Combination Chemotherapy for Neuroblastoma

Not currently recruiting at 162 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Oncology Group

Must not be taking: Systemic steroids, Immunosuppressives

Disqualifiers: Pregnancy, Myelodysplastic syndrome, 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: 18-24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of a combination of chemotherapy drugs, with or without the addition of eflornithine, for treating relapsed or refractory neuroblastoma. The aim is to determine if eflornithine enhances the treatment's effectiveness, particularly for patients whose neuroblastoma has not improved with standard treatments and who have measurable tumors or significant bone marrow involvement. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are on certain medications like systemic steroids, immunosuppressive drugs, or specific anticonvulsants. It's best to discuss your current medications with the trial team to see if they are allowed.

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

In a previous study, dinutuximab helped patients with high-risk neuroblastoma live longer, though it can cause side effects like pain and allergic reactions. Research shows dinutuximab works well, but monitoring for side effects is important.

The FDA has already approved eflornithine for high-risk neuroblastoma, confirming its safety. Studies suggest it helps prevent cancer recurrence without major safety issues, providing reassurance about its safety.

Temozolomide and irinotecan hydrochloride are common chemotherapy drugs used to treat cancer. They can cause side effects like nausea and lower blood cell counts. While usually well-tolerated, managing side effects is necessary.

Overall, previous studies or real-world use have shown the treatments in this trial to be safe. Participants should discuss possible side effects with their healthcare team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for neuroblastoma because they incorporate unique combinations of drugs that could enhance effectiveness against this challenging cancer. Unlike the standard chemotherapy options, Regimen A includes sargramostim, which might boost the immune system's ability to fight the cancer. Regimen B introduces eflornithine, a drug not commonly used for neuroblastoma, which could disrupt cancer cell growth in a novel way. These combinations aim to improve outcomes by targeting the cancer more aggressively and supporting the body's natural defenses.

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

In this trial, participants will receive one of two treatment regimens. Research has shown that dinutuximab, a medicine targeting cancer cells, helps patients with high-risk neuroblastoma live longer. Studies have found that patients receiving dinutuximab have better chances of staying cancer-free compared to those who do not. In Regimen A, participants will receive chemotherapy, dinutuximab, and sargramostim.

In Regimen B, participants will receive eflornithine in addition to chemotherapy and dinutuximab. Research suggests that eflornithine improves survival chances for these patients. The FDA has acknowledged evidence supporting eflornithine's effectiveness, especially as a follow-up treatment after immunotherapy. Together, these treatments aim to stop tumor growth, strengthen the immune system, and potentially improve survival rates for patients whose neuroblastoma has returned or is not responding to treatment. ^{1 2 4 5 6}

Who Is on the Research Team?

Margaret E Macy

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for patients with high-risk neuroblastoma that's either come back or isn't responding to treatment. They should have measurable tumor growth, more than 5% bone marrow disease involvement, and a performance status of ECOG 0-2. Patients must not have received certain prior treatments like long-acting myeloid growth factors within specific time frames and must meet various health criteria including adequate organ function.

Inclusion Criteria

Patients with elevated catecholamines (i.e. > 2 x ULN) only are NOT eligible for this study

My cancer is confirmed as neuroblastoma or ganglioneuroblastoma with high urinary catecholamines.

I took DFMO without my cancer getting worse during or within 3 months after treatment.

Exclusion Criteria

You cannot take medication orally or have difficulty absorbing medication from your digestive system.

I have a serious health issue not related to my cancer that could affect the study treatment.

I am not taking any immunosuppressive medications like cyclosporine or tacrolimus.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive chemotherapy and immunotherapy with or without eflornithine in cycles

18-24 weeks

Multiple visits per cycle, including in-person and possible virtual follow-ups

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Periodic visits

What Are the Treatments Tested in This Trial?

