Chemo-Immunotherapy for High-Risk Neuroblastoma

Recruiting at 77 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Oncology Group

Must not be taking: Corticosteroids, Immunosuppressives, Anticonvulsants, others

Disqualifiers: Progressive disease, MIBG therapy, 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: 4

Duration: 28 days per cycle, up to 5 cycles (6 cycles for isotretinoin)

41 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot be on certain medications like enzyme-inducing anticonvulsants or strong CYP3A4 inducers/inhibitors within 7 days before joining the study. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination for high-risk neuroblastoma?

Research shows that the combination of irinotecan, temozolomide, dinutuximab, and GM-CSF has demonstrated activity in patients with relapsed or refractory neuroblastoma, with response rates of up to 64% and some patients achieving complete remission. Additionally, dinutuximab combined with chemotherapy has been shown to improve survival rates in high-risk neuroblastoma patients. ^{1 2 3 4 5}

Is the chemo-immunotherapy treatment for high-risk neuroblastoma safe for humans?

The combination of irinotecan, temozolomide, and dinutuximab with GM-CSF has been shown to be well tolerated in patients with relapsed or refractory high-risk neuroblastoma, with side effects similar to those of the individual treatments. No treatment discontinuations due to toxicities were reported, indicating a generally safe profile in the studied patients. ^{1 2 3 4 5}

What makes this drug unique for treating high-risk neuroblastoma?

This treatment combines several drugs, including dinutuximab, which targets a specific marker (GD2) on neuroblastoma cells, with chemotherapy agents like irinotecan and temozolomide, and immune-boosting agents like sargramostim. This combination aims to improve survival rates by attacking the cancer cells directly and enhancing the body's immune response against them. ^{1 2 4 5 6}

What is the purpose of this trial?

This phase II trial studies if dinutuximab, GM-CSF, isotretinoin in combination with irinotecan, and temozolomide (chemo-immunotherapy) can be given safely to patients with high-risk neuroblastoma after Consolidation therapy (which usually consists of two autologous stem cell transplants and radiation) who have not experienced worsening or recurrence of their disease. Dinutuximab represents a kind of cancer therapy called immunotherapy. Unlike chemotherapy and radiation, dinutuximab targets the cancer cells without destroying nearby healthy cells. Sargramostim helps the body produce normal infection-fighting white blood cells. Isotretinoin helps the neuroblastoma cells become more mature. These 3 drugs (standard immunotherapy) are already given to patients with high-risk neuroblastoma after Consolidation because they have been proven to be beneficial in this setting. Chemotherapy drugs, such as irinotecan and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. They may also affect how well immunotherapy works on neuroblastoma cells. Giving chemo-immunotherapy after intensive therapy may work better in treating patients with high-risk neuroblastoma compared to standard immunotherapy.

Research Team

Ami V Desai

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for patients with high-risk neuroblastoma who've completed intensive therapy without disease worsening or recurrence. Eligible participants must have finished 4-6 cycles of chemotherapy, meet specific blood count and organ function criteria, and not have had certain prior treatments like 131I-MIBG therapy or single ASCT. Pregnant women, those on immunosuppressants, or with uncontrolled infections cannot join.

Inclusion Criteria

My cancer is advanced with specific genetic changes.

I have received treatment for my condition before.

I have completed 4-6 cycles of high-risk chemotherapy.

Exclusion Criteria

I've had more cancer treatment after my high-dose chemo and stem cell transplant.

You have had a severe allergic reaction to anti-GD2 antibodies in the past, or had to stop anti-GD2 therapy due to a reaction.

I had one high-dose chemotherapy session with stem cell transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive temozolomide, irinotecan, dinutuximab, sargramostim, and isotretinoin in cycles

28 days per cycle, up to 5 cycles (6 cycles for isotretinoin)

Daily visits during treatment days

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 months

Follow-up visits at 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 54, and 60 months

Treatment Details

Interventions

• Dinutuximab
• Irinotecan
• Isotretinoin
• Sargramostim
• Temozolomide

Trial Overview The study tests if a combination of dinutuximab (immunotherapy), GM-CSF (white blood cell booster), isotretinoin (cell maturation aid) along with irinotecan and temozolomide (chemotherapies) is safe after Consolidation therapy in high-risk neuroblastoma patients. This chemo-immunotherapy aims to improve treatment outcomes compared to standard immunotherapy alone.

