, hormonal therapy for non-cancer-related conditions is acceptable. The protocol does not specify other medications, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the treatment involving Cryoablation Therapy, Ipilimumab, Yervoy, Nivolumab, and Opdivo for pediatric solid cancers?

Research shows that combining nivolumab and ipilimumab, which are drugs that help the immune system fight cancer, improves response rates in many cancers compared to using each drug alone. Although these drugs are mainly studied in adults, some studies have explored their use in children with solid tumors, suggesting potential benefits. ^{1 2 3 4 5}

Is the combination of immunotherapy and cryoablation safe for children with solid cancers?

Ipilimumab, a part of this treatment, has been used in adults for melanoma and studied in children with advanced solid tumors, but it can cause immune-related side effects like skin rash, inflammation of the colon, liver, and pituitary gland. These side effects are usually treated with steroids and often improve. ^{1 3 6 7 8}

How is the treatment of Immunotherapy + Cryoablation for Pediatric Solid Cancers different from other treatments?

This treatment is unique because it combines cryoablation (a technique that freezes and destroys cancer cells) with immunotherapy drugs, ipilimumab and nivolumab, which help the immune system attack cancer cells. While these drugs have shown promise in adults, their use in children, especially in combination with cryoablation, is novel and not yet widely studied. ^{1 2 3 9 10}

Research Team

AeRang Kim, MD, PhD

Principal Investigator

Children's National Research Institute

Eligibility Criteria

This trial is for pediatric and young adult patients aged between 1 and less than 40 years with relapsed or refractory solid tumors, including osteosarcoma and Ewing sarcoma. Participants must have measurable disease, be candidates for cryoablation therapy, and have no other curative treatment options available. They should not be part of another clinical study or have unresolved severe side effects from previous treatments.

Inclusion Criteria

My organs and bone marrow are functioning well.

My cancer came back or didn't respond after initial treatment meant to cure it.

I have recovered from side effects of my previous cancer treatments.

Exclusion Criteria

I have or had an autoimmune or inflammatory disorder.

I do not have any unmanaged ongoing illnesses.

I don't have lasting side effects from cancer treatment, except for hair loss or skin changes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the pediatric RP2D of nivolumab and ipilimumab for one cycle and undergo cryoablation therapy of one tumor site. Treatment continues with cycles of checkpoint inhibition for up to 12 months unless there is disease progression or unacceptable toxicity.

12 months

Visits prior to every odd cycle for imaging and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cryoablation Therapy
• Ipilimumab
• Nivolumab

Trial Overview The trial investigates the effectiveness of combining cryoablation therapy (freezing cancer cells) with two immune checkpoint inhibitors: nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4). It's a phase II study where all participants receive this combination to see how well it works against various solid tumors in children and young adults.

Participant Groups

Group I: All patients Experimental Treatment 3 Interventions

Patients less than 40 years old with relapsed/refractory solid tumors and at least 2 sites of measurable disease will receive the current pediatric RP2D of nivolumab and ipilimumab for one cycle and undergo cryoablation therapy of one tumor site. Patients will continue to receive cycles of checkpoint inhibition as long as there is no disease progression of unacceptable toxicity (maximum of 13 cycles \[12 months\]). There are 4 patient cohorts: 1. Osteosarcoma 2. Ewing sarcoma 3. Rhabdomyosarcoma 4. All other solid tumors (non-statistical)

Who Is Running the Clinical Trial?

Children's National Research Institute

Lead Sponsor

Trials

227

Recruited

258,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

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]

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, 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]

Two cases of patients with multiple in-transit metastatic melanomas were successfully treated using intensity-modulated radiotherapy (IMRT) combined with immune checkpoint inhibitors ipilimumab or nivolumab.

The combination of IMRT and immune checkpoint inhibitors suggests a potential enhancement of antitumor effects, indicating a promising approach for improving treatment outcomes in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of multiple in-transit melanomas on the leg with intensity-modulated radiotherapy and immune checkpoint inhibitors: Report of two cases. Fujimura, T., Kambayashi, Y., Furudate, S., et al.[2018]

Ipilimumab, a monoclonal antibody that enhances the immune response against melanoma, can lead to immune-related adverse effects such as dermatitis, colitis, and hepatitis, which are typically managed with high-dose steroids.

In a reported case, a patient undergoing radiotherapy for metastatic melanoma developed an atypical generalized rash that worsened with concurrent ipilimumab treatment, highlighting the need for careful monitoring of skin reactions during combined therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab may increase the severity of cutenaous toxicity related to radiotherapy. Eryılmaz, MK., Mutlu, H., Salim, DK., et al.[2018]

In a study of 56 patients with metastatic melanoma who had severe immune-related adverse events (AEs) from ipilimumab, 36% experienced at least one immune-related AE after receiving anti-PD-1 therapy, indicating a notable risk of recurrence but also a manageable safety profile.

Despite the risk of AEs, anti-PD-1 therapy showed a 43% overall response rate and a median overall survival of 21 months, suggesting it may offer improved outcomes for patients previously affected by severe toxic effects from ipilimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Anti-Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma. Brunot, A., Grob, JJ., Jeudy, G., et al.[2021]

Ipilimumab, a monoclonal antibody used to enhance anti-tumor T-cell responses, can cause significant side effects, including ipilimumab-induced hypophysitis (IH), which affects hormone levels and requires hormone replacement therapy in most cases.

In a review of 10 patients with IH, early detection and management guidelines were developed, highlighting the importance of monitoring hormone levels and recognizing imaging abnormalities, which often resolve without high-dose glucocorticoid therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. Lam, T., Chan, MM., Sweeting, AN., et al.[2022]

References

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

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

2. 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]

3. England pubmed.ncbi.nlm.nih.gov

Phase II study of ipilimumab in adolescents with unresectable stage III or IV malignant melanoma. [2022]

4. 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]

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

Successful treatment of multiple in-transit melanomas on the leg with intensity-modulated radiotherapy and immune checkpoint inhibitors: Report of two cases. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Ipilimumab may increase the severity of cutenaous toxicity related to radiotherapy. [2018]

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

Association of Anti-Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Characterisation of the onset and severity of adrenal and thyroid dysfunction associated with CTLA4-related hypophysitis. [2022]

9. Greece pubmed.ncbi.nlm.nih.gov

Nivolumab for the Treatment of Advanced Pediatric Malignancies. [2020]

10. Australia pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. [2022]