Interventions

• Dinutuximab
• Eflornithine Hydrochloride
• Irinotecan Hydrochloride
• Temozolomide

Trial Overview The trial tests if combining chemotherapy drugs irinotecan hydrochloride and temozolomide with the immunotherapy drug dinutuximab improves when adding eflornithine in patients with relapsed or refractory neuroblastoma. It aims to see whether this combination can better stop cancer cells from growing by killing them, stopping their division, or preventing their spread.

How Is the Trial Designed?

Group I: Regimen B (eflornithine, chemotherapy, dinutuximab) Experimental Treatment 5 Interventions

Patients receive eflornithine PO, via NG, or G tube on days -6 to 7 and days 15-21 of cycle 1 and days 1-7 and 15-21 of subsequent cycles, temozolomide PO, via NG, or G tube on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12. Treatment duration is 28 days for cycle 1 and then every 21 days in subsequent cycles for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Regimen A (chemotherapy, dinutuximab, sargramostim) Active Control 4 Interventions

Patients receive temozolomide PO, via NG, or G tube on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12 of a 21-day cycle. Treatment repeats every 21 days for up to 6 cycles 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+

Published Research Related to This Trial

In a study of 25 patients with relapsed/refractory neuroblastoma, the combination of dinutuximab beta with chemotherapy regimens N5 and N6 showed an acceptable safety profile, with no unexpected severe toxicities reported.

The treatment resulted in a 48% objective response rate and a 1-year overall survival rate of 44%, indicating promising efficacy in heavily pretreated patients, suggesting the need for further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect and Tolerance of N5 and N6 Chemotherapy Cycles in Combination with Dinutuximab Beta in Relapsed High-Risk Neuroblastoma Patients Who Failed at Least One Second-Line Therapy. Lode, HN., Ladenstein, R., Troschke-Meurer, S., et al.[2023]

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]

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 28 children with high-risk neuroblastoma, the monoclonal antibody dinutuximab produced by United Therapeutics (UTC) showed pharmacokinetic comparability to the National Cancer Institute's (NCI) version, indicating similar drug exposure levels.

Both UTC and NCI products had comparable safety profiles and adverse events, suggesting that UTC's dinutuximab can be used interchangeably with NCI's version without compromising efficacy or safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy. Marachelian, A., Desai, A., Balis, F., et al.[2019]

In a study involving 35 children with relapsed or refractory neuroblastoma, the combination of irinotecan, temozolomide, and dinutuximab showed significant anti-tumor activity, with 53% of patients achieving an objective response, including complete responses.

In contrast, the combination of irinotecan, temozolomide, and temsirolimus had a much lower response rate, with only 6% of patients showing a partial response, indicating that the dinutuximab combination is more promising for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Mody, R., Naranjo, A., Van Ryn, C., et al.[2022]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10729685/

Safety and efficacy of dinutuximab in the treatment of ... Dinutuximab, which is a monoclonal antibody targeting GD2 expressed in neuroblasts, improves survival when included in the therapy regimen.

2. unituxin.com unituxin.com/hcp/about-unituxin/clinical-trial-data/

Efficacy and Clinical Trial Data 5-year EFS was 57±4.7% for patients randomized to the Unituxin group (n=114) vs 46±5.1% for those randomized to the RA-only group (n=112; P=0.042).4. 5-year EFS ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8046731/

Long-term follow-up of a Phase III Study of ch14.18 ... Conclusions: Immunotherapy with dinutuximab improved outcome for patients with high-risk neuroblastoma. Early stoppage for efficacy resulted in a smaller sample ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e22000

Efficacy and safety of dinutuximab in the management ... Conclusions: Our findings suggest that dinutuximab is linked to a significant reduction in overall mortality and a noteworthy improvement in the ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05421897

Rapid Administration Pilot for Infusing Dinutuximab Studies have shown that the anti-GD2 human-mouse chimeric monoclonal antibody dinutuximab has contributed significantly to the improvement of treatment for ...

6. link.springer.com link.springer.com/article/10.1007/s11523-025-01155-3

Efficacy and Safety of Anti-GD2 Immunotherapy with ... Where reported, 3-year OS rates for patients receiving dinutuximab beta were 54–86% overall, with better OS rates reported for refractory than ...