Participant Groups

Group I: Treatment (temozolomide, irinotecan, dinutuximab) Experimental Treatment 13 Interventions

Patients receive temozolomide PO or via enteral tube daily and irinotecan IV over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim SC or IV over 2 hours daily on days 6-12, and isotretinoin PO BID on days 8-21. Patients undergo MUGA during screening. Patients also undergo MRI, or CT, I23I-MIBG, or FDG-PET, BM aspiration, and BM biopsy on study. Treatment repeats every 28 days for up to 5 cycles (up to 6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity.

Dinutuximab is already approved in United States, European Union for the following indications:

Approved in United States as Unituxin for:

• Neuroblastoma

Approved in European Union as Dinutuximab for:

• High-risk neuroblastoma

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The combination treatment of irinotecan, temozolomide, dintuximab, and GM-CSF (I/T/DIN/GM-CSF) showed significant antitumor activity in patients with relapsed or refractory neuroblastoma, with an overall objective response rate of 41.5% across 53 patients.

The treatment was associated with a one-year progression-free survival rate of 67.9% and an overall survival rate of 84.9%, although it also resulted in notable grade ≥ 3 toxicities, including fever/infection and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group. Mody, R., Yu, AL., Naranjo, A., et al.[2021]

In a phase 3 trial involving 406 children and young people with high-risk neuroblastoma, the addition of subcutaneous IL-2 to dinutuximab beta did not improve event-free survival rates compared to dinutuximab beta alone, with 3-year event-free survival rates of 60% and 56% respectively.

The combination treatment with subcutaneous IL-2 resulted in significantly higher toxicity, leading to a lower treatment completion rate (62% vs. 87% for dinutuximab beta alone), indicating that dinutuximab beta with isotretinoin should remain the standard care for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Ladenstein, R., Pötschger, U., Valteau-Couanet, D., et al.[2022]

In a phase 2 trial involving patients with high-risk neuroblastoma, the combination of irinotecan, temozolomide, and immunotherapy (dinutuximab and GM-CSF) showed a response rate of 53% in the initial cohort, indicating its potential efficacy for treating relapsed or refractory cases.

The study found that specific genotypes related to natural killer (NK) cell activity, particularly KIR and their ligands, were associated with clinical outcomes, highlighting the importance of genetic factors in the effectiveness of the chemoimmunotherapy regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children's Oncology Group. Erbe, AK., Diccianni, MB., Mody, R., et al.[2023]

In a study of 25 children with relapsed or refractory high-risk neuroblastoma, combining irinotecan/temozolomide chemotherapy with the anti-GD2 antibody dinutuximab beta resulted in a 64% objective response rate, with 32% achieving complete remission.

The treatment was well tolerated, even in patients who had previously received dinutuximab beta, and no patients discontinued due to toxicities, suggesting it is a promising option for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dinutuximab beta combined with chemotherapy in patients with relapsed or refractory neuroblastoma. Wieczorek, A., Zaniewska-Tekieli, A., Ehlert, K., et al.[2023]

Dinutuximab is a monoclonal antibody that targets GD2, a glycolipid overexpressed in neuroblastoma, and has been approved by the US FDA for treating high-risk neuroblastoma in children when used in combination with other therapies.

The drug works by inducing immune responses that kill cancer cells, and its development has progressed through multiple phases, with ongoing regulatory reviews in the EU and other countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dinutuximab: first global approval. Dhillon, S.[2019]

In a study involving seven patients with high-risk neuroblastoma, dinutuximab treatment led to complete remission in two patients and partial response in three, highlighting its potential effectiveness in eradicating minimal residual disease.

While dinutuximab shows promise as a first-line treatment for high-risk neuroblastoma, it carries a significant risk of severe adverse reactions, necessitating administration by experienced pediatric oncology centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implementation of immunotherapy into the treatment of neuroblastoma - single center experience with the administration of dinutuximab and management of its adverse effects. Achbergerová, M., Hederová, S., Mikesková, M., et al.[2021]

References

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

Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. [2022]

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

KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children's Oncology Group. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Dinutuximab beta combined with chemotherapy in patients with relapsed or refractory neuroblastoma. [2023]

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

Dinutuximab: first global approval. [2019]

6. Czech Republic pubmed.ncbi.nlm.nih.gov

Implementation of immunotherapy into the treatment of neuroblastoma - single center experience with the administration of dinutuximab and management of its adverse effects. [2021]